3 years ago

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

Valérie Bergeron, Natalia Tamarina, Jens Fielitz, Louis H Philipson, Vincent Poitout, Kevin Vivot, Julien Ghislain
Beta-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 beta-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the beta cell and plays a critical role in the control of insulin secretion. However, the role of beta-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using beta-cell specific, inducible PKD1 knock-out mice (βPKD1KO), we examined the role of beta-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under chow diet presented no significant difference in glucose tolerance or insulin secretion compared to mice expressing the Cre transgene alone; however, when compared to wild-type mice, both groups developed glucose intolerance. Under high-fat diet, deletion of PKD1 in beta 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 fed βPKD1KO mice, without changes in islet mass. This study demonstrates an essential role for PKD1 in the beta-cell adaptive secretory response to high-fat feeding in mice.

Publisher URL: http://doi.org/10.2337/db17-0982

DOI: 10.2337/db17-0982

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