ResearchPad - islets-livers-placenta-and-vasculature—the-multitissue-impact-of-diabetes https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR14-01 FSTL3 Neutralizing Antibodies Restore Function to Diabetic Mouse and Human Islets: A New Approach for Treating Diabetes]]> https://www.researchpad.co/article/elastic_article_6947 Activin, GDF11 and myostatin are structurally related members of the TGFbeta superfamily of growth factors with many biological roles in animal models and humans. Their actions are neutralized by extracellular proteins such as follistatin and follistatin like-3 (FSTL3). We have previously demonstrated that genetic inactivation of Fstl3 results in enlarged pancreatic islets containing increased numbers of beta cells that produce more insulin in response to glucose compared to wild type litter mates. We further discovered that at least some of these new beta cells arise via transdifferentiation from alpha cells. We also demonstrated that functional human islets from normal donors produce very high levels of activin. In contrast, activin biosynthesis is vastly reduced and FSTL3 synthesis is significantly increased in human islets from diabetic donors suggesting that activin is critical for normal insulin production. This was substantiated by direct treatment of human diabetic islets with activin which restored their response to glucose. These observations support the hypothesis that an FSTL3 neutralizing antibody would constitute a novel therapeutic approach to curing diabetes through restoring beta cell function as well as accelerating generation of new beta cells through transdifferentiation. To test this hypothesis, we produced a mouse monoclonal antibody that neutralized hFSTL3 (FP-101), thereby releasing bioactive activin, GDF11, and myostatin. We have now tested this antibody for biological activity in vitro on mouse and human islets. We used islets from high fat diet (HFD) treated mice to model diabetes-inducing effects of obesity as well as 24-hour incubation in hyperglycemic (33 mM glucose) medium to create human islets that lose responsiveness to high glucose as a model for human diabetes. In mouse islets we found that stimulation of normal (chow diet) islets by high glucose produced a stimulation index (SI) of 3.5 that was reduced to 2 in HFD islets. Treatment with activin, FP-101, or a commercial polyclonal antibody to mFSTL3 all increased response of HFD islets to elevated glucose and partially restored SI to normal levels. In human islets, hyperglycemia eliminated the normal (2.5 SI) response to high glucose while activin or FP-101 treatments dose-responsively restored this response. These results demonstrate that anti-FSTL3 therapy can restore function to compromised beta cells from mouse and human diabetes models. The observation that activin has the same action as anti-FSTL3 antibody indicates that FP-101 works through enhancing the activin signaling pathway. Finally, these results demonstrate that the FSTL3-activin pathway is an important regulator of beta cell function in humans as well as mice, supporting further development of this therapy as a diabetes treatment.

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<![CDATA[OR14-03 The Transcriptional Coactivation Function of EHMT2 Restricts Chronic Glucocorticoid Exposure Induced Insulin Resistance]]> https://www.researchpad.co/article/elastic_article_6870 Glucocorticoids are required for metabolic adaptations during times of stress. However, chronic glucocorticoid exposure is associated with metabolic disorders such as insulin resistance. Glucocorticoids mainly convey their signals through an intracellular glucocorticoid receptor (GR). GR is a transcription factor that requires interactions with transcriptional coregulators to modulate the transcription of GR primary target genes, which in turn regulate specific aspects of physiology. Euchromatic Histone Methyltransferase 2 (Ehmt2) is a transcriptional coregulator for GR that can act as a corepressor or a coactivator. We found that glucocorticoid-induced insulin resistance was exacerbated when Ehmt2 levels were reduced in the liver. Intriguingly, this phenotype resulted from the transactivation function of Ehmt2. This is because a mutation at the lysine 182 automethylation site, which is required for the coactivation but not the corepression function of Ehmt2, results in similar exacerbated GC-induced insulin resistance. These results suggest that Ehmt2 coactivation dependent GR primary target genes restrict the extent of glucocorticoid-induced insulin resistance. Gene expression analysis identified Dusp4 (a.k.a. Mkp-2) as an Ehmt2 coactivation dependent GR-activated gene, which when overexpressed in liver, attenuated glucocorticoid-induced insulin resistance. Thus, we have identified a novel GR-Ehmt2-Dusp4 axis that plays a key role in controlling the extent of the development of insulin resistance. Notably, the classical view of how GC induce hepatic insulin resistance is that GR activates genes that inhibit insulin signaling and enhance hepatic gluconeogenesis. Our study, however, provides a revolutionary concept in which the extent of GC-induced insulin resistance is controlled by the balance of GR-activated genes that promote insulin sensitivity or insulin resistance.

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<![CDATA[OR14-02 Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response]]> https://www.researchpad.co/article/elastic_article_6016 The circadian clock is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolism with nutritional state and the sleep-wake cycle. Epidemiologic and genetic studies indicate circadian disruption as a risk factor in the development of diabetes. We have demonstrated that conditional ablation of the β cell clock in adult life leads to hypoinsulinemic diabetes, and through mRNA-sequencing in mouse and human islets we revealed clock control of gene networks involved in insulin secretion, nutrient sensing, and exocytosis. A remaining question is: How does the core molecular clock modulate time-of-day dependent chromatin state to regulate pancreatic islet response to glucose and insulin secretagogues? Here we report that loss of the pancreatic β cell molecular clock results in closed chromatin at cAMP-responsive gene regulatory elements and dysregulated cAMP-dependent coregulator recruitment following cAMP agonism, consistent with a role for the molecular clock in mediating cell response to environmental stimuli. Further, tandem analyses of ATAC- and ChIP-sequencing in synchronized islets revealed dynamic chromatin accessibility across the 24-hour cycle at genes regulating insulin secretion and at genomic regions enriched for signal-inducible and circadian transcription factor motifs. Our genome-wide sequencing reveals a new role for the clock in global chromatin remodeling underlying the incretin response in pancreatic β cells.

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<![CDATA[OR14-05 Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice]]> https://www.researchpad.co/article/N5bee7ad1-85ac-4fb4-b98c-c690e1f77d8f <![CDATA[OR14-04 A Novel ERRα-Dependent Insulin Signaling Pathway]]> https://www.researchpad.co/article/N89dbbc83-6805-4cf8-8b5a-98ce76ede256 <![CDATA[OR14-06 Inhibition of Protein Kinase C-beta2 Phosphorylation Restores Nuclear Factor-Kappa B Activation and Improves Peripheral Arterial Disease in Diabetes]]> https://www.researchpad.co/article/N36519875-21fb-4e36-9492-b00099ecde5f <![CDATA[OR14-07 Association Between Placental Glucose Uptake and Protein O-Glcnacylation and Birth Outcomes in Obese Non-Diabetic Mothers]]> https://www.researchpad.co/article/N4452e1c8-e394-4662-aa30-6ddb6a7204ab