Ionic channels are present in eucaryotic plasmatic and intracellular membranes. They coordinate and control several functions. One of the most diverse ionic channels family are the potassium (K) channels. Within this family are the ATP-dependent potassium channels (KATP), which belong to the potassium rectifier channel family. These channels were initially described in heart muscle, yet they are also present in different types of tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle. In ß-pancreatic cells, KATP are primarily responsible for maintaining membrane potential and for the depolarization mediated insulin release. KATP density/activity seems to be determinant in physiological the outcome, in pancreatic cells decrease of this density/activity may be related to Insulin resistance (IR). In extra pancreatic tissues KATP relation with IR is beginning to be explored. It is possible that in skeletal muscle, the KATP are involved in insulin dependent glucose recapture and that KATP activation leads to IR. In adipose tissue, KATP containing Kir6.2, could be related to increase in free fatty acids and insulin resistance, therefore, pathological processes leading to a prolonged adipocyte KATP inhibition might promote obesity related to insulin resistance. In central nervous system KATP activation can regulate peripheric glycemia and lead to brain IR which could be a much earlier manifestation of peripheral alterations that lead to the development of pathologies such as obesity and type 2 diabetes mellitus. In this review we aim to discuss the KATP channel characteristics, its relationship to known clinical disorders and the mechanisms and potential relations with peripheral and central insulin resistance.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has been proven a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Nutrition is one of the most influential environmental factor in both taxonomical shifts in gut microbiota as well as development of Type 2 Diabetes Mellitus (T2DM). Emerging evidence has shown that the effects of nutrition on both these parameters is not mutually exclusive and that changes in gut microbiota and related metabolites such as short chain fatty acids (SCFA) and branched chain amino acids (BCAA) may influence systemic inflammation and signaling pathways that contribute to pathophysiological processes associated with T2DM. With this background, our review highlights the effects of macronutrients, carbohydrates, proteins and lipids, as well as micronutrients, vitamins, and minerals, on T2DM, specifically through their alterations in gut microbiota and the metabolites they produce. Additionally, we describe the influences of common food groups, which incorporate varying combinations of these macronutrients and micronutrients, on both microbiota and metabolic parameters in the context of diabetes mellitus. Overall, nutrition is one of the first line modifiable therapies in the management of T2DM and better understanding of the mechanisms by which gut microbiota influence its pathophysiology provides opportunities for optimizing dietary interventions.

In obesity, white adipose tissue expresses inflammatory cytokines leading to insulin resistance. Non-physiological meta-tyrosine and ortho-tyrosine (meta-Tyr and ortho-Tyr), produced from phenylalanine by free radicals, may contribute to the development of insulin resistance. The resulting insulin resistance may have a significant impact on macrophage function. In this study we aim to investigate microscopically the effect of meta- and ortho-Tyr on insulin sensitivity and M1/M2 polarization of macrophages using Akt phosphorylation and the arginase 1/iNOS ratio. Macrophage cell lines were cultured in media containing para-, meta- or ortho-Tyr, 5 mmol/L or 25 mmol/L glucose (para25-Tyr group) and treated with insulin. Para25, meta- and ortho-Tyr increased pAkt levels and decreased the arginase 1/iNOS ratio in macrophages in the absence of insulin. In the case of physiological para-tyrosine treatment, insulin increased the amount of pAkt and decreased the arginase 1/iNOS ratio. Both meta- and ortho-Tyr treatment were able to abolish or reverse the insulin’s increasing effect on pAkt and the decreasing effect on arginase 1/iNOS ratio. Our results suggest that non-physiological tyrosine isomers may affect the insulin signaling of macrophages and influence their M1/M2 polarization.

In this perspective review, we describe a brief background on the status quo of diabetes mellitus related therapies and glycemic control among patients in rural communities of sub Saharan Africa. We specifically talk about insulin therapy and the challenges of access to insulin and oral hypoglycemic therapies among the diabetic patients living in sub-Saharan Africa. We crown up our discussion with suggestions on solutions and opportunities for future research to tackle this health challenge in these impoverished communities. Our ideas have been informed by the following inquiries: What is the current situation with diabetes in Sub-Saharan Africa? How well controlled are blood sugar levels among diabetes individuals in Sub-Saharan Africa? What is insulin therapy, and for which patient populations is it recommended? What proportions of diabetic patients are on insulin therapy and oral hypoglycemic drugs in Sub-Saharan Africa? Which is the most common therapy given to diabetic patients in the rural communities of sub Saharan Africa between insulin and oral hypoglycemic drugs? Who determines the choice of therapy between insulin and oral hypoglycemic drugs? How often is hypoglycemia and hyperglycemia encountered among people on insulin therapy? Is monitoring glucagon levels important for treating diabetic individuals receiving insulin? Is it normal practice to check the glucagon levels of diabetes patients in sub-Saharan African rural communities? What insulin therapy research has been done in the rural communities of sub Saharan Africa and what research gaps exist in this field? Addressing these research gaps is critical for improving insulin therapy in rural communities of sub-Saharan Africa and reducing the burden of diabetes in these populations.

Acne vulgaris has multifactorial pathogenesis which may include insulin resistance. To investigate whether insulin resistance is a causative factor in acne vulgaris development, this study and a systematic review were conducted. 41 acne vulgaris patients and 47 healthy BMI-matched controls were involved. Glucose and insulin fasting serum levels were obtained, HOMA-IR was calculated, insulin resistance was diagnosed in cases with HOMA-IR value over 2.1. The mean±SD values for glucose fasting serum level were as follows: 94.88±7.731 [mg/dl] in study group and 79.51±7.175 [mg/dl] in controls (p<0.001). The mean±SD insulin fasting serum levels were 14.47±6.394 [µIU/mL and 11.83±4.309 [µIU/mL](p=0.059), respectively. The HOMA-IR mean±SD value calculated for the study group was 3.4±1.49 and in the control group 2.34±0.909 (p<0.001).Out of 41 patients 32 were diagnosed with insulin resistance (78%) and 26 of the 47 controls 26 were diagnosed with IR (55%) (p=0.026). Insulin resistance diagnosis was statistically more common among the acne patients compared to the controls. In the articles reviewed insulin resistance was found to be more frequent in acne vulgaris patients. Both our study and the papers analysed indicate that insulin resistance might be an independent factor in acne vulgaris development and should be considered when diagnosing and treating acne.

Diabetes mellitus (DM) comprises a range of metabolic disorders characterized by high blood glucose levels caused by defects in insulin release, insulin action, or both. DM is a widespread condition that affects a substantial portion of the global population, causing high morbidity and mortality rates. The prevalence of this major public health crisis is predicted to increase in the forthcoming years. Although, several drugs are available to manage DM, these are associated with adverse side effects, which limits their use. In underdeveloped countries, where such drugs are often costly and not widely available, many people continue to rely on alternative traditional medicine, including medicinal plants. The latter serve as a source of primary healthcare and plant-based foods in many low and middle-income countries. Interestingly, many of the phytochemicals they contain have been demonstrated to possess antidiabetic activity such as lowering blood glucose levels, stimulating insulin secretion and alleviating diabetic complications. Therefore, such plants may provide protective effects that could be used in the management of DM. The purpose of this article was to review the medicinal plant-based foods traditionally used for the management of DM, including their therapeutic effects, pharmacologically-active phytoconstituents and antidiabetic mode of action at the molecular level. It also presents future avenues for research in this field.

Type 2 diabetes mellitus (T2DM) has emerged as a major health care concern in modern society, primarily due to lifestyle changes and dietary habits. Obesity-induced insulin resistance is considered as the major pathogenic factor in T2DM. In this study, we have investigated the effect of vindoline, an indole alkaloid of Catharanthus roseus on insulin resistance, oxidative stress and inflammatory responses in high glucose induced insulin resistant L6-myoblast cells, and dexamethasone (IR inducer)/1L-β (inflammation inducer) induced dysfunctional 3T3-L1 adipocytes. Results showed that dexamethasone induced dysfunctional 3T3-L1 adipocytes treated with different concentrations of vindoline significantly enhanced basal glucose consumption, accompanied by increased expression of GLUT-4, IRS-1 and adiponectin. Vindoline treatment significantly suppressed the ROS production and upregulated pro-inflammatory mediators in IL-1β induced dysfunctional adipocytes. Similarly, vindoline treated insulin resistant L6 myoblasts exhibited significantly enhanced glycogen content accompanied with upregulation of IRS-1 and GLUT-4. Thus, in vitro studies of vindoline in insulin resistant skeleton muscle and dysfunctional adipocytes confirmed that vindoline treatment significantly mitigate insulin resistance in myotubes and improves functional status of adipocytes. These results demonstrated that vindoline has the potential to be used as a therapeutic agent to ameliorate obesity-induced T2DM associated insulin resistance profile in adipocytes and skeletal muscles.

Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify three main factors that play a crucial role in the physiopathology of NAFLD: oxidative stress, insulin resistance, and the key role of carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.

Cognitive deficit is a frequent non-motor symptom in Parkinson 's disease (PD) with an unclear pathogenesis. Recent research indicates possible involvement of insulin resistance and glutamate excitotoxicity in PD development. We investigated cognitive performance and the brain glutamate and insulin signaling in a rat model of PD induced by bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). Cognitive functions were assessed with Passive avoidance (PA) and Morris Water Maze (MWM) tests. The expression of tyrosine hydroxylase (TH) and proteins involved in insulin (IR, pI3K, ERK) and glutamate receptor (AMPAR, NMDAR) signaling was assessed in the hippocampus (HPC), hypothalamus (HPT) and striatum (S) by immunofluorescence, Western blot and ELISA. Three months after 6-OHDA treatment, cognitive deficit was accompanied by decreased AMPAR activity and TH levels (HPC, S), while levels of the proteins involved in insulin signaling remained largely unchanged. Spearman’s rank correlation revealed a strong positive correlation for pAMPAR-PA (S), pNMDAR-pI3K (HPC) and pNMDAR-IR (all regions). Additionally, a positive correlation was found for TH-ERK and TH-pI3K, and a negative one for TH-MWM/errors and pI3K-MWM/time (S). These results suggest a possible association between brain glutamate (but not insulin) signaling dysfunction and cognitive deficit in a rat PD model, detected three months after 6-OHDA treatment.

Background Polycystic ovary syndrome (PCOS) is a common hormonal disorder worldwide among women of reproductive age. It is characterized by endocrine, reproductive, and metabolic abnormalities. Insulin resistance (IR) is one of its most important clinical features, associated with metabolic disorders and increased risk of type 2 diabetes (T2D). This study aimed to explore the whole blood gene expression profiling related to IR in PCOS patients compared to controls. Methods Blood RNA was extracted from 5 PCOS and 5 non-PCOS women with matched age and BMI. Homeostasis model assessment (HOMA-IR) was used to estimate the IR. The expression of IR genes was analyzed by Profiler PCR array. Results Both groups have similar levels of HOMA-IR (p>0.05). However, differential expression levels were observed between them. Fourteen genes were upregulated and 26 genes were downregulated in PCOS samples. Among the upregulated genes (>2 fold-change, p-value<0.05) are ADIPOQ, ADIPOR1, OLR, IGF-1, and APOE. Downregulated genes (>-2 fold-change, p-value<0.05) include HK-2, IRS1, and SERPINE1. These genes are involved in insulin and adipokines signaling, commonly dysregulated in T2D. They are also involved in innate immunity and inflammatory processes and are essential for lipid and carbohydrate metabolism. Conclusion Our finding suggests that despite both groups having no difference in IR level, there are differentially expressed genes involved in the IR pathway.

Patients with lean NAFLD make up an increasing subset of liver diseases. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and nonlean patients. The study comprised 606 adults from the community, stratified into lean or nonlean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The OR of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72-3.98; P for trend<0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09-3.98; P for trend 0.026), while nonlean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

Type 2 diabetes mellitus (T2DM) is an endocrine illness associate with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer T-cell. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. This is achieved by performing measurement of CLNK and insulin parameters (glucose, insulin, and HbA1c in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p=0.025) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F=7.445, p=0.008, partial η² =0.081) and its effect is approximately the same as the effect of insulin (F=8.107, p=0.006, partial η² =0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho=0.420, p<0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the nature of disease. Elevation of CLNK level may be used as a predictor for diabetes complications, which needs more investigations.

