Intermittent fasting protects 8-cell identity and function in a type-2 diabetes model

Type 2 diabetes (T2DM) is caused by the interaction of multiple genes and environmental factors. T2DM is characterized by hyperglycemia, insulin secretion deficiency and insulin resistance. Chronic hyperglycemia induces 8-cell dysfunction, loss of 8-cell mass/identity and 8-cell dedifferentiation. Intermittent fasting (IF) a commonly used dietary regimen for weight-loss, also induces metabolic benefits including reduced blood glucose, improved insulin sensitivity, reduced adiposity, inflammation, oxidative-stress and increased fatty-acid oxidation; however, the mechanisms underlying these effects in pancreatic 8-cells remain elusive. KK and KKAy, mouse models of polygenic T2DM spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. To determine the long-term effects of IF on T2DM, 6-weeks old KK and KKAy mice were subjected to IF for 16 weeks. While KKAy mice fed ad-libitum demonstrated severe hyperglycemia (460 mg/dL) at 6 weeks of age, KK mice showed blood glucose levels of 230 mg/dL, but progressively became severely diabetic by 22-weeks. Strikingly, both KK and KKAy mice subjected to IF showed reduced blood glucose and plasma insulin levels, decreased body weight gain, reduced plasma triglycerides and cholesterol, and improved insulin sensitivity. They also demonstrated enhanced expression of the 8-cell transcription factors NKX6.1, MAFA and PDX1, and decreased expression of ALDH1a3 suggesting protection from loss of 8-cell identity by IF. IF normalized glucose stimulated insulin secretion in islets from KK and KKAy mice, demonstrating improved 8-cell function. In addition, hepatic steatosis, gluconeogenesis and inflammation was decreased particularly in KKAy-IF mice, indicating peripheral benefits of IF. These results have important implications as an optional intervention for preservation of 8-cell identity and function in T2DM.