This paper presents a review of studies about insulin and insulin-like substances in prokaryotes, eukaryotes and fungi have been published over the last two decades, constituting an updating of our previous review (1988) which included references to invertebrate insulin or insulin-like substances both in uni- and pluricellular Monera, Protoctista, Fungii and Animal species. This present article reviews experiments and evidence obtained using modern techniques in the understanding of molecule evolution and behaviour, which confirm its very ancient molecular structure origin. The involvement of insulin-like and related material in signalling biological pathway and modulator effects is also reported.

Insulin resistance plays a major role in the pathogenesis of type 2 diabetes mellitus. The need for an effective treatment for type 2 diabetes mellitus has, therefore, become increasingly important. The ability of insulin to stimulate glucose uptake into muscle and adipose tissue is important for the maintenance of whole‐body glucose homeostasis. Glucose uptake in mammalian cells is mediated by a family of highly related facilitative glucose transporters (GLUT), and until now, 13 GLUT isoforms have already been identified in human, with their tissue specificity extensively studied. Members of the GLUT family exhibit distinct glucose transport kinetic capabilities and tissue‐specific patterns of expression that reflect energy requirements and metabolism. The insulin‐regulated glucose transporter GLUT4 is expressed mainly in insulin‐responsive tissues, i.e. white and brown adipose tissue, and in heart and skeletal muscles, where it mediates glucose uptake in response to acute insulin stimulation. Insulin resistance occurs partially from defective GLUT4 expression and/or trafficking, and as a result, blood glucose can rise to pathological levels. GLUT4 mRNA and protein are downregulated in adipose tissue in the setting of obesity and type 2 diabetes mellitus, in both rodents and humans. In contrast, skeletal muscle GLUT4 expression remains intact in these conditions, but alterations in the distribution of GLUT4 between intracellular membranes and the plasma membrane and in insulin‐stimulated translocation of GLUT4 to the plasma membrane results in impaired glucose transport. More than a decade ago, a GLUT4 knockout mouse was developed, and its phenotype was characterized. Surprisingly, the GLUT4 null mouse does not develop hyperglycemia1, and the soleus muscle from GLUT4 knockout mice retains its ability to increase the glucose uptake in response to insulin2. This evidence suggests that insulin‐sensitive GLUT, rather than GLUT4, may exist. In a recent article, Purcell et al.3 generated a transgenic mouse that overexpressed GLUT12 under a β‐actin promoter and showed that the increased expression of GLUT12 enhanced whole‐body insulin sensitivity through an increased glucose clearance rate in insulin‐sensitive tissues. GLUT12 is a member of class III glucose transporters, which preferentially transports D‐glucose and 2‐deoxy‐D‐glucose over other hexoses4. The presence of targeting motifs similar to GLUT4 and GLUT8, and localization primarily in insulin‐sensitive tissues, has led to research to clarify whether GLUT12 may represent a second insulin‐sensitive GLUT. In human skeletal muscle, GLUT12 translocates to the plasma membrane following euglycemic insulin infusion5. To further assess the function of GLUT12 as an insulin‐sensitive GLUT, Purcell et al. generated GLUT12 transgenic (TG) mice and analyzed the effects of GLUT12 overexpression on whole‐animal glucose homeostasis and insulin‐stimulated glucose clearance into peripheral tissues. GLUT12 overexpression was greatest in the brain and heart, followed by the soleus, fat, extensor digitorum longus (EDL) and liver. In the insulin‐sensitive tissues, increased GLUT12 expression ranged from 40% in the EDL to 75% in the heart. GLUT12 overexpression did not alter expression of GLUT4 in skeletal muscle and fat nor did it affect fasting glucose, but it decreased fasting insulin, suggesting improved insulin sensitivity. During glucose tolerance tests, TG mice exhibited a more rapid normalization of blood glucose than wild‐type mice, consistent with enhanced insulin sensitivity. Enhanced insulin sensitivity was more directly shown in the insulin tolerance tests. Compared with wild‐type mice, TG mice had a greater decrease in blood glucose concentration after administering insulin. The hyperinsulinemic‐euglycemic clamp confirmed enhanced insulin sensitivity, because mice that overexpressed GLUT12 required a 70% greater glucose infusion rate than wild‐type mice to maintain an eq

BRS-3 has an important role in glucose homeostasis. Its expression was reduced in skeletal muscle from obese and/or diabetic patients, and BRS-3 KO-mice developed obesity. In this work, focused on rat/human adipose tissue, BRS-3 gene-expression was lower than normal-levels in hyperlipidemic, type-2-diabetic (T2D), and type-1-diabetic rats and also in obese (OB) and T2D patients. Moreover, BRS-3 protein levels were decreased in diabetic rat and in obese and diabetic human fat pieces; but neither mutation nor even polymorphism in the BRS-3-gene was found in OB or T2D patients. Interestingly, in rat and human adipocytes, without metabolic alterations, [D-Tyr6,β-Ala11,Phe13,Nle14]bombesin6-14 -BRS-3-agonist-, as insulin, enhanced BRS-3 gene/protein expression, increased, PKB, p70s6K, MAPKs and p90RSK1 phosphorylation-levels, and induced a concentration-related stimulation of glucose transport, GLUT-4 membrane translocation and lipogenesis, exclusively mediated by BRS-3, and abolished by wortmannin, PD98059 or rapamacyn. These results confirm that BRS-3 and/or its agonist are a potential therapeutic tool for obesity/diabetes.

