Medicine and Pharmacology

Abstract: Background/Objectives: Hypovitaminosis-D is a highly prevalent condition worldwide, associated with adverse skeletal and extra-skeletal outcomes. Increasing demand for serum 25-hydroxyvitamin D (25(OH)D) testing points toward the need for simple tools to identify individuals at risk and optimize laboratory use. We aimed to develop and validate a clinical risk score for predicting hypovitaminosis-D based on easily assessable risk factors. Methods: This cross-sectional study included 1,408 adults across Italy. Demographic, clinical, lifestyle, and dietary data were collected through a standardized questionnaire. Univariable and multivariable logistic regression analyses identified predictors of 25(OH)D <20 ng/mL and <30 ng/mL. Risk scores were derived from models. Discriminative ability was assessed using ROC curves, and calibration by comparing predicted and observed probabilities. Results: Median age was 67 years, and 91.3% were female. Median 25(OH)D was 33.2 ng/mL; 9.8% had levels <20 ng/mL. Independent predictors of hypovitaminosis-D (25(OH)D <20 ng/mL) included higher body mass index, residence in Northern Italy, reduced summer sun exposure, sunscreen use, cardiovascular disease, glucocorticoid use, absence of cholecalciferol supplementation, and no prior vitamin D use. The score (range 9-18) showed good discrimination (Area under the curve; AUC: 79.1%, 95% CI 75.3-82.9) and excellent calibration (r=0.98, p<0.001). A screening cut-off (10.3-10.7) ensured high sensitivity (87.0-92.7%), while 11.9-12.0 balanced sensitivity (~62%) and specificity (~80%). A second score for 25(OH)D <30 ng/mL showed moderate discrimination (AUC: 69.6%). Performance remained stable across seasons and in untreated subjects (AUC: 72.7%). Conclusions: A simple, data-driven clinical risk score identifies individuals at risk of hypovitaminosis-D and may support targeted screening, reduce unnecessary testing, and improve cost-effectiveness in clinical practice.

Abstract: Glycated haemoglobin (HbA1c) has served for four decades as the standard biomarker for long-term glycaemic control, with global use approaching one billion measurements annually. The biomarker rests on a tacit assumption: that the rate of non-enzymatic haemoglobin glycation is determined chiefly by mean plasma glucose concentration, with erythrocyte intracellular glucose acting as a passive equilibrium with plasma. This assumption requires erythrocyte glucose uptake to be constant—that is, glucose transporter 1 (GLUT1) expression should not vary substantially with physiological state. The 2026 demonstration by Martí-Mateos and colleagues that chronic hypoxia upregulates erythrocyte GLUT1 approximately twofold and per-cell glucose uptake approximately threefold, together with growing evidence that the band 3 N-terminus operates as a bidirectional metabolic switch responsive to haemoglobin oxygenation state, invalidates the constancy assumption. We argue that HbA1c should be reconceived not as a record of extracellular glucose exposure but as the time-integral of erythrocyte intracellular glucose exposure—a quantity that diverges from plasma glucose in a directionally predictable manner under conditions of altered erythrocyte oxygen environment, chronic inflammation, or accelerated red cell turnover. We synthesise existing evidence showing HbA1c underestimates true glycaemia in high-altitude populations (where glycated albumin moves in the opposite direction, confirming the dilution-and-flux mechanism), with parallel implications for obstructive sleep apnoea, cyanotic congenital heart disease, intensive care unit hyperoxia exposure, and chronic kidney disease. We propose four testable predictions, outline a Red Cell Hypoxic Metabolic Index (RHMI) as a candidate correction factor, and argue that the next generation of diabetes monitoring should integrate HbA1c with glycated albumin, continuous glucose monitoring, and erythrocyte metabolic phenotyping in a population-specific manner. The framework does not displace HbA1c but provides the missing physiological lens required to read it correctly in 2026 and beyond.

