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

Diabetes. 2018 Jan;67(1):71-77. doi: 10.2337/db17-0982. Epub 2017 Oct 16.

Abstract

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. Using β-cell-specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO 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 β-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 βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.

MeSH terms

  • Animals
  • Blotting, Western
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat / adverse effects
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Glucose Tolerance Test
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*

Substances

  • Insulin
  • protein kinase D
  • Protein Kinase C