Preeclampsia (PE) is a common pregnancy complication. It is associated with high maternal morbidity and mortality rates and intrauterine foetal growth restriction. This condition is characterised by high blood pressure and urinary protein levels. Apelin and galectin-3 (Gal- 3) are peptides involved in the regulation of body fluid homeostasis, inflammation and cardiovascular functions. This study aimed to determine the correlations amongst serum apelin and Gal-3 levels and insulin resistance (IR) in women with PE. Sixty patients with PE and 30 healthy controls participated in this study. The PE group had significantly lower apelin levels (p < 0.01) and higher Gal-3 levels (p < 0.05) than the control group. The PE group had higher serum glucose levels and β-cell functions than the control group. Moreover, patients with PE exhibited dyslipidaemia. Correlation analysis indicated that apelin and Gal-3 levels were not significantly correlated. Moreover, no correlation existed between the apelin levels and any measured parameters of the PE group. In conclusion, the elevations in serum Gal-3 levels with increments in IR-related parameters and lipid profiles reflect the possible contribution of Gal-3 to the harmful effects of IR and dyslipidemia levels on women with PE.

Background and objectives: Diabetes mellitus is a disease of insulin deficiency or its inability of usage by the target tissues leading to impairment of carbohydrate, lipid, and protein metabolisms. Resveratrol, having robust anti-inflammatory and anti-oxidant properties, has a high potential to treat or prevent the pathogenesis of diseases. This study was conducted to reveal the relationship between diabetes-induced oxidative stress and tissue inflammation with changes in main enzymatic antioxidants (cat, sod, gpx, and gst) and the components of the insulin signaling pathway (insulin Rβ, irs-1, pi3k, akt, mtor) in kidney tissues. Additionally, the effects of resveratrol on these parameters were evaluated. Materials and Methods: Male Wistar rats were randomly divided into four groups; (1) control/vehicle; (2) control/20 mg/kg resveratrol; (3) diabetic/vehicle; (4) diabetic/20 mg/kg resveratrol. Gene and protein expressions of antioxidant enzymes and insulin signaling elements were evaluated in renal tissues. Results: Downregulation of antioxidant enzymes’ gene expression in the kidney tissues of diabetic rats was demonstrated and this situation was devoted partially to the reduced gene expression of nfκb. Moreover, the components of renal insulin signaling elements were upregulated at both gene and protein expression levels in diabetic rats, and resveratrol treatment decreased this sensitization towards the control state. Conclusion: Resveratrol partially improved diabetes-induced renal oxidative stress and inflammation due to healing action on renal antioxidant enzymes and insulin signaling pathway components.

Astronauts at are risk of losing 1.0 – 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs designed to preserve the musculoskeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth facor-1 and its receptor IGFR1 play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, and sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

Type 2 diabetes mellitus (T2DM) poses a significant public health challenge. Prioritising its prevention is essential. With the growing interest in wearable health technologies continuous glucose monitoring systems (CGMs) have expanded their scope, transitioning from exclusive use in diabetes management to lifestyle enhancement for individuals without diabetes. While CGMs primarily target glycaemic stabilization, their potential role in mitigating noncommunicable conditions, including T2DM, warrants exploration. This review examines the regulation of CGMs and critically assesses the purported benefits of CGMs for individuals without diabetes, as presented in the 'health and wellness' sector: (1) early dysglycaemia detection through glucose variability observation; (2) refining glycaemic control by tailoring nutrition according to postprandial glucose response; and (3) promoting and fine-tuning physical activity based on instantaneous data feedback. We find a lack of compelling evidence for the utility of CGMs in PNLD, including accuracy, data analysis and interpretation metrics, and user acceptability markedly under-researched. A paucity of research exists on the unanticipated negative consequences of CGM usage, such as obsessive symptom tracking and potential onset of disordered eating, like orthorexia. Given the increasing adoption of CGMs by individuals without diabetes, this review underscores the need of addressing these research gaps to ensure safety and reliability of CGMs in novel contexts. We emphasise the importance of refining CGM regulation in the UK, particularly when considering its ‘off-label’ use. Marrying robust scientific evidence with effective regulation is pivotal in fortifying the coherence, equity, and effectiveness of diabetes prevention initiatives, while protecting the wellbeing of CGM users.

A crucial aspect in developing machine learning algorithms (or any type of predictive models) is the comparison of different algorithmic candidates based on evaluation criteria that measure their accuracy and practical value in terms of successfully capturing the complexity of the underlying problem and generalizing in a wide range of real-world scenarios. In the domain of diabetes mellitus machine learning techniques are widely employed in the prediction of future values of glucose concentration in the blood in order to assist the patient in avoiding deviations from the normo-glycemic value range and the consequences of hyper- and hypoglycemia. In the relative literature there is an apparent lack of a uniformly adopted evaluation metric which could combine the clarity and direct comparative nature of statistical mathematical formulas dealing with prediction error residuals (e.g., the RMSE) with the clinical insights and the visual-qualitative approach of clinical evaluation tools (e.g., Clarke's EGA). Mean Adjusted Exponent (MADEX) error metric, proposed in this paper, attempts to address this need by providing a validation tool based on an easy to implement mathematical formula, that incorporates adjustable parameters of clinical significance.

It is unknown whether postprandial plasma glucose measured from blood taken between 4 and 7.9 h (PPG4-7.9h) is associated with mortality from hypertension, diabetes, or cardiovascular disease (CVD). This study aimed to investigate these associations in 4,896 US adults who attended the third National Health and Nutrition Examination Survey. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of PPG4-7.9h for mortality. This cohort was followed up for 106,300 person-years (mean follow-up, 21.7 years). A 1-natural-log-unit increase in PPG4-7.9h was associated with a higher risk of mortality from hypertension (HR, 3.50; 95% CI, 2.34-5.24), diabetes (HR, 11.7; 95% CI, 6.85-20.0), and CVD (HR, 2.76; 95% CI, 2.08-3.68) after adjustment for all the tested confounders except hemoglobin A1c (HbA1c). After further adjustment for HbA1c, PPG4-7.9h remained positively associated with mortality from hypertension (HR, 2.15; 95% CI, 1.13-4.08) and CVD (HR, 1.62; 95% CI, 1.05-2.51), but was no longer associated with diabetes mortality. Subgroup analyses showed that similar results were obtained in the sub-cohort of participants without a prior diagnosis of myocardial infarction or stroke. In conclusion, PPG4-7.9h predicts mortality from hypertension and CVD independent of HbA1c.

Millions of people worldwide are affected by diabetes, a chronic disease that continuously grows due to abnormal glucose concentration levels present in the blood. Monitoring blood glucose concentrations is therefore an essential diabetes indicator to aid in the management of the disease. Enzymatic electrochemical glucose sensors presently account for the bulk of glucose sensors in the market. However, their disadvantages are that they are expensive and are dependent on environmental conditions, hence affecting their performance and sensitivity. To meet the increasing demand, non-enzymatic glucose sensors based on chemically modified electrodes for the direct electrocatalytic oxidation of glucose are a good alternative to the costly enzymatic-based sensors currently on the market, and the research thereof continues to grow. Nanotechnology-based biosensors have been explored for their electronic and mechanical properties, resulting in enhanced biological signalling through the direct oxidation of glucose. Copper oxide and copper sulfide exhibit attractive attributes for sensor application, due to their non-toxic nature, abundance, and their unique properties. Thus, in this review, copper oxide and copper sulfide-based materials, are evaluated based on their chemical structure, morphology, and fast electron mobility as suitable electrode materials for non-enzymatic glucose sensors. The review highlights the present challenges of non-enzymatic glucose sensors that have limited their deployment into the market.

Equine metabolic syndrome (EMS) is a major health threat in veterinary endocrinology medicine worldwide, and there is growing interest in utilizing molecular agents for modulation of hepatocyte function for potential clinical applications with recent studies showing promising results in the inhibition of PTP1B on adipose-derived stromal cells. In this study, we investigated the effects of MSI-1436 on equine hepatic progenitor cells (HPCs) in terms of their proliferative activity, glucose uptake, and mitochondrial morphogenesis under lipotoxic condition. Our study found that MSI-1436 promotes the entry of HPCs in the cell cycle and rescues them from palmitate-induced apoptosis by regulating mitochondrial dynamics and biogenesis. MSI-1436 also increases glucose uptake and protects HPCs from palmitate-induced stress by reorganizing the morphological architecture of the cells. Additionally, our findings suggest that MSI-1436 enhances the 2-NBDG internalization by increasing the expression of SIRT1, which is associated with liver insulin sensitivity, and promotes mitochondrial dynamics by modulating their number and morphotype through PINK1, MFN1, and MFN2 increased expression. Our study provides evidence that MSI-1436 has a positive impact on equine hepatic progenitor cells, indicating its potential therapeutic value in the treatment of EMS and insulin dysregulation.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally used for diabetes mellitus, are gaining more popularity for other indications owing to their positive cardiovascular and renal effects. Initially, SGLT2 inhibitors were shown to reduce heart failure (HF) hospitalization and improve cardiovascular outcomes in patients with type 2 diabetes. Later, SGLT2 inhibitors were evaluated in patients with HF with reduced ejection fraction (HFREF) and had beneficial effects independent of the presence of diabetes. Recently, reduction in cardiovascular outcomes were also observed in patients with HF with preserved ejection fraction (HFPEF). SGLT2 inhibitors also reduced renal outcomes in patients with chronic kidney disease. Overall, these drugs have an excellent safety profile with a negligible risk of genitourinary tract infections and ketoacidosis. In this review, we discuss the current data regarding SGLT2 inhibitors in special populations including acute myocardial infarction, acute HF, right ventricular (RV) failure, patients with left ventricular assist device (LVAD), and patients with type1 diabetes. We also discuss the potential mechanisms behind the cardiovascular benefits of these drugs.

The number of obese people worldwide is rising dramatically, with 51% of the global population expected to be obese or overweight by 2035. And it is usually involved in a variety of chronic diseases, including diabetes, hypertension, cardiovascular and cerebrovascular diseases. In the process of obesity, adipose tissue expands indefinitely, which induces metabolic dysfunction. Here, we confirm the role of succinate in the intervention of obesity. Through adding succinate to drinking water, high-fat diet induced obese mice were associated with the lower fat mass, and improved glucose tolerance and energy expenditure. These metabolic changes are accompanied by increased expression of lipolysis genes and decreased lipogenesis genes, especially in subcutaneous adipose tissue. In summary, supplement of succinate improves lipid deposition and metabolic health in obese mice.

Catalyst with high catalytic activity and good stability are desirable in the electrocatalytic oxidation of glucose. Herein, Pt concave nanocubes with high-index facets (HIFs) supported by carbon black (Pt CNC/CB) are prepared through a hydrothermal method. The experimental results demonstrate that the peak current densities in different potential regions on the Pt CNC/CB anode are 0.22, 0.20, and 0.60 mA cm−2, respectively. The glucose oxidation reaction shows superior performances in basic and neutral conditions than in acid conditions. Better stability is achieved by Pt CNC/CB than Pt concave nanocubes (Pt CNCs). Abundant surface defects with low-coordinated atom numbers, such as the steps, kinks, and edges, are served as active sites in the electrocatalytic oxidation of glucose. With the addition of carbon black, the catalytic activity can be improved by facilitating the full exposure of the active surface defects on the HIFs of Pt CNCs. Moreover, to address the aggregation of Pt CNCs, caused by the high surface energy of HIFs, the introduction of carbon material is an effective way to preserve the HIFs, and thus enhance the stability of the catalyst. Hence, the prepared Pt CNC/CB electrocatalyst has great potential to be applied in the electrooxidation of glucose.

In order to improve the performance of soft plantation wood, an environmentally friendly inorganic-organic hybrid wood modifier was developed. First, using urea and melamine as crosslinking agents, the waterborne glucose silicone resin (MUG) was prepared with glucose under the catalysis of inorganic acid and metal ions. Then MUG resin was diluted to 10% and 20% mass fraction, and compounded with sodium silicate (S) of 20% and 10% mass fraction, so the inorganic-organic hybrid G10S20 and G20S10 wood modifier were obtained respectively. Then plantation poplar wood (Populus tomentosa) were impregnated and modified with them. Their physical and mechanical properties were tested and compared with those of the wood treated with S of 20% mass fraction (S20). Infrared analysis showed that amino resin characteristic structure (CO-NH-) existed in MUG resin. The resin has good permeability. Compared with S20 modified wood, the degree of shrinkage of G10S20 or G20S10 modified wood is reduced, their moisture absorption is reduced, and their dimensional stability is improved. Waterborne glucose silicone modifier can effectively improve the wood density, modulus of elasticity, modulus of rapture and compression strength. SEM analysis showed that the cell wall of G20S10 modified wood was significantly thicker than the untreated wood, and there were columnar and granular solid substances attached in some cell cavities, ducts and corners, etc. EDX showed that the number of Si elements on the cell wall was significantly increased compared with the control, indicating that the modifier effectively entered the wood cell wall. The waterborne glucose silicone resin can greatly improve the physical and mechanical properties of wood through organic-inorganic hybridization. It is a green, non-formaldehyde, eco-friendly, low cost, compound wood modifier with broad application prospects.