Abstract: Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are now a cornerstone anti-hyperglycaemic therapy for people with type 2 diabetes mellitus, especially with concurrent cardiovascular and/or kidney disease. Diabetic ketoacidosis, including euglycemic diabetic ketoacidosis, is an uncommon but serious adverse effect associated with SGLT2i use. Commonly reported risk factors include surgical stress, infection, fasting, dehydration and non-adherence with diabetes treatment; diabetic ketoacidosis is also more common in acute care settings. The objectives of this study are to detail the acute care and diabetes profiles of people who experienced SGLT2i-associated diabetic ketoacidosis during their hospitalisation, and to detail the DKA event. SGTL2i-DKA is also compared to concurrent inpatients with T2D taking SGLT2is but who did not experience DKA. Methods: A pragmatically driven part retrospective and part prospective electronic medical record audit was conducted recording patient demographics, diabetes history, admission parameters and hospital stay characteristics cases of SGLT2i-associated diabetic ketoacidosis referred to the Inpatient Diabetes team at an Australian quaternary hospital across 18-months. This patient cohort was compared to that of all inpatients prescribed with SGLT2i, but did not develop diabetic ketoacidosis, admitted at the same hospital during an overlapping 12-month period. Results: Thirty-five patients (54.3% male, aged 65.4±12.9 years) with SGLT2i-associated diabetic ketoacidosis were analysed. Almost 90% were admitted via emergency department. Lowest pH was 7.08 ± 1.20. Average blood glucose levels indicated hyperglycaemia (initial: 16.8 ± 12.0 mmol/L; peak: 19.5 ± 11.9 mmol/L). Mean time from detection to resolution of DKA was 12.4 hours. No deaths were reported. Patients with diabetic ketoacidosis had poorer glycaemic control than those without (HbA1c: 9.4 ± 2.3% vs 8.4 ± 2.7%, P = 0.013). Sepsis (P = 0.012) and surgery (P < 0.001) were identified as precipitating risk factors for SGLT2i-associatd DKA. Conclusion: SGLT2i-associated DKA was observed in inpatients with poorer glycaemic control and was more prevalent among emergency admissions who experienced sepsis or who underwent surgery. Although accompanied by moderate to severe acidosis, all episodes were treated promptly, and no deaths were reported.

Abstract: Background: Thyroid dysfunction is increasingly recognized as a common comorbidity in patients with chronic kidney disease (CKD), with prevalence rising as renal function declines. The aim of this review is to summarize current evidence and highlight unresolved clinical and pathophysiological aspects of thyroid dysfunction in CKD. Methods: A narrative review of the literature was conducted using major databases, including PubMed, Scopus, and Web of Science. Studies addressing epidemiology, pathophysiology, and clinical outcomes of thyroid dysfunction in CKD were analyzed. Results: The most frequent abnormalities in CKD include low triiodothyronine (T₃) syndrome and subclinical hypothyroidism. These changes are associated with impaired peripheral conversion of thyroid hormones, chronic inflammation, oxidative stress, and accumulation of uremic toxins. Observational studies demonstrate associations between thyroid dysfunction and adverse outcomes, including cardiovascular disease, anemia, and increased mortality. However, interpretation of thyroid function tests is complicated by altered protein binding and lack of CKD-specific reference ranges. Significant heterogeneity across studies limits comparability. Conclusions: Thyroid dysfunction in CKD represents a multifactorial and clinically relevant condition. Despite strong associations with adverse outcomes, causality remains uncertain, and the role of thyroid hormone replacement therapy is not clearly established. Further prospective and interventional studies are required to define its clinical significance and therapeutic implications.

