Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival

Endocrinology. 2010 Aug;151(8):3577-88. doi: 10.1210/en.2010-0233. Epub 2010 Jun 9.

Abstract

An absolute or functional deficit in beta-cell mass is a key factor in the pathogenesis of diabetes. We model obesity-driven beta-cell mass expansion by studying the diabetes-resistant C57BL/6-Leptin(ob/ob) mouse. We previously reported that cholecystokinin (Cck) was the most up-regulated gene in obese pancreatic islets. We now show that islet cholecystokinin (CCK) is up-regulated 500-fold by obesity and expressed in both alpha- and beta-cells. We bred a null Cck allele into the C57BL/6-Leptin(ob/ob) background and investigated beta-cell mass and metabolic parameters of Cck-deficient obese mice. Loss of CCK resulted in decreased islet size and reduced beta-cell mass through increased beta-cell death. CCK deficiency and decreased beta-cell mass exacerbated fasting hyperglycemia and reduced hyperinsulinemia. We further investigated whether CCK can directly affect beta-cell death in cell culture and isolated islets. CCK was able to directly reduce cytokine- and endoplasmic reticulum stress-induced cell death. In summary, CCK is up-regulated by islet cells during obesity and functions as a paracrine or autocrine factor to increase beta-cell survival and expand beta-cell mass to compensate for obesity-induced insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Survival / genetics
  • Cells, Cultured
  • Cholecystokinin / genetics*
  • Cholecystokinin / metabolism
  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / genetics
  • Insulin Resistance / genetics
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mice, Transgenic
  • Obesity / complications
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology*
  • Organ Size / genetics
  • Up-Regulation

Substances

  • Cholecystokinin