Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and beta- and alpha-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1 beta, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from beta-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in beta-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also alpha-cell mass was markedly decreased, resulting in a lower alpha- to beta-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in beta- and alpha-cell mass, but no weight loss. This indicates that long-term high-fat, low-carbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans.