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Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151588 | GEO | 2020/07/28

REPOSITORIES: GEO

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Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

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

Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

2014-04-01 | GSE48815 | GEO

Interruption of Hepatic Glucagon Signaling Reveals a Hepatic-α-Islet Cell Axis Where L-Glutamine Stimulates α-Cell Proliferation

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

Islet Sympathetic Innervation and Islet Neuropathology in Patients with Type 1 Diabetes

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

13C15N – Glucagon-based novel isotope dilution mass spectrometry method for measurement of glucagon metabolism in humans

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

Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes

Project description:Hyperinsulinemia often precedes type 2 diabetes but its role in disease progression is unknown. Palmitoylation, a protein modification implicated in regulated exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). We found altered APT1 biology in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic human islets caused insulin hypersecretion. Chow fed global and islet specific APT1 knockout mice had enhanced glucose tolerance due to islet autonomous increased glucose-stimulated insulin secretion. APT1 deficiency did not affect islet calcium dynamics but prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Knockdown of Scamp1 caused insulin hypersecretion. APT1 deficient insulinoma cells subjected to nutrient excess had increased apoptosis, and expression of a mutated Scamp1 incapable of being palmitoylated in APT1 deficient cells rescued insulin hypersecretion and nutrient induced apoptosis. Compared to APT1 sufficient controls, high fat fed islet specific APT1 knockout mice and global APT1 deficient db/db mice showed increased -cell failure. These findings suggest that the depalmitoylation enzyme APT1 is regulated in human islets, and that APT1 deficiency causes insulin hypersecretion leading to -cell failure, modeling the evolution of some forms of human type 2 diabetes.

2023-11-05 | PXD038554 | Pride

MicroRNA-21 Promotes Pancreatic β cell Function through Modulating Glucose Uptake

Project description:Pancreatic β cell dysfunction greatly contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we studied the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We found that miR-21βKO mice developed glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies revealed that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets resulted in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrated that delivery of miR-21 into the pancreas of type 2 diabetic db/db mice is able to promote Glut2 expression and significantly reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the adaptation of pancreatic β cell function in type 2 diabetes.

2022-05-16 | GSE191194 | GEO

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Project description:Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient cues adapt insulin secretion by modulating chromatin state and transcription of genes regulating β-cell nutrient sensing and metabolism. Feeding stimulates histone acetylation at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation, features we also observed in the db/db model of chronically increased insulin demand. Moreover, genetic variants associated with fasting glucose levels and type 2 diabetes risk are enriched at LSD1-bound sites in human islets, suggesting interindividual variation in β-cell functional adaptation in humans. These findings reveal nutrient state-dependent modulation of the islet epigenome and identify Lsd1 as a regulator of feeding-stimulated chromatin modification and adaptive insulin secretion.

2023-02-24 | GSE134901 | GEO

Benefits of a 6 week supplementation of sebacic acid on a mouse model of type 2 diabetes (db/db mice)

Project description:This study aimed at investigating the impact of chronic ingestion of sebacic acid (SA), a 10 carbons medium-chain dicarboxylic acid, on glycemic control in a mouse model of type 2 diabetes (db/db mice). Three groups of 15 mice were fed for 6 weeks either a chow diet (Ctrl), or a chow diet supplemented with 1.5% or 15% (SA1.5% and SA15% resp.) energy from SA. Fasting glycemia was measured once a week and HbA1c before and after supplementation. An oral glucose tolerance test (OGTT) was performed at the end of the supplementation. Gene expression was determined by transcriptomic analysis on the liver of the Ctrl and SA15% groups. Results-After 42 days of supplementation, fasting glycemia and HbA1c were ~70% and ~25% lower in the SA15% group compared to other groups showing a beneficial effect of SA on hyperglycemia. During OGTT, blood glucose area under the curve (AUC) was reduced after SA15% compared to other groups. This effect was associated with a tendency for an improved insulin response. In the liver, Pck1 and FBP mRNA were statistically decreased in the SA15% compared to Ctrl suggesting a reduced hepatic glucose output induced by SA. Conclusions-Dietary supplementation of SA largely improves glycemic control in a mouse model of type 2 diabetes. This beneficial effect may be due (1) to a reduced hepatic glucose output resulting from transcriptional down regulation of key gluconeogenesis genes and (2) to an improved glucose induced-insulin secretion. Microarray analysis of 6-8 wk old male BKS.Cg-m+/+Leprdb/J 000642 db/db mice. 2 groups. n=15/group: 1) Control group. 2) Sebacic acid high dose group - 15% (77.6g/kg food, â??9g/kg body weight per day).

2010-10-29 | E-GEOD-21083 | biostudies-arrayexpress

IRS1 plays a dominant role in regulating pancreatic alpha cell function

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

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