Abstract: Background: Type 2 diabetes (T2DM) increases the risk of mild cognitive impairment (MCI), however, the mechanisms of this process have not yet been fully identified. The aim of the study was to determine the levels of vitamin B12 and homocysteine in elderly diabetic patients, with and without cognitive impairment, and identify the risk factors associated with MCI in this group. Methods: A total of 385 elderly diabetic patients were to screened to for MCI. Several clinical and biochemical data were recorded. Results: In the study group, MCI subjects had lower vitamin B12 levels and higher homocysteine concentrations compared to controls. In MCI subjects, vitamin B12 levels were negatively correlated with homocysteine or HbA_1c levels and positively correlated with MoCA scores. The univariate logistic regression showed factors associated with MCI in elderly diabetic patients were the following: older age and fewer years of education, longer history of diabetes, a higher number of co-morbidities, higher levels of HbA_1c, triglycerides and homocysteine, lower levels of vitamin B12, presence of cardiovascular disease, hypertension, hyperlipidemia, retinopathy, and nephropathy. Independent factors associated with MCI evaluated in multivariate model included lower levels of vitamin B12, higher levels of triglycerides, a higher number of co-morbidities and fewer years of formal education. Conclusions: The association between T2DM and higher risk of MCI is partly mediated by lower levels of vitamin B12, and higher levels of homocysteine. The findings of this study highlight the importance of regular vitamin B12 screening and routine cognitive function testing in older adults with diabetes.

Abstract: Background: While many studies indicate a bidirectional relationship between type 2 diabetes (T2DM) and depression, its precise nature remains unclear. The aim of the study was to determine the levels of inflammatory markers in the oldest-old diabetic patients with depressive symptoms, and identify the risk factors associated with late-life depressive symptoms. Methods: The 195 diabetic participants, aged 85 and above, were screened for depressive symptoms. Several clinical and biochemical data were also collected. Results: Serum levels of TNF-α, IL-1β, and IL-6 were increased in depressive individuals and correlated with each other, and with HbA_1c level, GDS score, FBG and BMI. Univariate logistic regression found the following parameters to predict depressive symptoms in elderly T2DM patients: older age, female sex, living alone, smoking habit, no physical activity, higher BMI, longer duration of T2DM, increased number of co-morbidities, presence of cardiovascular disease, retinopathy, neuropathy, hypertension and hyperlipidaemia, insulin treatment, higher levels of HbA1c, total cholesterol, LDL and TG, lower concentrations of HDL, and higher levels of TNF-α, IL-1β, and IL-6. Conclusion: Low grade inflammation could be one of the mechanisms underlying co-morbid depression and diabetes. Hence, cytokines such as TNF-α, IL-1β, and IL-6 might serve as diagnostic biomarkers and potential therapeutic targets.

Abstract: Background: Hypertension commonly complicates diabetes mellitus (DM), contributing significantly to increased morbidity and mortality. This study determined the prevalence and factors associated with hypertension among people with DM at a tertiary health facility in Northern Uganda. Methods: A hospital-based cross-sectional study employing a quantitative approach was conducted between July 18 and October 24, 2024. Participants with confirmed DM were selected using systematic random sampling at Lira Regional Referral Hospital (LRRH), Lira city, Uganda. Data were collected using a structured questionnaire adapted from the WHO STEPS (2022) tool. Patient charts and registers were used to verify information. Data were analyzed using STATA version 16. Multivariable logistic regression was performed, and a p-value < 0.05 was considered statistically significant. Results: A total of 340 participants were enrolled into the study, the median age was 54.3 years (IQR 50-60), predominantly female 244 (71.8%), and most had attained primary education 162 (47.6%). Overall, 67.1% (228/340) of the participants with DM had hypertension. Factors independently associated with higher odds of hypertension were, age 61+ years (aOR=5.55, 95% CI:1.34-23.1, p=0.018), being overweight (aOR=3.77, 95%CI: 1.05-13.57, p=0.042), DM duration of more than five years (aOR=2.51, 95% CI: 1.41- 4.67, p=0.002), and being widowed (aOR=8.04, 95% CI: 1.87-34.61, p=0.005). Earning UGX 50,001–100,000 per month (aOR=0.35, 95% CI: 0.13-0.93, p=0.037) was associated with a 65% lower odds of having hypertension. Conclusion: In this study, almost two-thirds of patients with DM had hypertension, and factors such as older age, overweight, longer diabetes duration, and marital status significantly increase hypertension risk; meanwhile, moderate-income status offered a protective effect. The high burden of hypertension among patients with DM demonstrates the necessity for targeted public health interventions such as comprehensive lifestyle modification programs, routine screening for hypertension, early detection, and its management among patients with DM, through enhanced healthcare access. These need to focus on integrated care approaches that include monitoring and managing DM alongside hypertension.