Calorie restriction (CR) has been shown to prolong the lifespan of humans, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2-deoxy-D-glucose, D-glucosamine, and D-allulose, which show anti-aging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs.

This study aimed to investigate the effect of potassium poly-γ-glutamate (PGA-K) on mice fed a high-fat diet consisting of 60% of total calories for a duration of 12 weeks. PGA-K administration reduced the increase in body weight, epididymal fat, and liver weight caused by a high-fat diet compared to the obese group. The triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, which are blood lipid indicators, were significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. The administration of PGA-K resulted in a significant inhibition of pro-inflammatory cytokines, including tumor necrosis factor α and interleukin 6. Moreover, the levels of leptin and insulin, which are insulin resistance indicators, significantly increased in the obese group but were significantly decreased in the PGA-K-treated group. These results suggest that PGA-K exhibits a protective effect against obesity induced by a high-fat diet, underscoring its potential as a candidate for obesity treatment.

Insulin icodec of Novo Nordisk is a novel long-acting insulin analogue that exhibits an extended duration of action, providing a promising treatment option for individuals with diabetes. It has been reported that the incorporation of fatty acid moieties into insulin icodec plays a crucial role in its prolonged action, as these fatty acid chains facilitate the formation of stable hexameric structures, thereby delaying insulin absorption and promoting sustained release. Yet, the underlying biophysics still is elusive of the roles of the three site-specific mutations (Y14A\_E, Y37B\_H, F46B\_H) of insulin icodec in its prolonged activity. Thus, through a comprehensive structural and biophysical analysis of the insulin (both native and icodec) structures bound to its receptor, this article delves deep into the biophysics underlying the molecular design of insulin icodec, and identified a delicate biophysical mechanism through which two missense mutations of insulin icodec (Y37B\_H and F46B\_H) contribute to its prolonged duration of action. Overall, this structural and biophysical investigation provides valuable insights into the mechanisms underlying the relationship between three site-specific mutations and prolonged duration of action of insulin icodec, while understanding these modifications at a structural and biophysical level can aid in the rational design of future long-acting insulin analogues, offering further enhanced therapeutic options for diabetic patients.

Type 2 diabetes (T2D) has a complex pathophysiology which makes modeling the disease difficult. We aimed to develop a novel model for simulating T2D in vitro, including hyperglycemia, hyperlipidemia, and variably elevated insulin levels targeting muscle cells. We investigated insulin resistance (IR), cellular respiration, mitochondrial morphometry and the associated function in different T2D -mimicking conditions in rodent skeletal (C2C12) and cardiac (H9C2) myotubes. Physiological controls included 5mM glucose with 20mM mannitol as osmotic controls. To mimic hyperglycemia, cells were exposed to 25mM glucose. Further treatments included insulin, palmitate, or both. After short-term (24h) or long-term (96h) exposure, we performed radioactive glucose uptake and mitochondrial function assays. Mitochondrial size and relative frequencies were assessed by morphometric analyses using electron micrographs. C2C12 and H9C2 cells treated short- or long-term with insulin and/or palmitate and HG showed IR. C2C12 myotubes exposed to T2D -mimicking conditions showed significantly decreased ATP-linked respiration and spare respiratory capacity, and less cytoplasmic area occupied by mitochondria, implying mitochondrial dysfunction. In contrast, H9C2 myotubes showed elevated ATP-linked and maximal respiration and increased cytoplasmic area occupied by mitochondria, indicating better adaptation to stress and compensatory lipid oxidation in a T2D environment. Both cell lines displayed elevated fractions of swollen/vacuolated mitochondria after T2D -mimicking treatments.Our stable and reproducible in vitro model of T2D rapidly induced IR, changes in ATP-linked respiration, shifts in energetic phenotypes, and mitochondrial morphology, which are comparable to the muscles of patients suffering from T2D. Thus, our model should allow studying disease mechanisms, potential new targets, and screen candidate therapeutic compounds.

Transferrin (TF) is a key iron carrier protein. Studies in human cohorts and in cultured adipocytes suggested that decreased transferrin expression and intracellular iron in adipocytes leads to impaired insulin responsiveness and causes differential expression of genes involved in metabolism, insulin action, and obesity. While suggestive, these studies did not definitively prove in an intact organism that altering TF expression in adipocytes is sufficient to affect glucose homeostasis and insulin resistance. In this study we created a mouse model of decreased transferrin expression only in adipocytes (Trf+/-Cre+/-) to test the hypothesis that iron trafficking in adipose tissue is sufficient to affect insulin sensitivity. Area under the glucose curve (AUCg) after intraperitoneal glucose administration was increased in the Trf+/-Cre+/- mice compared to wild type (WT) mice on a normal chow diet, and the mice were slightly heavier (p=0.02 for both). Homeostasis Model of Insulin Resistance (HOMA-IR) values were also significantly higher in the Trf+/- Cre+/- mice (p<0.05). Thus, supporting our hypothesis, analysis of mice with decreased expression of TF restricted to adipocytes showed that a decrease in adipocyte TF is sufficient to affect insulin resistance, weight, and glucose homeostasis.

Many redox diseases, including diabetes, are associated with an imbalance of calcium homeostasis, regulated mainly by a Ca2+-ATPase pump (SERCA). Dysfunction of this enzyme may be prevented by natural polyphenolic compounds, representing a possible supporting treatment. Compounds that increase SERCA activity/expression may be useful for the treatment of diabetic complications. Stimulation of SERCA1 activity was analyzed experimentally and by molecular modeling. SERCA1 activity under methylglyoxal- and palmitate-induced oxidative stress was evaluated. The viability of INS-1E cells and insulin secretion were determined. [6]-Gingerol, resveratrol, and ellagic acid increased SERCA1 activity and exerted a protective effect under oxidative stress in the noncellular system. We found for the first time that the binding of polyphenols ([6]-gingerol, resveratrol, ellagic acid) to Glu439 in the SERCA1 P-domain may be critical for the stimulation of its activity. Moreover, this binding may also be important in the protective effects against oxidative stress. Direct stimulation of SERCA1 activity by ellagic acid was observed for the first time. In INS-1E cells, these compounds increased insulin secretion.

Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.

Background: Obesity and diabetes are two metabolic disorders linked by an inflammatory process named insulin resistance (IR). Various research on the role of gut microbiota in developing obesity and its associated disorders has led to the growing interest in probiotic supplementation. Considering the life-threatening complications of diabesity this mini-review explored the effects of probiotic supplementation on IR in obesity-associated diabetes. Method: This review is based on recent articles from 2005-2020, studying the role of probiotic supplementation on glucose and insulin parameters in healthy and diabetic mouse models. Result: Probiotic supplementation altered the gut microbiota composition, increased short-chain fatty acid production, and decreased pro-inflammatory cytokines. Additionally, they decreased intestinal permeability, circulating lipopolysaccharide, and metabolic endotoxemia hence improved insulin sensitivity and reduced obesity. Although multi-strain probiotic supplementation showed greater benefits than single strain interventions, variations in the concentration of probiotics used and the duration of treatment also influenced the results. Conclusion: Probiotic supplementation could manipulate the gut microbiota by reducing intestinal permeability, inflammation and ameliorate IR and obesity-associated diabetes in animal models which requires further long-term clinical studies in humans.

Certain studies have reported various insulin resistance responses to ambient heavy metal pollution, but few have reported such responses to occupational heavy metal pollution. Even fewer have demonstrated a relationship between mixture effects of heavy metals and insulin resistance in welding workers. Overall, we recruited 53 welders and 48 administrative staff from a shipyard located in northern Taiwan. Personal exposure to heavy metals was monitored for PM2.5 and urine. Blood samples from each participant were collected from the antecubital vein after fasting. Urine samples from each participant were collected in the same period as blood samples. The geometric mean levels for chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), and cadmium (Cd) in the PM2.5 of the personal breathing zone and urinary Mn of welders were significantly higher than those in administrative staffs. Ambient Cr, Co, Ni, and Cu levels in the PM2.5 and urinary Cd were positively related to HOMA2-IR after adjusting for personal covariates (PM2.5-Cr: β=0.036, 95%C.I.: 0.002 to 0.070; PM2.5-Co: β=0.040, 95%C.I.: 0.002 to 0.077; PM2.5-Ni: β=0.054, 95%C.I.: 0.013 to 0.094; PM2.5-Cu: β=0.049, 95%C.I.: 0.010 to 0.088; U-Cd: β=0.209, 95%C.I.: 0.052 to 0.366, respectively). Our findings indicated the PM2.5 metal components and urinary metals were associated with increased insulin resistance in shipyard welders.

Insulin lispro was the first fast acting insulin analogue to obtain regulatory approval for therapeutic use. This article puts forward a novel biophysical mechanism where the net impact of the simple B28Pro-B29Lys exchange from regular insulin to insulin lispro is the establishment of a novel set of interfacial electrostatic interactions between Lys28 of insulin lispro and Asp12 of insulin receptor (IR). In addition, a set of structural analysis was presented in this article to further strengthen the binding of insulin lispro to IR, where two polar amino acid residues (Gln51 and Asn74 of insulin lispro) were put forward as two potential targets for site-directed mutagenesis of insulin lispro at its binding interface with IR.

Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin resistance, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect seems involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented palmitate-induced insulin resistance. Similarly to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented palmitate-induced insulin resistance after 12 h. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier time points.

Gut microbiota play critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance, which highlighted the potential of gut microbiota-targeted therapies on these diseases. There are various ways that can manipulate gut microbiota including probiotics, prebiotics, synbiotics, antibiotics and some active components from herbal medicines. In this review, we first reviewed the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies on NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.

The rapid growth of the global wearable technologies market is projected to reach $61.30 billion by 2030 which reflects a shift towards personalised health monitoring embedded in everyday activities. This paper explores the potential of embroidered interdigitated transducer (IDT)-based sensors for non-invasive, continuous monitoring of human biomarkers, particularly glucose levels, in human sweat. The study employs innovative embroidery techniques to create flexible fabric-based sensors with gold-coated IDTs. Experimental results demonstrate the sensor’s capability to detect water droplets and glucose concentrations, showcasing promising applications for health monitoring. The embroidered IDT-based sensors offer a unique approach for seamless integration into clothing, paving the way for personalised, continuous health data capture.

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Achieving synchronization between the central and peripheral body clocks is essential for ensuring optimal metabolic function. Meal timing is an emerging field of research that investigates the influence of eating patterns on our circadian rhythm, metabolism, and overall health. This narrative review examines the relationship between meal timing, circadian rhythm, clock genes, circadian hormones, and metabolic function. It analyzes existing literature and experimental data to explore the connection between mealtime, circadian rhythms, and metabolic processes. The available evidence highlights the importance of aligning mealtime with the body’s natural rhythms to promote metabolic health and prevent metabolic disorders. Specifically, studies show that consuming meals later in the day is associated with a elevated prevalence of metabolic disorders, while early time-restricted eating, such as having an early breakfast and an earlier dinner, improves levels of glucose in the blood and substrate oxidation. Circadian hormones, including cortisol and melatonin, interact with mealtimes and play vital roles in regulating metabolic processes. Cortisol, aligned with dawn in diurnal mammals, activates energy reserves, stimulates appetite, influences clock gene expression, and synchronizes peripheral clocks. Consuming meals during periods of elevated melatonin levels, specifically during the circadian night, has been correlated with potential implications for glucose tolerance. Understanding the mechanisms of central and peripheral clock synchronization, including genetics, interactions with chronotype, sleep duration, and hormonal changes, provides valuable insights for optimizing dietary strategies and timing. This knowledge contributes to improved overall health and well-being by aligning mealtime with the body’s natural circadian rhythm.

