Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia

Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.