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