A pivotal metabolic function of insulin is the stimulation of glucose uptake into muscle and adipose tissues. The discovery of the insulin-responsive glucose transporter type 4 (GLUT4) protein in 1988 inspired its molecular cloning in the following year. It also spurred numerous cellular mechanistic studies laying the foundations for how insulin regulates glucose uptake by muscle and fat cells. Here, we reflect on the importance of the GLUT4 discovery and chronicle additional key findings made in the past 30 years. That exocytosis of a multispanning membrane protein regulates cellular glucose transport illuminated a novel adaptation of the secretory pathway, which is to transiently modulate the protein composition of the cellular plasma membrane. GLUT4 controls glucose transport into fat and muscle tissues in response to insulin and also into muscle during exercise. Thus, investigation of regulated GLUT4 trafficking provides a major means by which to map the essential signaling components that transmit the effects of insulin and exercise. Manipulation of the expression of GLUT4 or GLUT4-regulating molecules in mice has revealed the impact of glucose uptake on whole-body metabolism. Remaining gaps in our understanding of GLUT4 function and regulation are highlighted here, along with opportunities for future discoveries and for the development of therapeutic approaches to manage metabolic disease.

Tankyrase, a member of poly (ADP-ribose) polymerase (PARP) family, regulates various cellular pathways including wnt signaling, telomere maintenance and mitosis, has become a prime target for the development of cancer therapeutics. Inhibition of tankyrase, which leads to its increased cellular accumulation, reveal the role of tankyrase in the regulation of Glucose transporter type 4 (GLUT4) translocation and glucose homeostasis in peripheral insulin responsive tissues. While in adipocytes inhibition of tankyrase improves insulin sensitivity and glucose uptake, its inhibition in skeletal muscle leads to development of insulin resistance. Evidently further studies are required to determine the broader perspective of tankyrase in other cellular systems in regulating insulin signaling and insulin resistance. Role of tankyrase in neuronal tissues/cells has not been tested. In the present study, we investigated the effect of tankyrase inhibition in insulin-sensitive and insulin-resistant Neuro-2a cells. Here, we report that XAV939 treatment, a tankyrase inhibitor, improves insulin-stimulated glucose uptake in insulin-sensitive as well as in insulin-resistant neuronal cells via AMP-activated protein kinase (AMPK) - AKT Substrate of 160 kDa (AS160) mediated pathway without affecting the phosphorylation/activation of AKT. AMPK inhibition by Compound C repressed XAV939 treatment mediated increase in glucose uptake, confirming the role of tankyrase in glucose uptake via AMPK. We show fo

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson's disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4-NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic-neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress-characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood-brain barrier disruption-drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD.

ABSTRACT: Glucose Transporter 4 (GLUT4) is a crucial protein facilitating glucose uptake and metabolism across cell membranes in mammals. However, information on GLUT4 in birds has historically been limited. In this study, we investigated the dynamic expression profile of chicken GLUT4 using real-time quantitative PCR (RT-qPCR) and examined its potential effects and mechanisms via GLUT4 overexpression and RNA sequencing (RNA-seq) in chicken primary skeletal muscle satellite cells (CP-SMSCs). Our results demonstrated that chicken GLUT4 is differentially expressed across tissues, with predominant expression in skeletal muscles, and across developmental stages of CP-SMSCs, with notable upregulation during the phases of cell proliferation and early differentiation. Notably, 0.1 μM insulin for 60 min significantly elevated the expression of GLUT4 in CP-SMSCs (P < 0.05). GLUT4 overexpression in CP-SMSCs promoted cell proliferation, as evidenced by Cell Counting Kit-8 (CCK-8) (P < 0.05) and 5-Ethynyl-2′-Deoxyuridine (EDU) assays (P < 0.05), and enhanced glucose consumption following 0.1 μM insulin treatment (P < 0.05). However, it inhibited glucose consumption 12 h after the addition of 5 g/L glucose (P < 0.05). After overexpressing GLUT4, we identified 302 differentially expressed genes (DEGs) in CP-SMSCs, with 134 upregulated and 168 downregulated. These DEGs are primarily enriched in pathways such as oxidative phosphorylation, ribosome, cardiac muscle contraction, ATP metabolic p

