Dataset Information

Deletion of Protein Kinase D1 in Pancreatic ?-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

ABSTRACT: ??-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional ?-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the ?-cell and plays a critical role in the control of insulin secretion. However, the role of ?-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using ?-cell-specific, inducible PKD1 knockout mice (?PKD1KO), we examined the role of ?-cell PKD1 under basal conditions and during high-fat feeding. ?PKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in ?-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet-fed ?PKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the ?-cell adaptive secretory response to high-fat feeding in mice.

SUBMITTER: Bergeron V

PROVIDER: S-EPMC5741145 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

Bergeron Valérie V Ghislain Julien J Vivot Kevin K Tamarina Natalia N Philipson Louis H LH Fielitz Jens J Poitout Vincent V

Diabetes 20171016 1

Ββ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. U ...[more]

PMID: 29038309

Similar Datasets

Project description:BACKGROUND/OBJECTIVE:The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects. METHODS:In Cdkal1-deficient (Cdkal1?/?) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese. PRINCIPAL FINDINGS:On a standard diet, Cdkal1?/? mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1?/? mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P?=?0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1?/? mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1?/? mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1?/? mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI. CONCLUSIONS:Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.

Project description:BACKGROUND:Previously, we found a significant relationship in a rat study between energy intake and bile acid (BA) metabolism especially 12?-hydroxylated (12?OH) BAs. The present study was designed to reveal relationships among BA metabolism, glucose tolerance, and cecal organic acids in rats fed a high-fat and high-sucrose diet (HFS) by using multivariate and multiple regression analyses in two types of glucose tolerance tests (GTTs). METHODS:Male WKAH/HkmSlc rats were fed with a control or a HFS for 13?weeks. Oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were performed at week 9 and 11, respectively. BAs were analyzed by using ultra high-performance liquid chromatography-mass spectrometry. Organic acid concentrations in cecal contents were analyzed by using ultra high-performance liquid chromatography with post-column pH buffered electric conductivity method. RESULTS:A positive correlation of aortic 12?OH BA concentration was observed with energy intake and visceral adipose tissue weight. We found that an increase of 12?OH BAs in enterohepatic circulation, intestinal contents and feces in the HFS-fed rats compared to those in control rats regardless of no significant increase of total BA concentration in the feces in the test period. Fecal 12?OH BA concentration was positively correlated with maximal insulin level in OGTT and area under curve of insulin in IPGTT. There was a positive correlation between aortic 12?OH BAs concentration and changes in plasma glucose level in both OGTT and IPGTT. In contrast, a decrease in the concentration of organic acids was observed in the cecal contents of the HFS-fed rats. Multiple linear regression analysis in the IPGTT revealed that the concentrations of aortic 12?OH BA and cecal acetic acid were the predictors of insulin secretion. Moreover, there was a positive correlation between concentration of portal 12?OH BAs and change in insulin concentration of peripheral blood in the IPGTT. CONCLUSION:The distribution analysis of BA compositions accompanied by GTTs revealed a close relationship between 12?OH BA metabolism and insulin secretion in GTTs in rats.

Dataset Information

Deletion of Protein Kinase D1 in Pancreatic ?-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

Publications

Deletion of Protein Kinase D1 in Pancreatic β-Cells Impairs Insulin Secretion in High-Fat Diet-Fed Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure