REVIEW | doi:10.20944/preprints202212.0276.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Biguanides; Antihyperglycemic agents; Liver alpha-cell axis; gluconeogenesis; Protein metabolism; insulin sensitivity
Online: 15 December 2022 (08:37:28 CET)
Metformin, the treatment of first choice in type 2 diabetes (T2D), is known to mainly act by decreasing endogenous glucose production (EGP) in the liver. Paradoxically, in the last decade several reports documented increased EGP after metformin treatment. This increase, was often attributed to pronounced rises in glucagon, consistent with counter-regulatory response to the glucose lowering effect of metformin. However, considering that hyperglucagonemia, but not hypoinsulinemia, is a main driver of EGP in T2D, increased EGP should have been a common finding. This observation, together with the finding that metformin antagonizes glucagon effects on energy expenditure and protein synthesis, concurrently to its effects on EGP and the emerging evidences demonstrating increased branched chain and gluconeogenic amino acids in response to metformin treatment may points to a liver alpha-cell skeletal muscle cross talk similar to that observed in the liver-alpha cell axis. Here, we provide a mechanistic perspective to this latter possibility, based on mechanistic studies of metformin’s transcriptional targets; retaining thus its glucagon antagonistic and presumably anti-gluconeogenic effects on liver and attributing the increase in EGP to renal gluconeogenesis. We finally discuss how increased EGP might reflect an adverse response to metformin treatment, providing support from clinical and epidemiological data.
REVIEW | doi:10.20944/preprints201810.0166.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: FTO; liver; gluconeogenesis; lipogenesis; glucose; insulin; type 2 diabetes; non-alcoholic fatty liver disease
Online: 9 October 2018 (03:52:49 CEST)
Common genetic variants of the fat mass and obesity associated (FTO) gene are strongly associated with obesity and type 2 diabetes. FTO is ubiquitously expressed, but appears to have tissue-specific roles. Earlier studies have focused on the role of hypothlamic FTO in the regulation of metabolism. However, it appears that FTO plays a role in the regulation of metabolism in a tissue-specific manner. Recent studies suggest that expression of hepatic FTO is regulated by metabolic signals such as nutrients and hormones and altered FTO levels in liver affects glucose and lipid metabolism. This review outlines recent findings on hepatic FTO in the regulation of metabolism, with particular focus on hepatic glucose and lipid metabolism. It is proposed that abnormal activity of hepatic signaling pathways involving FTO links metabolic impairments such as obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Therefore, a better understanding of these pathways may lead to therapeutic approaches to treat these metabolic diseases by targeting hepatic FTO. The overall goal of this review is to place FTO within the context of hepatic regulation of metabolism.
REVIEW | doi:10.20944/preprints202009.0299.v1
Subject: Biology, Physiology Keywords: Lactate Shuttle; Lactate; Exercise; Postabsorptive Metabolism; Postprandial Metabolism; Gene Adaptation; Muscle; Fiber Type; Gluconeogenesis; Glycogenolysis
Online: 13 September 2020 (16:31:28 CEST)
After a Century it is time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling as an important component of intermediary metabolism in vivo. Cell-Cell and intracellular Lactate Shuttles fulfill purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where roles of driver and recipient cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristic such as improved physical work capacity, metabolic flexibility and cognition. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signaling and shuttling are dysregulated as occur in illness and injury. Like a Phoenix, lactate rises again in importance in 21st Century Biology.
REVIEW | doi:10.20944/preprints201806.0163.v2
Subject: Life Sciences, Molecular Biology Keywords: SIRT6, Diabetes, Gluconeogenesis, Cancer, Aging, Heart Disease, Pharmacological SIRT6 Inhibitor, Cardiac Hypertrophy, Tumorigenesis, Neurodegeneration, Neurodegenerative Diseases, AD
Online: 29 August 2018 (13:04:23 CEST)
SIRT6 is a NAD+ dependent enzyme and stress response protein that has sparked the curiosity of a plethora of researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in several different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses and so on. Only in recent times however did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles and structure . Even until very recently, SIRT6 was known more for chromatin signaling but being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases namely, diabetes, cancer, neurodegenerative diseases and heart disease has been demonstrated. It is pivotal to explore the mechanistic workings of SIRT6 since future research may hold the key to engendering strategies, involving SIRT6, that may have significant implications for human health and expand upon possible treatment options. In this review, we are primarily concerned with exploring the latest understanding of SIRT6 and how it can alter the course of several life-threatening diseases that cripple today’s society such as processes related to aging, cancer, neurodegenerative diseases, heart disease and diabetes. In addition, SIRT6 has shown to be involved in liver disease, inflammation and bone related issues but more emphasis is given to the former. Lastly, any recent promising pharmacological investigations and study of potential therapeutic targets are also delineated in this review.
Subject: Life Sciences, Biochemistry Keywords: glucose; glycogen; gluconeogenesis; early life adversity; acute stress; chronic stress; psychosocial stress; hypothalamus-pituitary-adrenal axis; ageing; immuno-senescence; inflamm-ageing; Developmental origins of health and disease
Online: 23 March 2021 (09:04:41 CET)
The physiological response to a psychological stressor broadly impacts energy metabolism. In-versely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA) and sympathetic nervous system activation. Glu-cocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of ener-gy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physi-ological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunc-tion, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothe-sise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.