liver to other tissues in the body via the bloodstream. Cellular glucose uptake is primarily regulated by insulin, a hormone produced in the pancreas. The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (154 lb) human, approximately four grams of dissolved glucose (also called "blood glucose") is maintained in the blood plasma at all times. Glucose that is not circulat The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (154 lb) human, approximately four grams of dissolved glucose (also called "blood glucose") is maintained in the blood plasma at all times. Glucose that is not circulating in the blood is stored in skeletal muscle and liver cells in the form of glycogen; in fasting individuals, blood glucose is maintained at a constant level by releasing just enough glucose from these glycogen stores in the liver and skeletal muscle in order to maintain homeostasis. Glucose can be transported from the intestines or liver to other tissues in the body via the bloodstream. Cellular glucose uptake is primarily regulated by insulin, a hormone produced in the pancreas. Once inside the cell, the glucose can now act as an energy source as it undergoes the process of glycolysis. In humans, properly maintained glucose levels are necessary for normal function in a number of tissues, including the human brain, which consumes approximately 60% of blood glucose in fasting, sedentary individuals. A persistent elevation in blood glucose leads to glucose toxicity, which contributes to cell dysfunction and the pathology grouped together as complications of diabetes. Glucose levels are usually lowest in the morning, before the first meal of the day, and rise after meals for an hour or two by a few millimoles per litre. Abnormal persistently high glycemia is referred to as hyperglycemia; low levels are referred to as hypoglycemia. Diabetes mellitus is characterized by persistent hyperglycemia from a variety of causes, and it is the most prominent disease related to the failure of blood sugar regulation. Diabetes mellitus is also characterized by frequent episodes of low sugar, or hypoglycemia. There are different methods of testing and measuring blood sugar levels. Drinking alcohol causes an initial surge in blood sugar and later tends to cause levels to fall. Also, certain drugs can increase or decrease glucose levels.

BACKGROUND AND AIMS: Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown. METHODS: Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection. RESULTS: Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in

Incubation of placental tissue with 10(-8) M insulin did not influence D-glucose efflux from the BBM vesicles. Finally, direct incubation of the membranes with insulin had no effect on the glucose influx into these membrane vesicles. We conclude that insulin, at physiological concentrations, enhances glucose uptake by the BBM, and that such a regulation might contribute to the glucose homeostasis in the fetal circulation, independent of the maternal variations in glycemia. Published in Molecular and cellular endocrinology (1990)

The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet dysfunction declines. Therapeutic interventions either improve islet dysfunction and raise plasma insulin levels, reduce hepatic glucose production, or improve the efficiency of tissue glucose uptake. All result in a decline in the fasting glucose level regardless of the cause of hyperglycemia. It is concluded that non-insulin-dependent diabetes mellitus is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role. Published in The American journal of medicine (1988)

Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms in different organs or "stations" of its bodily journey. In this Beyond the Cell review, we focus on these five stages of the journey of insulin through the body and the captivating cell biology that underlies the interaction of insulin with each organ. We first analyze insulin's biosynthesis in and export from the β-cells of the pancreas. Next, we focus on its first pass and partial clearance in the liver with its temporality and periodicity linked to secretion. Continuing the journey, we briefly describe insulin's action on the blood vasculature and its still-debated mechanisms of exit from the capillary beds. Once in the parenchymal interstitium of muscle and adipose tissue, insulin promotes glucose uptake into myofibers and adipocytes, and we elaborate on the intricate signaling and vesicle traffic mechanisms that underlie this fundamental function. Finally, we touch upon the renal degradation of insulin to end its action. Cellular discernment of insulin's availability and action should prove critical to understanding its pivotal physiological functions and how their failure leads to diabetes.

hormones insulin and glucagon. Insulin is a hormone that regulates glucose levels, allowing the body's cells to absorb and use glucose. Without it, glucose cannot Glucose is a sugar with the molecular formula C6H12O6. It is the most abundant monosaccharide, a subcategory of carbohydrates. It is made from water and carbon dioxide during photosynthesis by plants and most algae. It is used by plants to make cellulose, the most abundant carbohydrate in the world, for use in cell walls, and by all living organisms to make adenosine triphosphate (ATP), which is u Glucose is a ubiquitous fuel in biology. It is used…

agonists, these agents inhibit insulin-stimulated glucose transport. This inhibition results … diverse as neurotransmission, cellular metabolism, secretion, cellular differentiation and growth … effects on insulin secretion were assessed. CL produced a large increase in insulin secretion

significantly higher levels of plasma glucose and insulin area after glucose ingestion than those with low VFAs … dysfunction is caused by cellular insulin resistance or factors related insulin resistance and may be a … protein regulation in Hep G2 cells. Insulin negatively regulates MTP gene expression. J Lipid Res 36:1073-1081