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

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 K channel gain-of-function (K -GOF) mutations, which models human neonatal diabetes, were fed an HFD.

RESULTS

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