High-fat-diet-induced remission of diabetes in a subset of K ATP -GOF insulin-secretory-deficient mice

Diabetes Obes Metab. 2018 Nov;20(11):2574-2584. doi: 10.1111/dom.13423. Epub 2018 Jul 11.

Abstract

Aims: To examine the effects of a high-fat-diet (HFD) on monogenic neonatal diabetes, without the confounding effects of compensatory hyperinsulinaemia.

Methods: Mice expressing KATP channel gain-of-function (KATP -GOF) mutations, which models human neonatal diabetes, were fed an HFD.

Results: Surprisingly, KATP -GOF mice exhibited resistance to HFD-induced obesity, accompanied by markedly divergent blood glucose control, with some KATP -GOF mice showing persistent diabetes (KATP -GOF-non-remitter [NR] mice) and others showing remission of diabetes (KATP -GOF-remitter [R] mice). Compared with the severely diabetic and insulin-resistant KATP -GOF-NR mice, HFD-fed KATP -GOF-R mice had lower blood glucose, improved insulin sensitivity, and increased circulating plasma insulin and glucagon-like peptide-1 concentrations. Strikingly, while HFD-fed KATP -GOF-NR mice showed increased food intake and decreased physical activity, reduced whole body fat mass and increased plasma lipids, KATP -GOF-R mice showed similar features to those of control littermates. Importantly, KATP -GOF-R mice had restored insulin content and β-cell mass compared with the marked loss observed in both HFD-fed KATP -GOF-NR and chow-fed KATP -GOF mice.

Conclusion: Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.

Keywords: glucose metabolism; high fat diet; insulin resistance; insulin secretion; islets; β-cell function.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / diet therapy*
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diet, High-Fat*
  • Female
  • Gain of Function Mutation*
  • Gene Knock-In Techniques
  • Insulin Resistance / genetics
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Obesity / complications
  • Obesity / genetics
  • Obesity / pathology
  • Organ Specificity / genetics
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Remission Induction

Substances

  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying