Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms

Abstract

SUMMARY Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

“…In a b-cell line and in whole islets, disruption of Ofd1 and Bbs4 leads to decreased activation of two major nodes of the insulin signalling network, the p85/p55 regulatory subunits of PI3-kinase and the serine/threonine kinase Akt. A reduction of SNARE proteins has been reported in PI3K-signalling-deficient mice 42 and preassembled t-SNARE complexes have been implicated in first phase insulin secretion 44 . We found a reduction in SNARE components Snap25 and Syntaxin1A, both targets of PI3K/FoxO1 transcriptional regulation.…”

“…Pik3r2 À / À mice with a b-cell-specific deletion of Pik3r1 manifest marked glucose intolerance, at least partially due to a loss of acute insulin secretion when challenged with intraperitoneal glucose injections 42 . Islets of these animals express significantly less exocytotic proteins involved in SNARE (soluble N-ethylmaleimide attachment receptor) complex formation because of impaired FoxO1 transcriptional activity 42 .…”

“…Islets of these animals express significantly less exocytotic proteins involved in SNARE (soluble N-ethylmaleimide attachment receptor) complex formation because of impaired FoxO1 transcriptional activity 42 . One of these proteins regulated by FoxO1, Syntaxin1A, interacts with the a1D subunit of the L-type voltage-gated Ca 2 þ channel 43 and is implicated in SNARE formation and insulin release 44 .…”

APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

“…The Akt/FoxO1 signaling cascade plays a pivotal role in the regulation of SNARE protein expression and insulin secretion (4,26). Because APPL1 has been shown to potentiate Akt signaling in adipocytes (16), hepatocytes (14), and muscle cells (15), we next investigated whether APPL1 deficiency has any impact on this signaling cascade in pancreatic islets.…”

“…β-cell-specific inactivation of several components involved in insulin signaling, including insulin receptor (IR), insulin receptor substrate (IRS)-2, class IA phosphatidylinositol 3-kinase (PI3K), and Akt, leads to impaired insulin secretion and/or decreased β-cell mass (4)(5)(6)(7). By contrast, transgenic expression of active Akt or IRS-2 in β cells increases β-cell mass and enhances insulin secretion, thereby rendering the mice resistant to experimental diabetes (8,9).…”