Chia seed, high in dietary-fiber and protein, may have potential to increase satiety. However, previous studies are confounded by differences in energy intake, and none investigated doses &lt;7g. We compared the subjective appetite and glycaemic responses elicited by 30g cookies containing 0, 3, 5 or 7g chia seed (CS0, CS3, CS5 or CS7, respectively, 140-150kcal, 7-8g fat, 4g protein, 0-2g dietary-fiber, 16g available-carbohydrate) using a randomized, double-blind, cross-over design. Overnight-fasted heathy adults (24 males, 22 females; mean±SD age 37±13y; BMI 27.4±3.9kg/m²) consumed test-cookies and had appetite and plasma-glucose measured before and intermittently for 3h after eating. Data were analyzed by ANOVA with Tukey’s test to adjust for multiple comparisons; the criterion for significance was 2-tailed p&lt;0.025 for the primary endpoints of total area under the curve (tAUC0-3h) for hunger and fullness. Hunger tAUC0-3h was similar among treatments (p=0.49) but fullness differed (p=0.019) with tAUC0-3h after CS3&gt;CS7 (mean±SEM) (140±9 vs 122±10mm×h, p&lt;0.025). Mean incremental glucose AUC0-2h after CS3, CS5 and CS7, respectively, were 22%, 23% and 30% less than CS0 (p&lt;0.05). Thus, although chia reduced glycemic responses, we were unable to demonstrate a significant effect of ≤7g chia seed on the primary endpoints of hunger or fullness tAUC0-3h versus control.

Objectives and Background: Gestational diabetes (GDM) is a common pregnancy complication, defined as a glucose intolerance diagnosis during pregnancy. GDM is strongly associated with adverse fetal and maternal outcomes. In Germany, to screen and diagnose GDM we use a 1-hour 50g oGCT (oral glucose challenge test) followed by a 2-hour 75g oGTT if the first was pathological. This analysis examines the correlation of 75g oGTT glucose levels and fetomaternal outcome. Methods: Data of 1664 patients from a gestational diabetes consultation clinic at the Charité University hospital in Berlin, Germany, were analyzed retrospectively from 2015 until 2022. The 75g oGTT blood glucose levels were categorized into isolated fasting hyperglycemia (GDM-IFH), isolated post-load hyperglycemia (GDM-IPH) and combined hyperglycemia (GDM-CH), using the levels of the fasting, 1-hour and 2-hour values after glucose application. These subtypes were compared regarding baseline characteristics as well as fetal and maternal outcome. Results: GDM-IFH and GDM-CH women displayed higher preconceptional BMI and required insulin therapy more frequently (p<0,001). The GDM-IFH group was at higher risk of having a primary cesarean section (p=0,047), while GDM-IPH women were significantly more likely to have an emergent cesarean section (p=0,013). The offspring of GDM-IFH and GDM-CH women were born with a significantly higher mean birthweight (p<0,001) and birth weight percentiles (p<0,001) and were at increased risk of being large for gestational age (LGA) (p=0,004). Women from the GDM-IPH group delivered significantly more neonates who were small for gestational age (p=0,027) or with low fetal weight <30th percentile (p=0,003). Conclusion: This analysis shows a strong association between glucose response pattern in the 75g oGTT and adverse perinatal fetomaternal outcome. The differences among the subgroups, specifically concerning insulin therapy, mode of delivery and fetal growth, suggest an individualized approach in prenatal care after a GDM diagnosis.

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation is closely associated with metabolism in mammalian cells acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. Also, we discuss the impact of these metabolic pathways on autophagy in lung cancer.

Abstract: Non-alcoholic fatty liver disease (NAFLD) begins with lipid accumulation within hepatocytes, but the relative contributions of different macronutrients is still unclear. We inves-tigated the impact of fatty acids, glucose and fructose on lipid accumulation in primary human hepatocytes (PHH) and three different hepatoma cell lines: HepG2, Huh7 and McA-RH7777 (McA). Cells were treated for 48 hours with fatty acids (0 or 200μM), glucose (5mM or 11mM) and fructose (0mM, 2mM or 8mM). Lipid accumulation was measured via Nile Red staining. All cell types accumulated lipid in response to fatty acids (P<0.001). PHH and McA, but not HepG2 or Huh7 cells, accumulated more lipid with 11mM glucose plus fatty acids (P=0.004, fatty acid x glucose interaction, for both), but only PHH increased lipid accumulation in response to fructose (P<0.001). Considerable variation was observed between PHH cells from different individuals. Lipid accumulation in PHH was increased by insulin (P=0.003) with inter-individual variability. Similarly, insulin increased lipid accumulation in both HepG2 and McA cells, with a bigger response in McA in the presence of fatty acids (P<0.001 for fatty acid x insulin). McA were more insulin sensitive than either HepG2 or Huh7 cells in terms of AKT phosphorylation (P<0.001 insulin x cell type interaction). Hence glucose and fructose can contribute to the accumulation of lipid in PHH with considerable inter-individual variation, but hepatoma cell lines are not good models of PHH.

The glucose-insulin regulatory system and its glucose oscillations is a recurring theme in the literature because of its impact on human lives, mostly the ones affected by diabetes mellitus. Several approaches were proposed, from mathematical to data-based models, with the aim of modeling the glucose oscillation curve. Having such a curve, it is possible to predict, when injecting insulin in type 1 diabetes (T1D) individuals. However, the literature presents prediction horizons no longer than 6 hours, which could be a problem considering their sleeping time. This work presents Tesseratus, a model that adopts a multi-agent approach to combine machine learning and mathematical modeling to predict the glucose oscillation up to 8 hours. Tesseratus uses the pharmacokinetics of insulins and data collected from T1D individuals. Its outcome can support endocrinologists while prescripting daily treatment for T1D individuals, and provide personalized recommendations for such individuals, to keep their glucose concentration in the ideal range. Tesseratus brings pioneering results for prediction horizons of 8 hours for nighttime, in an experiment with seven real T1D individuals. It is our claim that Tesseratus will be a reference for classification of glucose prediction model, supporting the mitigation of short- and long-term complications in the T1D individuals.

The integration of metal nanoparticles and solid carriers can achieve ideal stability, high load and good conductivity. In this work, copper nanoparticles (Cu NPs) were sequentially deposited on a cobalt metal-organic framework (Co-MOF) by bonding with exposed imino groups, followed by a reduction reaction to prepare a new Cu@Co-MOF composite. Cu@Co-MOF acts as a non-enzymatic electrochemical sensor to detect glucose (Glu) in an alkaline medium. The composite working electrode of Cu@Co-MOF/GCE (GCE = glassy carbon electrode) improves the electrocatalytic activity for Glu oxidation. Cu@Co-MOF/GCE shows excellent electrocatalytic performances in Glu concentration ranging 0.005~1.8 mmol∙L⁻¹ (mM): the sensitivities are 282.89 μA∙mM⁻¹∙cm⁻² in 0.005-0.4 mM Glu and 113.15 μA∙mM⁻¹∙cm⁻² in 0.4-1.8 mM Glu respectively with low detection limit of 1.6 μM (S/N = 3) and high selectivity and stability.

To cope the high glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) in diabetes. We compared the effect of low dose metformin 750mg/d adding vildagliptin 100mg/d (DPP4+LMET) or the high dose metformin 1500mg/d (HMET), in type 2 diabetes (T2D) with MDI, evaluating GV by continuous glucose monitoring (CGM). Single center, open-label, 12 weeks - 2 period crossover design. Twenty T2D with inadequately controlled (7.0% <HbA1c ≦9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM performed after each 12 weeks treatment periods. There was no significant difference in HbA1c, body weight changes, total daily dose of insulin. DPP4+LMET compared to the HMET, significantly reduced the calculated GV value, mean (7.15±1.3 vs 7.82±1.6, p<0.05), standard deviation (1.78±0.55 vs 2.27±1.11, p=0.03), continuous overlapping net glycemic action (6.44±1.28 vs 7.12±1.69, p<0.05), J-Index (26.7±11.0 vs 34.9±19.8, p<0.05), high blood glucose index (3.01±1.96 vs. 6.73±4.85, p=0.02), and mean amplitude of glycemic excursions (4.53±1.35 vs 5.50±2.34, p=0.03). The GV metrics with hypoglycemia and nocturnal hypoglycemia were not significantly different. DPP4+LMET decreased GV associated with hyperglycemia. Adding DPP4 inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI.

We assessed the growth performance, physiological traits, and gene expressions in steers fed with dietary rumen-protected L-tryptophan (RPT) under cold environment. Eight Korean native steers were assigned to two dietary groups, no RPT (Control) and RPT (0.1% RPT supplementation on a dry matter basis), 6 wks. Maximum and minimum temperatures throughout the experiment were 6.7°C and -7.0°C, respectively. Supplementation of 0.1% RPT to a total mixed ration did not increase body weight but had positive effects of elevating average daily gain (ADG) and reducing the feed conversion ratio (FCR) at day 27 and 48. Metabolic parameter showed higher glucose level (at day 27) in the 0.1% RPT group compared to the control group. Real-time PCR analysis showed no significant differences in the expression of muscle (MYF6, MyoD, and Desmin) metabolism genes between the two groups, whereas the expression of fat (PPARγ, C/EBPα, and FABP4) metabolism genes was lower in the 0.1% RPT group than in the control group. Thus, we demonstrate that long-term (6 wks) dietary supplementation of 0.1% RPT was beneficial owing to enhanced growth performance by increasing ADG and glucose level, decreasing FCR, and maintaining homeostasis in immune responses in beef steers during cold environment.

An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungus \textit{Neurospora crassa} is a well established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock of \textit{Neurospora} is composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedbacks among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 hrs. Our model reveals a switch between WC1 induced transcription and FFC assisted inactivation of WC1. Using the new model we also study possible mechanisms of glucose compensation. A fairly simple model with just 3 non-linearities helps to elucidate clock dynamics revealing a mechanism of rhythms production. The model can further be utilized to study entrainment and temperature compensation.

Worldwide epidemiological data indicates insufficient diagnosis of diabetes as an increasing problem of public health. Searching for solutions in this disadvantageous situation, occupational medicine health services seem to open up a unique opportunity to recognize some abnormalities in early steps, especially among the asymptomatic working-age population. 316 workers underwent obligatory prophylactic examinations. In patients with twice assayed FGL ≥ 126 mg/dl (7.0 mmol/l) the additional intervention was implemented, including further diagnostic process and therapy in General Practice (GP), followed by examination by an occupational health specialist within 3 months. The diagnosis of previously unknown diabetes was established among 2.5% of examined workers. All patients referred to the GP due to detected glycaemia impairment visited their doctor and finished the diagnostic process, took up therapy constrained by the occupational health physician to show the effects of intervention within 3 months. Prophylactic medical check-ups allow improved compliance and medical surveillance over glycaemia impairment in patients with prediabetes states, unknown diabetes or uncontrolled clinical course of diabetes. Considering fasting glucose level during mandatory prophylactic examination helps effective prevention of diabetes and its complications and thus give public health system benefits.

Facilitative glucose transporters (GLUT) are transmembrane transporter of proteins involved in glucose transport across the plasma membrane. To date, there is no information about glucose transporter 2 (GLUT2) in blunt snout bream (Megalobram aamblycephala). In this study, GLUT2 were cloned and characterized from blunt snout bream, and its-expression in response to diets with different carbohydrate levels (17.1%; 21.8%; 26.4%; 32.0%; 36.3% and 41.9% of dry matter). In this study, the full-length cDNA of GLUT2 was 2577 bp, including a 5’-untranslated region (UTR) of 73 bp, a 3’-UTR of 992 bp, and an open reading frame of 1512 bp, encoding a polypeptide of 503 amino acids with predicted molecular weight of 55.046 kDa and theoretical isoelectric point of 7.52. GLUT2 has twelve across the membrane area locating at 7-29; 71-93; 106-123; 133-155; 168-190; 195-217; 282-301; 316-338; 345-367; 377-399; 412-434; 438-460 aimo acids respectively. Conservative structure domains located at 12-477 aimo acids belonging to sugar porter family major facilitator superfamily (MFS) transporter. The blunt snout bream GLUT2 showed high identity to their orthologs in other fish species and mammals. Quantitative real-time (qRT)-PCR assays revealed that GLUT2 expression was high in the liver, intestine and kidney; highest in the liver. Compared with the control group (17.1%), high dietary carbohydrate levels (32.0%; 36.3% and 41.9%) resulted in high plasma glucose at 3h after feeding, but high plasma glucose were back to basal at 24h after feeding. Furthermore, high dietary carbohydrate levels significantly improved the glycolysis and inhibitied gluconeogenesis by augmentation of GK and PK expression, inhibition of PEPCK and G6P mRNA levels (P<0.05). However, GLUT2; GK; PK; PEPCK and G6P mRNA levels were back to basal.