Abstract: Background and Clinical Significance: Phosphatidylinositol-3-kinase (PI3K) inhibitors have transformed the treatment of advanced hormone receptor-positive, HER2-negative breast cancer harboring PIK3CA mutations. Hyperglycemia is a well-recognized on-target adverse effect of this drug class; however, progression to diabetic ketoacidosis (DKA) is rare and potentially life-threatening. Inavolisib, a next-generation PI3Kα-selective inhibi-tor, has demonstrated promising efficacy, yet no detailed case of inavolisib-associated DKA has been reported in the peer-reviewed literature. We present what appears to be the first such case, highlighting an important and underrecognized endocrine toxicity.Case Presentation: A 76-year-old woman with metastatic hormone receptor-positive, HER2-negative, PIK3CA-mutated breast cancer and type 2 diabetes well controlled on oral hypoglycemics for over a decade was started on inavolisib in combination with palbo-ciclib and fulvestrant for newly diagnosed pulmonary metastases. Approximately two weeks after treatment initiation, she presented with generalized weakness, inability to tol-erate oral intake, and a mechanical fall. Laboratory evaluation revealed severe hypergly-cemia (glucose >500 mg/dL), metabolic acidosis (venous pH 7.27, bicarbonate 14 mmol/L), an elevated anion gap (27), and moderate ketonuria, consistent with DKA. Her glycated hemoglobin had risen from 5.8% to 8.9% within two months. No alternative precipitants, including infection, steroid use, or dietary changes, were identified. She was admitted to the intensive care unit and treated with intravenous fluids and insulin infusion, with dis-continuation of inavolisib, resulting in rapid metabolic recovery. At two-month follow-up, her HbA1c had normalized to 4.7% on her prior oral regimen alone. Conclusions: This case represents the first detailed peer-reviewed report of DKA associat-ed with inavolisib. The close temporal relationship, absence of alternative precipitants, and rapid recovery after drug discontinuation strongly support a causal association. Cli-nicians prescribing PI3Kα inhibitors should implement rigorous baseline metabolic as-sessment and close glucose monitoring, particularly during the first two weeks of therapy, even in patients with previously well-controlled diabetes.

Abstract: X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.

Abstract: Metabolic syndrome (MetS) is a complex and multifactorial condition characterized by insulin resistance, visceral obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to increased cardiovascular risk. Central to its pathophysiology is metainflammation, a persistent inflammatory state closely linked to oxidative stress and mitochondrial dysfunction. This review aims to provide an inte-grated and updated overview of the interplay between metaflammation, oxidative stress, mitochondrial dysfunction, and organokine signaling in the development and progression of MetS and its cardiovascular complications. Current evidence indicates that mitochondrial dysfunction plays a pivotal role by promoting excessive production of reactive oxygen species (ROS), impairing ATP synthesis, and disrupting redox bal-ance, thereby exacerbating insulin resistance and endothelial dysfunction. In parallel, dysregulated secretion of organokines—including adipokines, myokines, hepatokines, cardiokines, osteokines, and renokines—alters interorgan communication and ampli-fies pro-inflammatory and atherogenic pathways. Additionally, gut microbiota con-tributes to metabolic homeostasis through the production of short-chain fatty acids, whereas dysbiosis is associated with worsening metabolic parameters. Collectively, these interconnected mechanisms establish a self-perpetuating cycle that drives meta-bolic dysfunction and cardiovascular disease progression. This review highlights the central role of the metainflammation–mitochondrial dysfunction axis and emphasizes the importance of organokine-mediated crosstalk as a key regulator of systemic me-tabolism. Targeting these pathways may represent a promising strategy for the pre-vention and management of MetS and its associated complications.

