Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA211832 | ENA |
REPOSITORIES: ENA
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Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM.
2014-04-01 | GSE48815 | GEO
Project description:Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), exhibiting opposing effects on cell signaling, feeding, and hormonal secretion compared to ghrelin. However, despite an emerging interest in LEAP2’s physiology and pharmacology, its endocrine regulation remains unclear. Here, we show that plasma LEAP2 levels decrease significantly upon supraphysiological glucagon infusions during pancreatic somatostatin clamps in humans and that a hypercaloric diet and a sedentary lifestyle for two weeks impair this effect. Moreover, in patients with obesity and type 2 diabetes, plasma LEAP2 levels decrease significantly following glucagon infusion. Additionally, we find that postprandial upregulation of LEAP2 in mice is insulin-dependent. In the postprandial state, insulin receptor antagonism offsets the upregulation of hepatic Leap2expression and plasma LEAP2 levels. Finally, we show that insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression. This coincides with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus in the liver. Collectively, these findings implicate insulin and glucagonin the regulation of LEAP2 and highlight the need for further investigations into the endocrine mechanisms both upstream and downstream of LEAP2.
2025-02-10 | GSE287171 | GEO
Project description:Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.
2020-07-28 | GSE151588 | GEO
Project description:Inappropriate glucagon secretion deteriorates glycemic control in type 1 and type 2 diabetes. While insulin is known to regulate glucagon secretion via its receptor in alpha cells, the role of downstream proteins and signaling pathways underlying the actions of insulin are not fully defined. Using in vivo (knockout) and in vitro (knockdown) studies targeting insulin receptor substrate (IRS) proteins, we compared the relative roles of IRS1 versus IRS2 in regulating alpha cell function. Alpha cell-specific IRS1 knock out (alpha IRS1KO) mice exhibit glucose intolerance and inappropriate glucagon suppression during glucose-tolerance tests. In contrast, alpha cell-specific IRS2 knock outs (alpha IRS2KO) manifest normal glucose tolerance and suppression of glucagon secretion after glucose administration. Alpha cell lines with stable knockdown of IRS1 (alpha IRS1KD) are unable to repress glucagon mRNA expression and exhibit reduction in phosphorylation of AKT. However, glucagon mRNA expression was suppressed in response to insulin stimulation in a stable IRS2 knock down alpha cell line (alpha IRS2KD). Alpha IRS1KD cells also display suppressed global protein translation including glucagon, impaired cytoplasmic Ca2+ response and mitochondrial function. These data argue for IRS1 as a dominant regulator of pancreatic alpha cell function.
2021-04-07 | GSE130329 | GEO
Project description:Current treatments for type 1 diabetes (T1D) focus on optimizing insulin replacement. We demonstrate the therapeutic potential of the large secreted protein fraction from brown adipose tissue (BAT), independent of insulin. This secreted fraction mediates insulin receptor-dependent recovery of euglycemia in diabetic nonobese diabetic (NOD) mice by suppressing glucagon secretion. It also promotes white adipocyte differentiation and browning, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. From this fraction, we identify nidogen-2 as a brown adipocyte-secreted factor that reverses hyperglycemia in T1D NOD, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the secreted fraction. These findings provide proof of principle that the pleiotropic effects of BAT-derived peptides represent a novel approach to diabetes management.
2025-03-13 | PXD051972 | Pride
Project description:Glucagon is secreted from pancreatic α-cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma by high-resolution-proteomics, we identified several glucagon variants among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 was secreted in obese subjects before and as well after gastric bypass surgery with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β-cells demonstrated that PG 1-61 dose-dependently increased levels of cAMP, through the glucagon receptor, and increased insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. As a consequence, PG 1-61 increased blood glucose and plasma insulin and decreased plasma levels of amino acids in vivo. Glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.
2017-10-20 | PXD005677 | Pride
Project description:Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac b-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.
2021-08-09 | GSE181674 | GEO
Project description:Decreasing glucagon action lowers blood glucose and may be a useful therapeutic approach for diabetes. However, interrupted glucagon signaling in mice leads to hyperglucagonemia and α-cell hyperplasia. We show using islet transplantation, mouse and zebrafish models, an in vitro islet culture assay that a hepatic-derived, circulating factor in mice with interrupted glucagon signaling stimulates α-cell proliferation, which was dependent on mTOR signaling and the FoxP transcription factors. α-cells of transplanted human islets also proliferated in response to this signal in mice. A combination of liver transcriptomics and serum fractionation with proteomics/metabolomics found changes in hepatic gene expression relating to amino acid catabolism predicting the observed increase in serum amino acid levels. Amino acid concentrations that mimicked the levels in mice with interrupted glucagon signaling, specifically L-glutamine, stimulated α-cell proliferation. These results indicate a hepatic-α-islet cell axis where glucagon regulates serum amino acid availability and L-glutamine regulates α-cell proliferation via mTOR-dependent nutrient sensing.
2017-03-31 | GSE89035 | GEO
Project description:Glucagon serves as an important regulatory hormone for regulating blood glucose concentrations with tight feedback control with insulin and glucose. There are critical gaps in our understanding of glucagon kinetics, pancreatic α cell function and intra-islet feedback network that are disrupted in type 1 diabetes. This is important for translational research applications of evolving dual-hormone (insulin+glucagon) closed-loop artificial pancreas algorithms and their usage in type 1 diabetes. Thus, it is important to accurately measure glucagon kinetics in vivo and to develop robust models of glucose-insulin-glucagon interplay that could inform next generation of artificial pancreas algorithms.
2022-06-09 | PXD028715 | Pride