Insulin therapy is a cornerstone in the management of diabetes, yet the pursuit of optimizing its pharmacokinetic profile remains a focal point in diabetes research. For instance, insulin icodec of Novo Nordisk is a novel long-acting insulin analogue that exhibits an extended duration of action, providing a promising once-weekly treatment option for diabetic patients. However, designing insulin analogues with lower receptor affinity than that of insulin icodec could still produce a further extended duration of action than that of insulin icodec through the suppression of receptor-mediated internalization of insulin analogues. In this study, therefore, I present the design of a novel series of insulin analogues engineered towards lower binding affinity to the insulin receptor compared to that of insulin icodec. Through computational structural biophysics-based rational design strategies, this article aims to further extend the duration of action while maintaining therapeutic efficacy of insulin analogues. Utilizing homology molecular modeling and structural biophysics-based binding affinity calculations, this article puts forward a set of insulin analogues with lower binding affinity to insulin receptor than that of insulin icodec from a structural and biophysical point of view. Overall, this article calls for subsequent in vitro and in vivo evaluations of the efficacy and prolonged action of the engineered insulin analogues to pharmacokinetically test whether these analogues acutally surpass that of insulin icodec as hopeful candidates for next-generation insulin analogue therapies with improved duration of action and enhanced control of blood glucose levels for diabetic patients in future.

Amylin, also known as islet amyloid polypeptide (IAPP), is a metabolic homeostasis-related hormone that is produced and released by the β cells of the pancreas, the same cells that produce insulin. Insulin-degrading enzyme (IDE) is a protease enzyme that plays an essential role in the breakdown and degradation of various peptides, including insulin and amylin. Direct binding & interaction between amylin and IDE is inextricably linked to the degradation of amylin, and research and development effort in this area is crucial to understand the potential therapeutic implications of disrupting the IDE-amylin interaction in the context of conditions where metabolic homeostasis needs to be regulated, such as diabetes and obesity. Here, this article incorporates currently available experimental complex structure of amylin and IDE, and delves deep into the interstructural biophysics underlying the binding interface of the two interacting partners. With a set of comprehensive structural biophysical analysis, this article identified an intriguing region of high electrostatic potential indicative of strong binding sites between the first N-terminal lysine (Lys1, K1) residue of amylin and Glu341 (E341) of IDE. This unique electrostatic hotspot presented herein paves the way for the rational design of drug-like small molecules that can selectively disrupt this interaction, offering a targeted therapeutic strategy for improved metabolic homeostasis, particularly for patients with diabetes and obesity.

Abstract The heart serves as the pivotal organ generating rhythmic contractions allowing blood ejection from the ventricles and its circulation in the cardiovascular system. Contractions of the heart requires oxygen and energy consumption and removal of metabolic factors from cardiac myocytes. The mechanical performance of the cardiac muscle and production of the vasoactive factors are significantly affected in cardiovascular and metabolic diseases, especially in the heart failure, hypertension and diabetes mellitus. The processes affecting coronary blood flow and cardiac contractility in these diseases are not fully recognized. The present review draws attention to specific role of angiotensin peptides, vasopressin and insulin in the regulation of the coronary blood flow and cardiac contractions. There is evidence for intracardiac production of some of these compounds and their importance in the regulation of the cardiac tissue oxygenation, energy production and metabolism, and generation of other cardiovascular compounds, such as nitric oxide, bradykinin and endothelin. Presence of receptors for angiotensin II, angiotensin-(1-7) and insulin in the coronary vessels and cardiomyocyes sets up conditions for interaction of these factors at the signaling level. Coronary vessels and cardiac muscle possess AT1 and AT2 receptors, angiotensin-1-7 receptor, vasopressin V1 receptor, and insulin receptor substrates. Expression of these receptors and responsiveness to angiotensins, vasopressin and insulin are altered during heart failure, hypertension, obesity and diabetes mellitus, especially when these diseases occur simultaneously. The survey of the literature presented in the review provides evidence for the belief that very individualized treatment, including interactions of angiotensins and vasopressin with insulin, should be selected for patients suffering simultaneously for cardiovascular and metabolic diseases.

Obesity, characterized by the excessive accumulation of body fat, contributes to a multitude of physiological dysfunctions. This paper explores the complex relationship between obesity and various risk factors and complications, shedding light on critical health implications. Obesity triggers alterations in insulin, leptin, adiponectin, cytokines, and insulin-like growth factors, fostering conditions conducive to cancer initiation. Aberrations in nutrient-dependent intracellular signaling pathways, driven by the excess nutrition characteristic of obesity, contribute to the neoplastic transformation of cells. The Body Mass Index (BMI) correlates directly with adiposity, underlining its significance in cancer risk. Furthermore, insulin and insulin-like growth factors, notably IGF-2, play pivotal roles in this relationship. The expression of IR-A receptors is elevated in cancer. Obesity and cardiovascular diseases share a strong association. Obesity elevates the risk of fatal events like myocardial infarction. High cholesterol levels contribute to atherosclerosis in the aorta and coronary arteries. The severity of coronary artery disease is influenced by plaque formation characterized by calcium deposits. Obesity is also linked to hypertension and increased ventricular mass, exacerbating cardiovascular risks. Hypercholesterolemia and hypertension correlate with a high Body Mass Index (BMI). Obesity is intricately connected to insulin resistance, particularly evident in childhood obesity. It entails a gradual decline in insulin sensitivity, leading to elevated insulin levels in the bloodstream. Insulin resistance is a central factor in the development of Type 2 Diabetes Mellitus. Obesity also results in elevated triglyceride levels and reduced high-density lipoproteins, contributing to atherogenic dyslipidemia and a heightened risk of atherosclerosis. Additionally, obesity is associated with various other disorders, including epilepsy, depression, and neuropsychological problems. Beyond its physiological impact, obesity is associated with significant psychosocial challenges. Studies indicate that individuals with obesity face a higher risk of depressive symptoms, often related to overeating and unhealthy dietary patterns. The social withdrawal tendencies of obese individuals exacerbate these symptoms, with higher rates of depression observed in this group. OSA, a sleep disorder characterized by intermittent breathing cessation during sleep, is strongly correlated with obesity. Approximately 58% of obese individuals experience OSA, with higher Body Mass Index (BMI) associated with an increased risk. Weight reduction has been found to mitigate the severity of OSA and related arrhythmias. Continuous positive airway pressure (CPAP) therapy demonstrates effectiveness in reducing visceral fat accumulation and leptin levels. This comprehensive review underscores the intricate web of health implications associated with obesity, emphasizing the critical need for preventive measures and intervention strategies to address the multifaceted challenges posed by this global health concern.

Strong evidence indicates that insulin resistance contributes to the development of Alzheimer´s disease by promoting inflammation, oxidative stress, and blood vessel damage. Conversely, neuroinflammation induces insulin resistance by targeting insulin signaling molecules: the insulin receptor substrates 1 and 2 (IRS1/2). In addition, neuroinflammation is strongly linked to reduced levels of brain-derived neurotrophic factor (BDNF) expression. BDNF is a key factor for neuronal survival, and its expression is compromised in neurodegenerative disorders. In this study, we show that, in a triple-transgenic (3xTg) mice model of Alzheimer’s disease, the BDNF and IRS2 but not the IRS1 mRNA expression levels were reduced in the hippocampus, together with higher levels of TNFα, compared with wild-type mice. Subgroups of control and 3xTg mice received short and long treatments of Abscisic Acid (ABA), a phytohormone with anti-inflammatory and insulin-sensitizing capabilities. We found that the short ABA treatment can increase the IRS1 and IRS2 mRNA expression both in wild-type and 3xTg mice, concomitant with reducing pro-inflammatory cytokine TNFα in 3xTg mice. However, earlier, and thus longer treatments are required to rescue the BDNF mRNA levels. Our data strongly confirm that ABA administration is a potential treatment to prevent Alzheimer´s disease, via lowering neuroinflammation, potentially rescuing insulin signaling molecules and BDNF mRNA expression.

Background: Nutrient supplements are widely used for type 2 diabetes (T2D) yet evidence-based guidance for clinicians is lacking. Methods: We searched the four electronic databases from November 2015–December 2021. The most recent, most comprehensive, high-ranked systematic reviews, meta-analyses and/or umbrella reviews of randomised controlled trials in adults with T2D were included. Data were extracted on study characteristics, aggregate outcome measures per group (glycemic control, measures of insulin sensitivity and secretion), adverse events, and GRADE assessments. Quality was assessed using AMSTAR-2. Results: Twelve meta-analyses and one umbrella review were included. There was very low certainty evidence that chromium, Vitamin C and omega-3 polyunsaturated fatty acids (-3 PUFAs) were superior to placebo for the primary outcome of HbA1c (MD -0.54%, -0.54% and ES -0.27 respectively). Probiotics were superior to placebo for HbA1c (WMD -0.43%). There was very low certainty evidence that Vitamin D was superior to placebo for lowering HbA1c in trials of <6 months (MD -0.17%). Magnesium, zinc, Vitamin C, probiotics and polyphenols were superior to placebo for FBG. Vitamin D was superior to placebo for insulin resistance. Data on safety was limited. Conclusions: Future research should identify who may benefit from nutrient supplementation, safety, and optimal regimens and formulations.

Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Glucose and insulin tolerance tests (GTT/ITT) were conducted at weeks 1, 5 and 2, 6, respectively. Cocoa provided mild non-significant protection against weight gain vs. ob/ob control in males but not females. Male ob/ob + c had increasing fasting glucose at weeks 1 and 5 GTTs, with significantly higher levels of fasting glucose than ob/ob control at week 5. This was not seen in females. Cocoa protected against elevated 4-hour fasting glucose in week 2, but not week 6, ITTs. Cocoa partly suppressed hyperinsulinemia in males but significantly amplified it in females and protected against loss of beta cell area in females only. The mechanisms of these sex-specific effects remain to be elucidated. This study informs additional experiments with larger sample sizes and demonstrates that sex differences must be considered when designing dietary interventions for T2D.

Background and Aims: We aimed to investigate cross-sectional relationships of relative handgrip strength (RHGS) with presence of diabetes and hypertension in a community setting. Methods and Results: Between 2016 and 2018, we enrolled 601 consecutive women with an average age of 70.7 ± 6.9 years (mean ± SD). Nutritional status was evaluated by the Mini Nutritional Assessment (MNA) score. Muscular strength and level of fitness were assessed by handgrip strength (HGS) and other standardized physical functional tests. The majority of participants were overweight or obese (80% with BMI > 25). Prevalence of diabetes and hypertension was 13 and 60%, respectively. Participants in the lowest quartile of HGS adjusted for BMI (RHGS) had significantly higher prevalence of diabetes and hypertension compared with those in the lower quartile (20.7 vs. 5.3% and 49.3 vs. 39.3%, respectively, p < 0.01 for both), whereas differences in nutritional status were not observed. Likelihood of having diabetes was significantly reduced in women with higher RHGS values (OR 0.77; 0.59–0.86 CI95%; p=0.002), independently of age, abdominal adiposity and presence of hypertension. RHGS was positively correlated with most of the physical functional tests performed. Conclusion: RHGS is an easy-to-obtain and inexpensive measure of muscular strength, independently associated with presence of diabetes in overweight elderly women. Prospective studies are required to assess its predictive value in individuals at risk of new onset or progression of diabetes.