Abstract: Background: Imeglimin is a novel oral antidiabetic agent that improves mitochondrial function and glucose metabolism in patients with type 2 diabetes mellitus (T2DM). Its effects on liver enzymes remain unclear. We investigated the effects of imeglimin on hepatic biomarkers, particularly γ-glutamyl transpeptidase (γ-GTP), and the reversibility of these changes after treatment discontinuation. Methods: This post-hoc analysis of the prospective INFINITY Study included 25 patients with T2DM who completed 6 months of imeglimin treatment followed by a 3-month withdrawal period. Clinical parameters were averaged within predefined 3-month study phases. Treatment responses and withdrawal rebounds were analyzed. Results: Imeglimin significantly improved glycemic control. The geometric mean γ-GTP decreased from 36.2 (27.1–48.4) U/L during the Baseline Phase to 31.1 (23.5–41.1) U/L during the Late Treatment Phase (P < 0.05). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) also showed downward trends, although these changes were not statistically significant. During the Withdrawal Phase, γ-GTP returned to 35.6 (26.4–48.5) U/L (P < 0.05 vs. Late Treatment Phase). Patients with baseline γ-GTP >50 U/L showed larger but non-significant changes. Treatment response and withdrawal rebound were inversely correlated (r = −0.480, P = 0.015). Only total cholesterol correlated with γ-GTP during both treatment (r = 0.554, P = 0.005) and withdrawal (r = 0.450, P = 0.024). Conclusions: Imeglimin selectively reduced γ-GTP in patients with T2DM, and this effect was reversible after treatment discontinuation. The close association between γ-GTP and total cholesterol suggests that imeglimin may influence hepatic metabolism beyond glucose lowering.

Abstract: Thyroid hormone physiology has traditionally been interpreted through the hypothalamic–pituitary–thyroid (HPT) axis and genomic signaling mediated by triiodothyronine (T3). However, accumulating evidence indicates that thyroid hormone action extends beyond classical nuclear receptor pathways and involves rapid, non-genomic mechanisms that influence cellular metabolism. Among the metabolites generated during thyroid hormone metabolism, 3,5-diiodothyronine (3,5-T2) has emerged as a biologically active iodothyronine capable of modulating mitochondrial respiration and energy metabolism. Experimental studies demonstrate that T2 can rapidly increase oxygen consumption, enhance fatty acid oxidation, and stimulate resting metabolic rate, particularly in hepatic and skeletal muscle tissues. These metabolic effects have generated interest in T2 as a potential modulator of metabolic disorders characterized by mitochondrial dysfunction, including obesity and non-alcoholic fatty liver disease (NAFLD). Despite these promising findings, important translational questions remain. Evidence from animal studies suggests that exogenous T2 administration may suppress the hypothalamic–pituitary–thyroid axis and induce central hypothyroidism, highlighting potential safety considerations. In addition, limited human data and challenges in reliably measuring circulating T2 have restricted understanding of its physiological relevance. This review examines the biochemical origins, molecular mechanisms, and metabolic actions of 3,5-diiodothyronine within the broader framework of mitochondrial thyroid hormone signaling. We discuss experimental evidence supporting its metabolic effects, the analytical challenges involved in studying thyroid hormone metabolites, and the unresolved questions surrounding its physiological role in humans. A deeper understanding of T2 biology may expand current paradigms of thyroid hormone signaling and provide new insight into tissue-specific metabolic regulation.

Abstract: Lipoprotein(a) [Lp(a)] is a predominantly genetic risk factor for atherosclerotic cardiovascular disease and calcified aortic valve disease (CAVD). In addition to its epidemiological and genetic association with aortic stenosis, Lp(a) transports oxidized phospholipids, lysophosphatidylcholine, and autotaxin, components capable of promoting inflammation, oxidative stress, and valvular fibrocalcifying remodeling. This review synthesizes the molecular, cellular, and clinical evidence linking Lp(a) to CAVD progression. Retention of Lp(a) and other apolipoprotein B-containing lipoproteins in the valvular matrix promotes endothelial activation, monocyte and macrophage recruitment, and the release of proinflammatory mediators. Oxidized phospholipids and the autotaxin-lysophosphatidic acid axis activate redox-dependent pathways and promote the transition of valvular interstitial cells to myofibroblastic and osteogenic phenotypes. These processes converge in alterations in cholesterol metabolism, the release of procalcifying extracellular vesicles, and hydroxyapatite nucleation. Genetic and imaging evidence support an association between elevated Lp(a), microcalcifying activity, and accelerated hemodynamic progression. Although anti-Lp(a) therapies substantially reduce plasma Lp(a) concentrations, their effect on valvular outcomes has not yet been demonstrated.

