High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

Am J Physiol Endocrinol Metab. 2015 Apr 1;308(7):E573-82. doi: 10.1152/ajpendo.00460.2014. Epub 2015 Jan 27.


Both short- (1 wk) and long-term (2-12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.

Keywords: high-fat diet; insulin resistance; mouse models; β-cell mass; β-cell proliferation.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation* / drug effects
  • Diet, High-Fat* / adverse effects
  • Dietary Fats / pharmacology
  • Glucose Clamp Technique
  • Glucose Intolerance / etiology
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Insulin Resistance*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Time Factors


  • Dietary Fats