β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions

Nat Commun. 2017 Feb 1;8:14295. doi: 10.1038/ncomms14295.

Abstract

β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in β-cells. Importantly, overexpression of barr2 in β-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of β-cell function, which may serve as a new target to improve β-cell function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Diet, High-Fat
  • Gene Expression
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Signal Transduction / genetics*
  • beta-Arrestin 2 / genetics*
  • beta-Arrestin 2 / metabolism

Substances

  • Insulin
  • beta-Arrestin 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2