Abstract: Background: Diagnosis is a dynamical process, encompassing clinical presentation of pathophysiology, workup investigations and appropriate interpretations/integration of all data. Diagnostic accuracy is expected when based on multiple tests/investigations. However, when diagnosis is based on a single laboratory test, considered to be fundamental and deterministic, an early test’s error could cascade and propagates, triggering unnecessary investigations, longer hospitalisation and possible diagnostic misapplications. Finding: Up to 70% of diagnoses involve laboratory tests. Immunologically based analyses (immunoassays) have two fundamental features (a) inherently high analytical error rate than other routine tests and (b) universality, affecting measurements regardless of analyte’s nature or the immunoassay’s provider. Conclusions: Averting potentially erroneous result necessitates a paradigm shift which can be made by (a) intuitive use of a statistical paradigm (Bayesian reasoning) which will be explained by example and without equations and (b) appropriate and more use of follow up confirmatory tests available in all hospital laboratories.

Abstract: The progressive failure of pancreatic beta-cells under chronic glucolipotoxicity drives the pathogenesis of type 2 diabetes mellitus (T2DM). This metabolic stress overwhelms the folding capacity of the endoplasmic reticulum (ER), hyperactivates the unfolded protein response (UPR), engages terminal pro-apoptotic signaling (CHOP), and promotes beta-cell dedifferentiation. In this systematic review and meta-analysis, registered with PROSPERO (CRD420261370436), we evaluated the preclinical efficacy of the low-molecular-weight chemical chaperones tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) in preserving beta-cell exocytotic identity and mitigating ER stress. Following PRISMA 2020 guidelines, a systematic search of PubMed, Scopus, and Web of Science (January 2016–May 2026) identified four eligible experimental studies. Preclinical models (INS-1 and βTC-6 cell lines, Wistar rats, and C57BL/6 mice) exposed to high-fat or high-fat/high-fructose diets, cholesterol loading, or protein restriction followed by high-fat feeding showed impaired or dysregulated glucose-stimulated insulin secretion (GSIS) and upregulated ER stress markers. Co-administration of TUDCA or 4-PBA consistently reversed these defects, restoring the GSIS stimulation index and reducing pro-apoptotic markers. A hierarchical Bayesian random-effects meta-analysis estimated a robust pooled restoration ratio of 1.87 (95% credible interval [CrI]: 1.39 to 2.46), with the entire credible mass above the null (posterior probability of benefit > 0.99) and modest between-study heterogeneity. In conclusion, TUDCA and 4-PBA act as structural ER scaffolds that prevent terminal UPR activation and preserve the beta-cell exocytotic machinery, positioning them as candidate disease-modifying agents that merit confirmatory clinical evaluation.