Aims: To study the effects of pyridoxal phosphate (PLP) on oxidative stress in isolated pancreatic acinar cells. We have previously shown that PLP has cytoprotective and insulinotropic effects on mice islet cells in vivo and in vitro studies. Main methods: Acinar cells were isolated from three months old WNIN male rats and were cultured in vitro for a period of 24 h in CO₂ incubator. Later the cells were divided into four groups as untreated (group 1), H₂O₂ treatment (group 2)_, PLP treatment (group 3) and PLP followed by H₂O₂ treatment (group 4). Cell viability was confirmed using MTT assays, oxidative stress levels were measured with ROS assay, change in different protein levels were recorded by flow cytometry. The acinar cells insulin secretion assay was performed with ELISA. The amylase protein expression was assessed using confocal microscopy. Key findings: The cell viability of acinar cell in group 1 was considered as 100%, while in group 2 it was reduced to 82% due to H₂O₂ effect, and in group 3 (99.8%) and group 4 (99.5%) were near to group 1 due to the cytoprotective effect of PLP. The ROS levels were increased by 1.47 folds in group 2, while PLP decreased to 1.02 fold in group 4, which was comparable with the changes in group 1. Beneficial effects of PLP were also observed from the increased expression levels of acinar cells are amylase -2.01, neurogenin-3-9.51, PDX-1- 23.6 and insulin-13.5 in group 3 compared to group 1. The specificity of PLP’s response was confirmed by amino oxy acetic acid (AOAA), a specific PLP inhibitor. The increased amylase protein localization with PLP was confirmed by confocal microscopy. Insulin secretion efficiency of acinar cells was observed to be 6.13 folds higher at basal and 24.63 fold higher at stimulated levels in group3 compared to group1. Significance: Our results advocate the antioxidant and cytoprotective effects of PLP on the pancreatic acinar cell along with increased pancreatic marker expressions of amylase,PDX-1, neurogenin-3 and insulin proteins.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by fluid-filled sacs in the ovaries and various symptoms including high androgen levels, endometrial irregularities, and cysts. While the cause of PCOS is unknown, it has been linked to genetic, endocrine, and metabolic factors, and there are several treatment options, including lifestyle modifications, medications, and surgery. Natural products, such as medicinal plants and fruits, are being explored as potential treatments for PCOS due to their bioactive compounds with pharmacological effects related to antioxidant, antimicrobial, anticancer, and antidiabetic properties. Some of these compounds improve insulin sensitivity, reduce inflammation, and enhance glucose metabolism, which is beneficial for women with PCOS. This review examined the effects of natural products on PCOS, including their effects on ovarian histological changes, blood glucose, sex hormones, and lipid profile, based on animal and human studies. This study suggests that the use of natural products as complementary medicine can be a promising resource for the development of effective therapeutics for PCOS, but that further research is needed to fully understand their benefits

The objective of this pilot study was to compare glucose concentrations in capillary blood (CB) samples analysed in a laboratory by a validated method and glucose concentrations measured in the interstitial fluid (ISF) by continuous glucose monitoring under different physical activity levels in a postprandial state in healthy and active subjects without diabetes. Ten healthy, active subjects (26±4 years, 67±11 kg bodyweight (BW), 11±3 h) were included in the study. Within 14 days, they underwent six tests consisting of a) resting fasted (R/Fast), b) resting after intake of 1 g glucose/kg BW (R/Glc) and c) running for 60 minutes at moderate (65/Glc) and d) high (85/Glc) intensity after intake of 1 g glucose/kg BW. Data were collected in the morning, following a standardised dinner before test day. Sensor-based glucose concentrations were compared to simultaneous capillary blood glucose concentrations. Pearson’s r correlation coefficient was highest for R/Glc (.92, p<.001) compared to R/Fast (.45, p<.001), 65/Glc (.60, p<.001) and 85/Glc (.70, p<.001). Mean absolute relative deviation (MARD) and standard deviation (SD) was smallest for resting fasted and similar between all other conditions (R/Fast: 8±6%, R/Glc: 17±12%, 65/Glc: 22 ± 24%, 85/Glc: 18±17%). However, Bland-Altman plot analysis showed a higher range between lower and upper limits of agreement (95% confidence interval) of paired data under exercising compared to resting conditions. Under resting fasted conditions, both methods produce similar outcomes. Under resting postprandial and exercising conditions, respectively, there are differences between both methods. However, further data in healthy subjects need to be gathered considering physical activity and nutrition status.

The kidney and the heart work together in balancing the body circulation and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidney physiology is primarily designed to maintain a stable metabolic rate and has limited capacity to cope with any steep increase in renal metabolism. In the kidneys the glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of renal glucose transport in disease states is providing better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over-exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.

This study explored the effects of a comprehensive health care program (CHCP) on blood pressure, blood glucose, body composition, and depression in older adults living alone. We used a quasi-experimental, two-group, pre-posttest design. The CHCP consisted of open lectures, health counseling, exercise classes, nutrition counseling, and self-help group meetings at a local senior welfare center. Fifty-eight subjects participated in this study, with thirty subjects in the experimental group and twenty-eight subjects in the control group. Data were analyzed using the descriptive statistics, χ²-test, and t-test. Comparisons of the pretest and posttest systolic blood pressure (t = - 2.530, p < .016) and blood glucose (t = 3.089, p < .004) between the experimental and control groups showed significant differences. In both the experimental (t = 3.949, p < .001) and control groups (t = 3.816, p < .002), depression symptoms showed a significant decrease post-test, compared with pre-test. Our findings infer that older adults require physical and psychosocial healthcare and that more efforts must be made to improve the general health and wellbeing of this population group.

In this work, an enzymatic sensor, based on a bionanocomposite film consisting of a polyelectrolyte complex (PEC) [Chitosan/kappa-carrageenan] doped with gold nanoparticles (AuNPs) encapsulating glucose oxidase (GOD) deposited on a gold electrode (Au) for glucose sensing, is described. Using the electrocatalytic synergy of AuNPs and GOD as a model of enzyme, the variation of the current (µA) as a function of the log of the glucose concentration (log [glucose]), shows 3 times higher sensitivity for the modified electrode (283.9) compared to that of the PEC/GOD modified electrode (93.7), with a detection limit of about 5 µM and a linearity range between 10µM and 7mM. The response of the PEC/AuNPs/GOD based biosensor also presents good reproducibility, stability and negligible interfering effects from ascorbic acid, uric acid, urea and creatinine. The applicability of the PEC/AuNPs/GOD based biosensor was tested in glucose-spiked saliva samples and acceptable recovery rates were obtained.

Diabetic patients need long-term and frequent glucose monitoring to assist in insulin intake. The current finger-prick devices are painful and costly which make noninvasive glucose sensors highly demanded. In this review paper, we discuss several advanced electromagnetic (EM) wave based technologies for noninvasive glucose measurement, including infrared (IR) spectroscopy, photoacoustic (PA) spectroscopy, Raman spectroscopy, fluorescence, optical coherent tomography (OCT) and microwave sensing. Development and progress of each method are discussed regarding fundamental principle, system setup and experimental results. Despite the promising achievements reported previously, there is no established product to obtain FDA approval or survive marketing test. Limitations and prospects of these techniques are discussed at the end of this review.

A cuprous oxide (Cu₂O) thin layer served as the base for a non-enzymatic glucose sensor in an alkaline medium, 0.1 NaOH solution, with a linear range of 50-200 mg/dL using differential pulse voltammetry (DPV) measurement. An X-ray photoelectron spectroscopy (XPS) study confirmed the formation of the cuprous oxide layer on the thin gold film sensor prototype. Quantitative detection of glucose in both phosphate-buffered saline (PBS) and undiluted human serum were carried out. Neither ascorbic acid nor uric acid even at a relatively high concentration level of 100mg/dL in serum interfered with the glucose detection, demonstrating the excellent selectivity of this non-enzymatic cuprous oxide thin layer based glucose sensor. Chronoamperometry (CA) and single potential amperometric voltammetry were used to verify the measurements obtained by differential pulse voltammetry (DPV), and the positive results validated that the detection of glucose in a 0.1 M NaOH alkaline medium by DPV measurement was effective. Nickel, platinum and copper are commonly used metals for non-enzymatic glucose detection. The performance of these metal-based sensors for glucose detection using DPV were also evaluated. Cuprous oxide (Cu₂O) thin layer based sensor showed the best sensitivity for glucose detection among the sensors evaluated.

Zidovudine (AZT) has significantly reduced the mortality and morbidity rates among AIDS patients, but it has been associated with hepatotoxicity. AZT treatment has been linked to disrupted lipid and glucose metabolism, and the enhancement of pro-inflammatory chemokines and other mediators, which can lead to liver steatosis. In contrast, the administration of adenosine (ADO) has proven to be an effective hepatoprotector against both acute and chronic liver damage. Therefore, present study was aimed to investigate the harmful effects of chronic AZT administration and the beneficial effects of the co-administered ADO. Chronic oral AZT administration did not induce hyperglycemia or dyslipidemia, but serum liver marker enzyme activities were increased, as well as evidence of liver steatosis and inflammation. These findings were associated with low insulin and glucagon levels, elevated serum levels of pro-inflammatory cytokines and disruptions in cell redox states in these animals. ADO co-administration attenuated the deleterious effects induced by AZT: blocking the production of inflammatory molecules, increasing serum insulin and glucagon levels, and restoring liver cellular redox state. Then, blood insulin levels seemed to be greatly influenced by the cellular redox state, which was altered by AZT administration. This alteration is likely to be connected to mitochondrial integrity and metabolism.

C-peptide is used as a measure of endogenous insulin production. Given that insulin and C-peptide are produced in equal amounts, C-peptide is typically used to differentiate between external and endogenously produced insulin in insulin-treated type 1 diabetes mellitus (T1DM). In a clinical setting, a decline in C-peptide is regarded as a loss of beta cell function. However, physiological conditions may also be associated with low C-peptide levels. The authors of this paper use a low-carbohydrate diet, the so-called paleolithic ketogenic diet (PKD), in the treatment of various conditions and observed that C-peptide is typically low on this diet. In order to characterize C-peptide levels on this diet, we designed a study to retrospectively assess C-peptide levels in 100 non-T1DM subjects. We found that 55% of the subjects had a C-peptide level below the standard reference range. C-peptide levels correlated with glucose levels. A significant correlation was found between C-peptide and age, with younger subjects having lower C-peptide levels. Males also showed lower C-peptide levels than females. Given the increasing number of patients using low-carbohydrate diets worldwide, physicians should be aware of laboratory correlates of low-carbohydrate diets, including low C-peptide levels, most importantly to prevent incorrect T1DM diagnosis.

Ovulatory infertility is a serious clinical problem whose direct causes are still largely unknown. In addition to pathologies that make it impossible for a couple to establish a pregnancy, there are a number of other factors that have a bearing on fertility, including lifestyle factors, particularly diet. Although numerous studies have been performed linking such factors with ovulatory infertility, most of them lack the necessary clinical significance, focusing instead on observational data and establishing associative relationships. This paper includes a literature review focusing on connections between lifestyle factors such as diet, physical exercise, oxidative stress, sleep, and supplementation, and ovulatory infertility. Special emphasis was given to issues such as obesity and insulin resistance and their mutual relationship with other factors linked to ovulatory infertility. In addition, making use of the conclusions of literature review, the authors propose a classification of relationships between ovulation disorders and lifestyle factors in ovulatory infertility based on the WHO classification of ovulation disorders, and indicate areas that merit further research. The data presented in the paper shows that the issues of proper diet and physical exercise are those that would merit from robust clinical studies focused specifically on ovulation infertility, while studies concerning the relationship between oxidative stress, sleep, and supplementation and ovulatory infertility do not seem to be promising directions as far as clinical significance is concerned.

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD such that AD may be a form of brain insulin resistance. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect of AD pathobiology. Ceramides are a class of bioactive sphingolipids that have been hypothesized to drive insulin resistance. Here we describe preliminary work that tests the hypothesis that hyperinsulinemia pathologically alters cerebral mitochondrial function in AD mice via accrual of the ceramides. Homozygous male and female ApoE4 mice were given chronic injections of PBS (control), insulin, myriocin (an inhibitor of ceramide biosynthesis), or insulin and myriocin over four weeks. Cerebral ceramide content was assessed using liquid chromatography-mass spectrometry. Mitochondrial oxygen consumption rates were measured with high-resolution respirometry, and H2O2 emissions were quantified via biochemical assays on brain tissue from the cerebral cortex. Significant increases in brain ceramides and impairments in brain oxygen consumption were observed in the insulin-treated group. These hyperinsulinemia-induced impairments in mitochondrial function were reversed with the administration of myriocin. Altogether, these data demonstrate a causative role for insulin in promoting brain ceramide accrual and subsequent mitochondrial impairments that may be involved in AD expression and progression.

This scoping review comprehensively explores the existing literature on fenugreek (Trigonella foenum-graecum), a versatile herb known for its culinary and traditional medicinal uses. The review focuses on two key aspects: the hypoglycemic mechanism of fenugreek and its impact on milk production in breastfeeding women. By systematically analyzing and synthesizing the available evidence, this review aims to enhance our understanding of fenugreek's potential applications and identify research gaps for future systematic reviews. The search strategy targeted English-language animal studies published within the last five years that specifically investigated fenugreek's hypoglycemic mechanism and its effects on milk production. A total of 15,236 articles were initially identified from databases such as PubMed, Sci finder and ScienceDirect. After a rigorous selection process, including thorough evaluation of titles, abstracts, and full-texts, a subset of articles (including those titled "Impact of Fenugreek on Milk Production in Rodent Models of Lactation Challenge" and "Fenugreek Stimulates the Expression of Genes Involved in Milk Synthesis and Milk Flow through Modulation of Insulin/GH/IGF-1 Axis and Oxytocin Secretion") were included for detailed analysis. The findings 18 articles from the included studies demonstrate promising results regarding fenugreek's potential to stimulate milk production and regulate blood glucose levels. However, further research is necessary to unravel the underlying molecular pathways, establish optimal dosage guidelines, and assess long-term side effects. Overall, this scoping review offers valuable insights for lactating women seeking to enhance milk production and individuals managing blood sugar levels, providing potential alternative approaches for supporting lactation and glycemic control.

