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Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults

ABSTRACT: Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults

PROVIDER: PRJNA297625 | ENA |

REPOSITORIES: ENA

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Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults [ChIP-seq]

Project description:Although mutations in the nuclear receptor HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) nearly two decades ago, the mechanisms by which HNF4A regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to an unexpected role for dHNF4 within mitochondria to directly regulate mtDNA transcription, while also promoting the expression of nuclear genes involved in oxidative phosphorylation (OXPHOS) and Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward OXPHOS and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.

2015-11-28 | GSE73675 | GEO

Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults [RNA-seq]

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Drosophila HNF4 promotes glucose-stimulated insulin secretion and increased mitochondrial function in adults

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-11-28 | GSE73676 | GEO

The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults.

Project description: Not available

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Transcription profiling of HNF4 alpha null mice to investigate the phenotype of dis-regulated insulin secretion and abnormal beta cell growth

Project description:The aim of this experiment was to use microarray analysis to examine the phenotype of dis-regulated insulin secretion and abnormal beta cell growth in HNF4 alpha null mice. These mice show impaired glucose tolerance and elevated fasting and fed plasma insulin levels. Rana Gupta from Klaus Kaestner's Lab extracted RNA from isolated islets. Three controls and five mutants were provided for the study.

2006-09-05 | E-CBIL-6 | biostudies-arrayexpress

GDF15 Secretion is Increased in Resposne to Skeletal Muscle Contraction and Potentiates Glucose-Stimulated Insulin Release in Pancreatic β-cells

Project description:Lifestyle intervention including exercise restores glucose homeostasis and pancreatic β-cell function in type 2 diabetes (T2D). However, exercise compliance is a challenge. Novel alternative or adjuvant approaches are necessary. During exercise, the contracting skeletal muscle acts as endocrine organ via the secretion and endocrine signaling of functional proteins. We postulated that contracting skeletal muscle secretes proteins that target pancreatic β-cells and regulate insulin secretion and glucose metabolism. To test this hypothesis, we used an in vitro cell-based skeletal muscle contraction system to uncover proteins released in the muscle secretome. Using an RNAseq screen, we identified growth differentiation factor 15 (GDF15) as a lead candidate. β-cells, human pancreatic islets, and C57BL/6J mice exposed to acute GDF15 treatment exhibited increased glucose-stimulated insulin secretion, and the mechanism involved activation of the insulin release pathway. Chronic GDF15 treatment in db/db mice reduced insulin resistance and preserved pancreatic PDX-1 expression. Consistently, plasma GDF15 increased concurrently with C-peptide prior to the onset of chronic hyperglycemia in humans with pre-diabetes. In addition, in humans with T2D, exercise-induced GDF15 was associated with enhanced β-cell function. These findings support GDF15 as a potential therapeutic target for type 2 diabetes and associated co-morbidities.

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Pim3 negatively regulates glucose-stimulated insulin secretion.

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Insulin enhances glucose-stimulated insulin secretion in healthy humans.

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Checkpoint Kinase 2 Controls Insulin Secretion and Glucose Homeostasis

Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.

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Deletion of Histone Deacetylase 3 in Adult Beta Cells Improves Glucose Tolerance via Increased Insulin Secretion

Project description:Objective: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and -cell knockout islets. Results: HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions: HDAC3 plays an important role in regulating insulin secretion in vivo and therapeutic intervention may improve glucose homeostasis.

2016-11-26 | GSE90531 | GEO

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