Abstract: Background and Clinical Significance: Tirzepatide, a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes mellitus (T2DM) and obesity, has been associated with rare cases of ketoacidosis. However, tirzepatide-induced diabetic ketoacidosis (DKA) in latent autoimmune diabetes in adults (LADA) has not previously been reported. LADA accounts for approximately 8.9% of adult-onset diabetes and is frequently misdiagnosed as T2DM. Current tirzepatide prescribing information contraindicates use in type 1 diabetes mellitus (T1DM) but does not address LADA, despite shared autoimmune pathophysiology. Case Presentation: A 57-year-old woman with hypertension and LADA—initially diagnosed as T2DM in 2002 and reclassified based on a GAD65 titer >25,000 U/mL and C-peptide <0.1 ng/mL—presented with intractable vomiting two weeks after starting tirzepatide for weight management. She reported full adherence to her basal-bolus insulin regimen (insulin glargine 27 units nightly, insulin lispro 7 units three times daily). Laboratory evaluation revealed glucose 608 mg/dL, arterial pH 7.13, bicarbonate 6 mEq/L, anion gap 24 mEq/L, and beta-hydroxybutyrate 7.5 mmol/L, consistent with severe DKA. Infectious workup and troponin were negative; no alternative precipitants were identified. She was managed in the intensive care unit with intravenous fluids and insulin infusion, stabilized over two days, and discharged on hospital day three on adjusted insulin therapy. Tirzepatide was permanently discontinued. At one-month follow-up, there was no recurrence of DKA, and her HbA1c improved from 8.6% to 7.5%. Conclusions: To our knowledge, this is the first reported case of tirzepatide-induced DKA in a patient with LADA. Notably, DKA occurred despite continued basal-bolus insulin therapy, distinguishing this case from previously reported incretin-associated DKA in LADA, where insulin was concurrently discontinued. This case highlights the importance of screening for autoimmune diabetes markers (GAD antibodies and C-peptide) before initiating incretin-based therapies in patients with atypical T2DM features, and the need for close monitoring for ketosis during tirzepatide dose titration in patients with known or suspected LADA.

Abstract: Introduction: Diabetic retinopathy (DR) is а major microvascular complication of diabetes mellitus (DM). Among the established risk factors for DR, “metabolic memory” plays a key role. Its development is mainly driven by advanced glycation end-products (AGEs), some of which possess characteristic fluorescent properties. Aims: To examine the relationship between skin AGEs, noninvasively assessed through skin autofluorescence (SAF), and the presence and severity of DR in subjects with long-standing type 1 DM (T1DM) and no history of atherosclerotic cardiovascular disease. Methods: 81 subjects with T1DM and 45 healthy controls were included. All individuals underwent SAF measurements and fundus photographs were taken in subjects with T1DM. Associations between SAF, its change over time and the presence and severity of DR were analyzed. Results: A significant positive correlation was found between SAF and the severity of DR. Only SAF and renal parameters showed a significant positive association with the presence of sight-threatening DR (STDR). There was a statistically significant increase in SAF levels over 3 years in STDR. Conclusion: SAF, but not HbA1c or diabetes duration, was associated with the severity of DR. SAF may therefore represent a promising, rapid, and non-invasive biomarker for identifying individuals at increased risk of STDR.

Abstract: Objective. The present study aimed to elucidate if the metabolic effects of probiotic bacterium Hafnia alvei 4597 depend on the melanocortin receptors (MCRs) signaling. Methods. The response to a 3-week intragastric treatment with the H. alvei bacterial suspension or total protein extract was compared between genetically similar mouse sub-strains but with different sensitivity of MCRs, KK and KK.Cg-Ay/a (KK-Ay), the latter overproducing agouti protein. Results. Treatment of KK mice with H. alvei protein extract stimulated energy expenditure and carbohydrate oxidation but reduced lipid oxidation, leptin level, pancreatic weight, and hypothalamic insulin and leptin receptor mRNA expression. Live bacteria in KK mice reduced food intake and stimulated hypothalamic mRNA expression of proopiomelanocortin, agouti-related peptide, and insulin receptors. In the sub-strain KK-Ay, probiotics had no effect on the aforementioned metabolic parameters. H. alvei-based probiotics improved glucose tolerance and deceased body fat and liver glycogen in both mouse sub-strains. Activation of MC4R by H. alvei protein extract was revealed by in vitro study showing of β-arrestin recruitment. Conclusion. These findings confirm beneficial effects of the H. alvei bacteria and show that, for several parameters, the bacterial protein extract may be a more efficacious than bacterial suspension. Differential responses to the treatment between the mouse sub-strains, particularly in energy metabolism, as well as in vitro data, indicate that the effects of H. alvei are mediated by MCRs signaling.