The Sry-related HMG-box (Sox) family is a group of transcriptional regulators that play a critical role in many important developmental processes in both vertebrates and invertebrates. In aquatic animals, the function of Sox genes on sexual development has been gained particular attentions. The present study reported the molecular characterization of a Sox member (PtSoxE) in the swimming crab, Portunus trituberculatus, and tissue distribution analysis showed it was male-specific. Since the most highly expression of PtSoxE was found in the androgenic gland (AG), its relation to the insulin-like androgenic gland hormone (IAG) was further investigated. The PtSoxE siRNA caused a significant decrease in IAG expression in both AG and testis, whereas PtSoxE expression could be induced by treating with AG homogenate and rIAG. The result suggested a transcriptional interaction between PtSoxE and IAG. In addition, PtSoxE expression showed a closely positive correlation with several reported spermatogenesis-related genes, suggesting its involvement in testicular development of P. trituberculatus.

The risks for complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection are higher in obese individuals. Obesity is a state of chronic low-grade inflammation, with high leptin levels due to leptin resistance, high basal levels of other pro-inflammatory cytokines such as TNF-alpha, MCP-I and IL-6, and low adiponectin levels, thus contributing to a state of defective innate immunity as well as impaired B and T cell responses. Obesity is a risk factor for metabolic syndrome, diabetes, cardiovascular disease and hypertension. It has been observed that pre-existence of these diseases confers a higher risk of severe SARS CoV2 infection as well as the need for intensive care; even below the age of 60 years if their body mass index (BMI) is greater than 30 kg/m2, and even more so if it is > 35 kg/m2. The metabolic factors contributing to the changes in altering the immune mechanisms in obese individuals and how this enhances the susceptibility to infection and development of serious SARS-CoV2 infection have been the subject of many debates. Future development of targeted therapy and guidelines will be benefited by greater understanding into these metabolic pathways.

Insulin signaling plays a crucial role in cellular uptake of glucose and different metabolic pathways. Impairment in cellular insulin sensitivity due to various molecular pathways leads to Insulin resistance (IR) as well as fatty liver. In this review, mechanisms by which zinc involved in decreasing IR are described, focusing on oxidative stress, inflammation, immune system, gut flora and hepatic lipophagy. This study reviews the cause of IR and highlights the role of zinc in mechanisms diminishing IR and fatty liver.

The prevalence of cardiometabolic risk factors has increased in Slovakian adolescents as a result of serious lifestyle changes. This cross-sectional study aimed to assess the prevalence of insulin resistance (IR) and the associations with cardiometabolic and selected lifestyle risk factors in a sample of Slovak adolescents. In total, 2,629 adolescents (45.8% males) aged between 14 and 18 years were examined in the study. Anthropometric parameters, blood pressure, and resting heart rate were measured, fasting venous blood samples were analysed, and HOMA-IR was calculated. The mean HOMA-IR was 2.45±1.91 without a significant intersexual difference. IR (cut-off point for HOMA-IR=3.16) was detected in 18.6% of adolescents (19.8% males, 17.6% females). IR was strongly associated with overweight/obesity (especially central) and with almost all monitored cardiometabolic factors, except for TC and systolic BP in females. The multivariate model selected variables such as low level of physical fitness, insufficient physical activity, breakfast skipping, a small number of daily meals, frequent consumption of sweetened beverages, and low educational level of fathers as the significant risk factors of IR in adolescents. Recognizing the main lifestyle risk factors and early IR identification is important in terms of the performance of preventive strategies. Weight reduction, regular physical activity, and healthy eating habits can improve insulin sensitivity and decrease the incidence of metabolic syndrome, type 2 diabetes, and CVD in adulthood.

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptionally and metabolically. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insu- lin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissues contexts that may be relevant to future work in insulin resistance and T2D.

Hyperlipidemia and insulin-resistance are often associated with Non Alcoholic Fatty Liver Disease (NAFLD) thereby representing a true issue worldwide, due to increased risk of developing cardiovascular and systemic disorders. Although clear evidence suggests that circulating fatty acids contribute in pathophysiological mechanisms underlying NAFLD and hyperlipidemia, further studies are required for better identify potential beneficial approaches for counteracting such a disease state. Recently, several artichoke extracts have been used for both reducing hyperlipidemia, insulin-resistance and NAFLD, though the mechanism is unclear. Here we used a wild type of Cynara Cardunculus extract (CyC), rich in sesquiterpens and antioxidant active ingredients, in rats fed and High Fat Diet (HFD) compared to Normal Fat Diet (NFD). In particular, in rats fed HFD for four consecutive weeks, we found a significant increase of serum cholesterol, triglyceride and serum glucose. This effect was accompanied by increased body weight and by histopathological features of liver steatosis. The alterations of metabolic parameters found in HFD were antagonised dose-dependently by daily oral supplementation of rats with CyC 10 and 20 mg/Kg over 4 weeks, an effect associated to significant improvement of liver steatosis. The effect of CyC (20 mg/Kg) was also associated to enhanced expression of both OCTN1 and OCTN2 carnitine-linked transporters. Thus, present data suggest a contribution of carnitine system in the protective effect of CyC in diet-induced hyperlipidemia, insulin-resistance and NAFLD.

In this review, we discuss the insulin resistance (IR) and its development in the insulin target tissues that leads to diabetes. Also, we highlight the use of induced pluripotent stem cells (iPSCs) to understand the mechanisms underlying the development of IR. IR is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Although there are currently several mouse models for both IR and T2D that had provided a lot of information about the disease, these models cannot recapitulate all the aspects of this complex disease as seen in each individual. Patient-specific iPSCs can overcome the hurdles faced with the classical mouse models for studying IR. iPSC technology can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of the genome editing and iPSCs may provide important information about the inherited factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the widely practiced treatment; however, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to high blood glucose level. However, determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for treatment of diabetes is still debated upon. While hPSC-derived beta cells are perceived as the ultimate candidate, the efficiency needs further improvement in order to obtain a sufficient number of glucose responsive β-cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address co-generation of functionally relevant islet cell subpopulations and structural properties contributing to glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.

For the diagnosis of disease, the ability to quantitatively detect trace amounts of the causal proteins from bacteria/viruses as biomarkers in patient specimens is highly desirable. Here we introduce a simple, rapid, and colorimetric assay as a de novo, ultrasensitive detection method. This ultrasensitive assay consists of sandwich enzyme-linked immunosorbent assay (ELISA) and thionicotinamide-adenine dinucleotide (thio-NAD) cycling, forming an ultrasensitive ELISA, in which the signal substrate (i.e., thio-NADH) accumulates in a triangular manner, and the accumulated thio-NADH is measured at its maximum absorption wavelength of 400 nm. We have successfully achieved a limit of detection of ca. 10–18 moles/assay for a target protein. As an example of infectious disease detection, HIV-1 p24 could be measured at 0.0065 IU/assay (i.e., 10⁻¹⁸ moles/assay), and as a marker for a lifestyle-related disease, adiponectin could be detected at 2.3 × 10⁻¹⁹ moles/assay. In particular, despite the long-held belief that the trace amounts of adiponectin in urine can only be detected using a radioisotope, our ultrasensitive ELISA was able to detect urinary adiponectin. This method is highly versatile, because simply changing the antibody enables the detection of various proteins. This assay system requires only the measurement of absorbance, thus it requires equipment that is easily obtained by medical facilities, which facilitates diagnosis in hospitals and clinics. Moreover, we describe an expansion of our ultrasensitive ELISA to a non-amplification nucleic acid detection method for nucleic acids using hybridization. These de novo methods will enable simple, rapid, and accurate diagnosis.

The combination of freeze-dried aronia, red ginseng, ultraviolet-irradiated shiitake mushroom and natokinase (AGM; 3.4: 4.1: 2.4: 0.1) was examined to evaluate its effects on insulin resistance, insulin secretion and gut microbiome in a non-obese type 2 diabetic animal model. Pancreatectomized (Px) rats were provided high fat diets supplemented with either of 1) 0.5 g AGM (AGM-L), 2) 1 g AGM (AGM-H), 3) 1 g dextrin (control), or 4) 1g dextrin with 120 mg metformin (positive-control) per kg body weight for 12 weeks. AGM (1 g) contained 6.22 mg cyanidin-3-galactose, 2.5 mg ginsenoside Rg3 and 0.6 mg β-glucan. Px rats had decreased bone mineral density in the lumbar spine and femur and lean body mass in the hip and leg compared to the normal-control and AGM-L and AGM-H prevented the decrease. Visceral fat mass was lower in the control group than the normal-control group and its decrease was smaller by AGM-L and AGM-H. HOMA-IR was lower in descending order of the control, positive-control, AGM-L, AGM-H and normal-control groups. Glucose tolerance was deteriorated in the control group and it was improved by AGM-L and AGM-H more than in the positive-control group. Glucose tolerance is associated with insulin resistance and insulin secretion. Insulin tolerance indicated insulin resistance was highly impaired in diabetic rats, but it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Insulin secretion capacity, measured by hyperglycemic clamp, was much lower in the control group than the normal-control group and it was improved in the ascending order of the positive-control, AGM-L and AGM-H. Diabetes modulated the composition of gut microbiome and AMG prevented the modulation of gut microbiome. In conclusion, AGM improved glucose metabolism by potentiating insulin secretion and reducing insulin resistance in insulin deficient type 2 diabetic rats. The improvement of diabetic status alleviated body composition changes and prevented changes of gut microbiome composition.

Elevated blood glucose levels, known as glycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding this link has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment, in-silico model of the human atrial node's action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on atrial node action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the sinoatrial node action potential frequency. In summary, our model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death.

A key response to glucose stress is an increased production of unsaturated fatty acids to balance the increase of saturated fatty acids in the membrane. The C. elegans homolog of stearoyl-CoA desaturase, FAT-7, introduces the first double bond into saturated C18 fatty acids yielding oleic acid and is a critical regulatory point for surviving cold and glucose stress. Here, we incorporated 13C stable isotopes into the diet of nematodes and quantified the 13C-labelled fatty acid by GC-MS and HPLC/MS-MS to track the metabolic response to various concentrations of glucose. Previous work has analyzed membrane composition of C. elegans when responding to mild glucose stress and showed few alterations in overall fatty acid composition in the membrane. Here, in nematodes exposed to higher concentrations of glucose, a specific reduction of oleic acid and linoleic acid was observed. Using time courses and stable isotope tracing, the response of fatty acid me-tabolism to increasing levels of glucose stress has been characterized, revealing a funneling of monounsaturated fatty acids to preserve polyunsaturated fatty acid abundance. Taken together, higher levels of glucose unveil a specific reduction of oleic and linolenic acid in the metabolic re-wiring required to survive glucose stress.

Sulfite and kraft pulping are two principal methods of industrial delignification of wood. In recent decades, those have been considered as possibilities to pretreat recalcitrant wood lignocellulosics for enzymatic hydrolysis of polysaccharides and subsequent fermentation of obtained sugars to valuable bioproducts. Current work compares chemistry and technological features of two different cooking processes in the preparation of polysaccharide substrates for deep sacchari-fication with P. verruculosum glycosyl hydrolases. Bleached kraft and sulfite pulps were subjected to hydrolysis with enzyme mixture of high xylanase, cellobiohydrolase and β-glucosidase activities at a dosage of 10 FPU/g of dry pulp and fiber concentration of 2.5, 5 and 10%. HPLC was used to analyze soluble sugars after hydrolysis and additional acid inversion of oligomers to monosaccharides. Kraft pulp demonstrated higher pulp conversion after 48 h (74-99%), mostly resulted from deep xylan hydrolysis. Sulfite-pulp hydrolysates, obtained in similar conditions, due to higher hexose concentration (more than 50 g/L), had higher fermentability for industrial strains producing alcohols, microbial protein or organic acids. Along with saccharification, enzymatic modification of non-hydrolysed residues occurred, which led to decreased degree of polymerization and composition changes in two industrial pulps. As a result, crystallinity of kraft pulp increased by 1.3%, which opens possibilities for obtaining new types of cellulosic products in pulp and paper industry. The high adaptability and controllability of enzymatic and fermentation processes creates prospects for the modernization of existing factories.

Canine mammary tumors (CMTs) are among the most common disease in female dogs and share similarities with human breast cancer, which have placed these animals as a model of study in comparative oncology. Metabolic reprogramming is one of them and is known as a hallmark of carcinogenesis whereby cells undergo adjustments to supply the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as therapeutic strategies which have been tested mostly in human clinical trials, but poorly explored in CMTs. In this dedicated review, we compilated the metabolic changes described for CMTs emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial function. We observed here key factors associated with the presence and aggressiveness of CMTs, such as the increase in glucose uptake followed by enhanced anaerobic glycolysis via upregulation of glycolytic enzymes, changes in glutamine catabolism due to overexpression of glutaminases, raise in fatty acid oxidation and distinct effects depending on the lipid saturation, in addition to mitochondrial DNA which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiate an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of alternation in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method in the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in near future.

