Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA669991 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12828500_1.fastq.gz | Fastqsanger.gz | |||
| SRR12828500_2.fastq.gz | Fastqsanger.gz | |||
| SRR12828501_1.fastq.gz | Fastqsanger.gz | |||
| SRR12828501_2.fastq.gz | Fastqsanger.gz | |||
| SRR12828502_1.fastq.gz | Fastqsanger.gz |
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2021-11-24 | GSE159527 | GEO
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53754 | GEO
Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.
2014-10-15 | GSE53753 | GEO
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2014-10-15 | E-GEOD-53753 | biostudies-arrayexpress
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.
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