Abstract: Background: Thalassemia represents the world’s most prevalent inherited hemoglobin disorder, affecting approximately 4.4 per 10,000 live births globally. Accurate genetic characterization is indispensable both for definitive diagnosis and for lifetime clinical monitoring. The past two decades have witnessed a paradigm shift from conventional protein-based assays toward comprehensive molecular techniques, including next-generation sequencing (NGS), third-generation (long-read) sequencing, and preimplantation genetic testing for monogenic disease (PGT-M). Objectives: (1) To systematically evaluate the molecular techniques available for confirming the diagnosis of alpha- and beta-thalassemia, including their diagnostic accuracy, indications, and limitations; (2) to examine how genotype–phenotype correlation and genetic modifier profiling inform clinical prognosis and therapeutic decision-making; and (3) to define evidence-based genetic monitoring parameters for longitudinal follow-up of patients receiving transfusions, iron chelation, and novel curative therapies including gene therapy. Methods: A comprehensive narrative review was conducted by systematically searching PubMed/MEDLINE for English-language peer-reviewed articles published between January 2000 and December 2024. Forty-three studies were ultimately included after applying predefined inclusion and exclusion criteria. Quality of included studies was assessed using SANRA (Scale for the Assessment of Narrative Review Articles). Results: HPLC and capillary electrophoresis remain first-line phenotyping tools; DNA-based confirmation is mandatory for complete genotyping. NGS-based targeted panels detect >95% of common mutations but require MLPA co-testing or long-read sequencing for structural variants. Genotype–phenotype prediction is substantially enhanced by profiling three major modifier loci: XmnI (Gγ), BCL11A, and HBS1L-MYB. PGT-M using NGS achieves near-complete genotyping accuracy (>99%) with live birth rates of 40–60% per frozen embryo transfer cycle. For patients receiving curative gene therapy (exagamglogene autotemcel / Casgevy), molecular follow-up protocols spanning 15 years are now recommended. Cardiac T2* MRI remains the most reliable non-invasive tool for iron overload follow-up, superior to serum ferritin alone. Conclusion: A tiered, genotype-informed approach—combining HPLC/CE phenotyping, targeted molecular diagnostics, genetic modifier profiling, and periodic re-evaluation—optimizes diagnostic precision and guides individualized management across the thalassemia spectrum. Integration of PGT-M and long-read sequencing into standard care pathways, alongside robust gene therapy follow-up protocols, will define the next era of thalassemia genetics.

Abstract: Phosphate is an essential element for energy metabolism, bone mineralization and chondrocyte function, particularly during growth. Its homeostasis involves complex interactions between dietary intake, renal excretion and hormonal regulation, notably through fibroblast growth factor 23 (FGF23) and growth hormone (GH). The intricate balance of phosphate and its interplay with FGF23 and GH are examined in the context of normal development and disorders such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CKD), which disrupt this balance through mechanisms of hypophosphatemia or hyperphosphatemia. FGF23 emerges as a key regulator, mediating phosphate excretion and vitamin D metabolism, while GH exerts a counter-regulatory effect by promoting phosphate reabsorption and chondrocyte proliferation. This hormonal interaction maintains skeletal integrity but becomes dysregulated in pathological conditions, leading to impaired growth and mineralization. Recent insights into the molecular mechanisms of phosphate transporters and the role of the PHEX gene in FGF23 regulation provide promising avenues for therapeutic interventions. Emerging treatments, including phosphate binders, calcitriol supplementation and anti-FGF23 antibodies such as burosumab, offer potential to address the complications of phosphate dysregulation. However, challenges remain in optimizing therapies for pediatric populations and mitigating adverse effects like vascular calcification. Future research into phosphate homeostasis, transporter dynamics and gene-based approaches holds the promise of advancing clinical outcomes for phosphate-related disorders. This review explores the dual role of phosphate in skeletal growth, highlighting its critical contributions to chondrocyte maturation, apoptosis and hydroxyapatite formation during endochondral ossification.