Nanocomposite hydrogels offer remarkable potential for applications in bone tissue engineering. They are synthesized through the chemical or physical crosslinking of polymers and nanomaterials, allowing for the enhancement of their behaviour by modifying the properties and compositions of the nanomaterials involved. However, their mechanical properties require further enhancement to meet the demands of bone tissue engineering. Here, we present an approach to improve the mechanical properties of nanocomposite hydrogels by incorporating polymer grafted silica nanoparticles into a double network inspired hydrogel (gSNP Gels). The gSNP Gels were synthesised via a graft polymerization process using a redox initiator. gSNP Gels were formed by grafting 2-acrylamido-2-methylpropanesulfonic acid (AMPS) as the first network gel followed by a sequential second network acrylamide (AAm) onto amine functionalized silica nanoparticles (ASNPs). We utilized glucose oxidase (GOx), to create an oxygen-free atmosphere during polymerization resulting in higher polymer conversion compared to argon degassing. The gSNP Gels showed excellent compressive strengths of 13.9 ± 5.5 MPa, a strain of 69.6 ± 6.4%, and a water content of 63.4% ± 1.8. The synthesis technique demonstrates a promising approach to enhance the mechanical properties of hydrogels, which can have significant implications for bone tissue engineering and other soft tissue applications.

Accumulation of extra fats in the body results in disturbance in homeostasis causing obesity. The pathophysiology of obesity has been associated with various genetic, epigenetic factors and the disturbed lifestyles of an individual. One of the outcomes is disturbance in the sleep cycle which leads to sleep disorders. The evolutionary significance of sleep lies in the fact that it saves energy and is crucial for adjustment of an individual to ecological and environmental factors, and thus maintains homeostasis. Sleep has an anabolic function and replenishes the wakefulness-associated loss of glycogen stores. However, the modern lifestyle is well known to disrupt sleep behavior and patterns affecting human health negatively. Alteration in homeostasis leads to several acute and chronic pathophysiological conditions like obesity and related metabolic morbidities being one amongst them. Shorter sleep duration and poor sleep quality are important risk factors associated with the development of obesity and have more adverse effects on energy homeostasis. Consequently, it is crucial to comprehend the obesity and sleep relationship and its therapeutic strategies, given that strong crosstalk exists between energy balance that favors obesity and sleep apnea. It is therefore highly recommended to the people with a high risk of obesity to maintain sleep discipline and good sleep hygiene in our daily life. Interventions are required to improve both sleep quality and quantity, and associated obesity. More focused research is needed for uncovering the pieces of evidence that determine whether such interventions can improve obesity-related health consequences. The present review discusses the important findings on the therapeutic and neuroendocrine mechanisms regulating sleep and obesity.

Keywords: Obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC; NTS; incretins.

Beyond plasma glucose-lowering in patients with type 2 diabetes, sodium- glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced the hospitalization for heart failure (HF) and retarded the progression of chronic kidney disease (CKD). Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), and is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2i have shown an improvement in endothelial dysfunction, as assessed by flow-mediated vasodila-tion, in individuals at high risk for CVD. Along with an improvement of endothelial dysfunction, SGLT2i showed improvements in oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity such as advanced glycation end products signaling and nitric oxide bioavailability. The improvements in endothelial dysfunc-tion and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy which cause HF and in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2i might have been largely induced by the improvement of vascular endothelial function by SGLT2i.

In humans and animal models, intermittent fasting (IF) interventions promote body weight loss, improve metabolic health, and are thought to lower cardiovascular disease risk. However, there is a paucity of reports on the relevancy of such nutritional interventions in the context of dyslipidemia and atherosclerotic cardiovascular diseases. The present study assessed the metabolic and atheroprotective effects of intermittent fasting intervention (IF) in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice. Groups of male and female Apoe-/- mice were fed a regular (chow) or atherogenic (high-fat, high-cholesterol, HFCD) diet for 4 months, either ad libitum or in an alternate-day fasting manner. The results show that IF intervention improved glucose and lipid metabolism independently of sex. However, IF only decreased body weight gain in males fed chow diet and differentially modulated adipose tissue parameters and liver steatosis in a diet composition-dependent manner. Finally, IF prevented spontaneous aortic atherosclerotic lesions formation in mice fed chow diet, irrespective of sex but failed to reduce HFCD-diet-induced atherosclerosis. Overall, the current work indicates that IF interventions can efficiently improve glucose homeostasis and treat atherogenic dyslipidemia, but a degree of caution is warranted with regard to the individual sex and the composition of the dietary regimen.

Background: Nonalcoholic fatty liver disease (NAFLD) is regarded as a component of metabolic syndrome, which has insulin resistance (IR) as the primary physiopathological event. The aim of study was to establish the association between IR, assessed using triglyceride and glucose index (TyG), and histopathological features of NAFLD lesions. Methods: The study included patients with metabolic syndrome. Fasting plasma glucose (FPG), fasting lipid profiles and liver enzymes were measured. IR was assessed by TyG index. Liver biopsy was performed for assessment steatosis and fibrosis. Results: TyG index had a mean value of 8.93 ± 1.45, with a higher value in the patients with overweight (p=0.002) and obesity (p=0.004) than in the patients with normal weight. TyG index mean value of 8.78 ± 0.65 in subjects without NASH, 8.91 ± 0.57 in patients with borderline NASH and 9.13 ± 0.55 in patients with definite NASH. Significant difference was found between subjects without NASH and the ones with definite NASH (p=0.004). The analysis of the area under the ROC curve proved that TyG index is a predictor for NASH (p=0.043). Conclusion: TyG index is a facile tool used to identify individuals at risk for NAFLD, but not for the progression of liver lesions.

Sugar-sweetened beverages are associated with metabolic dysfunction, particularly in those with increased risk factors. Artificial sweeteners (AS) are often promoted as a healthier alternative, yet findings remain conflicting as to their effects on metabolic function. Further, there is a lack of data exploring the interaction between AS and high-fat diets (HFD). We therefore examined the effects of HFD and the AS Acesulfame-potassium (Ace-K) on glucose intolerance and adipose tissue physiology in male and female C57BL/6 mice. 40 mice were randomised to receive either a) a control diet (CDCon; standard control diet/water), b) control diet and Ace-k (CDAS; CD/7.5mM AS in drinking water), c) HFD (HFCon; HFD (45%kcal from fat)/water), or d) HF and AS (HFAS; HFD/7.5mM AS in drinking water) for 6 weeks. A HFD increased body weight in male and female mice independently of AS supplementation. AS induced sex-specific effects protecting against HFD-induced hyperglycaemia and adipocyte hypertrophy in male mice and reducing inflammatory gene expression in the adipose tissue. Conversely in females, AS induced hyperinsulinemia in HFD mice and increased expression of immune-related genes. These findings suggest that supplementation of HFD with AS exacerbates metabolic dysfunction in female mice. This work supports the importance of studying sexually dimorphic responses to an altered nutritional environment and highlights the need for further investigation into the intake of AS, particularly in those already at risk of metabolic disease such as the obese or overweight.

Non-enzymatic glucose sensing is a crucial field of study because of the current market demand. This study proposes a novel design of glucose sensor with enhanced selectivity and sensitivity by using graphene Schottky diodes, which is composed of Graphene/Platinum Oxide/n-Silicon heterostructure. The sensor was tested with different glucose concentrations and interfering solutions to investigate its sensitivity and selectivity. Different structures of the device were studied by adjusting the platinum oxide film thickness to investigate its catalytic activity. It was found that the film thickness plays a significant role in the efficiency of glucose oxidation and hence in overall device sensitivity. Moreover, theoretical investigations were conducted using Density Function Theory (DFT) to better understand the detection method and the origins of selectivity. The working principle of the sensors puts it in a competitive position with other non-enzymatic glucose sensors. DFT calculations provided a qualitative explanation of the charges distributed across the graphene sheet within a system of a platinum substrate with D-glucose molecules above. The proposed graphene/PtO/n-Si heterostructure has proven to satisfy these factors, which opens the door for further developments of more reliable non-enzymatic glucometers for continuous glucose monitoring systems.

Key features of glycogen metabolism in excitable tissues are not well-explained by current concepts. Glycogen stores in brain and skeletal muscle are generally considered to function as local glucose reserves, to be utilized during transient mismatches between glucose supply and demand; however, quantitative measures show that blood glucose supply is likely never rate-limiting for energy metabolism in either brain or muscle under physiological conditions. These tissues nevertheless do normally utilize glycogen during intervals of increased energy demand, despite the availability of free glucose, and despite the ATP cost of cycling glucose through glycogen polymer. This seemingly wasteful shunt can be explained by considering the effect of glycogenolysis on the amount of energy derived from ATP (ΔG’ATP). ΔG’ATP is diminished by elevations in Pi, such as occur at sites of rapid ATP hydrolysis and net phosphocreatine consumption. Glycogen utilization counters this effect by sequestering Pi in glycolytic metabolites (glycogen_n + Pi → glycogen_n-1 + glucose-1-phosphate → phosphorylated glycolytic intermediates), and thereby maintains the amount of energy obtained from ATP at sites of rapid ATP consumption. This thermodynamic effect may be particularly important in the narrow, spatially constricted astrocyte processes that ensheath neuronal synapses. This effect can also explain the co-localization of glycogen and cytosolic phosphocreatine in brain astrocytes, glycolytic super-compensation in brain when glycogen is not available, and aspects of exercise physiology in muscle glycogen phosphorylase deficiency (McArdle’s disease).

Introduction. The use of probiotics demonstrate efficacy against obesity and metabolic syndrome (MetS). Detection effective probiotic strains for hyperglycemia and immunity associated with is important task. The aim of the study was to evaluate an influence of Lactobacillus casei IMV B-7280 separately and composition L. casei IMV B-7280 / Bifidobacterium animalis VKB / B. animalis VKL on the levels of blood glucose and immunity in obese mice. Meterials and methods. Obesity was induced by fat-enriched diet (FED) in male BALB/c mice. Obese mice were transferred to standard diet and received per os probiotic strains daily during 10 days. We measured tumor necrosis factor-a (TNF-a) in blood serum using enzyme-linked immunosorbent assay and functional activity of peritoneal exudate macrophages (PEMs). Glucose levels in blood was defined with glucometer. Results. We ascertained that all probiotic strains induced reducing mice weight and visceral fat, normalization of TNF-a production and functional activity of PEMs. Treatment with L. casei IMV B-7280 was associated with decreasing blood glucose levels. No normalization of glucose and TNF-a levels in obese mice, transferred to standard diet without probiotic treatment, although we revealed decreasing their weight and visceral fat and partial recover of functional activity of PEMs. Conclusions. Probiotic strain L. casei IMV B-7280 (separately) and composition L. casei IMV B-7280 / B. animalis VKB / B. animalis VKL can re-equilibrate metabolic and inflammation indices in mouse obesity model. L. casei IMV B-7280 alone was more efficient in decreasing glucose levels than composition of strains.

The performance of modified electrode of nanocomposite film consisting of polypyrrole-chitosan-titanium dioxide (Ppy-CS-TiO2) has been explored as non-enzymatic glucose biosensors. The synergy effect of TiO2 nanoparticles and conducting polymer on the current response of electrode resulted in higher sensitivity for nanocomposite modified electrode. The incorporation of TiO2 nanoparticles in the nanocomposite films were confirmed by XPS spectra. The FESEM and HR-TEM provided more evidences for the presence of TiO2 in Ppy-CS structure. Glucose biosensing properties were determined by amperommetry and cyclic voltammetry (CV) methods. The interfacial properties of nanocomposite electrodes were studied by electrochemical impedance spectroscopy (EIS). The developed biosensors showed a good sensitivity over the liner range of 1-14 mM with a detection limit of 614 μM for glucose. It also exhibited good selectivity and long term stability with no interference effect. The Ppy-CS-TiO2 nanocomposites film presented high electron transfer kinetics.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent world-wide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBP) is a family of secreted proteins involved in senescence and scarring mainly synthetized in the liver. Here we aimed to study the association of IGFBP and its induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: 16 weeks old male C57BL/6 mice weighing 23 ± 3 g were fed either Methionine-Choline Deficient or control diet for 2, 8 or 12 weeks. Blood and liver samples were collected; histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in liver and serum. Data was expressed as Mean ± SD and analyzed by one-way ANOVA followed Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p