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 β- and α-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-1β, 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 β-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in β-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also α-cell mass was markedly decreased, resulting in a lower α- to β-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in β- and α-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. high-fat, low-carbohydrate ketogenic diets (KD) are used in weight loss programs and are associated with improvement of the glycemic status in obese subjects (30, 35) and patients with type 2 diabetes (11, 19). KD are also used as an effective treatment for refractory epilepsy (7, 27, 33). Blood glucose levels are tightly controlled by the hormones insulin and glucagon produced by pancreatic β- and α-cells, respectively. When the consumption of carbohydrates is limited, the body switches from a glucose-based energy metabolism to a fat-based metabolism in which β-oxidation of free fatty acids (FFA) serves as the primary source of energy. This leads to a permanent state of ketosis. Insulin counteracts ketogenesis by stimulating the use of glucose as primary energy source and by decreasing the release of FFA in the circulation (21). In contrast, glucagon stimulates ketogenesis, hepatic glucose production, and lipolysis (1, 40). Changes in glucose metabolism are associated with adaptation of the number and/or function of β-cells to produce and secrete an adequate amount of insulin (6, 34). Also α-cell mass can be modulated by dietary changes (14). Inadequate adaptation leads to glucose intolerance and eventually results in diabetes mellitus (9, 21). Despite their beneficial effects on weight loss and epileptic seizures, KD may have adverse side effects such as kidney stones, impaired growth, osteoporosis, and hyperlipidemia (3, 23) on the long term. Furthermore, several short-term studies in rodents have shown that KD leads to hepatic steatosis, insulin resistance, and glucose intolerance (4, 16, 20). It is unknown whether the metabolic effects induced by long-term KD also affect the endocrine pancreas. In addition, the effect of KD on glucose metabolism has only been studied in mice after short-term diets (2, 16, 20). Therefore, we investigated the effects of a long-term KD on glucose tolerance and pancreatic β- and α-cell mass.