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.