Metabolic and Cardiovascular Impact of Ketotic Extreme Carbohydrate Restriction

Abstract

Human trials of ketogenic diets (KDs) have shown promise in weight and glucose management in subjects with type 2 diabetes (T2D), prompting organizations, including Diabetes Canada, to condone their use through recent position statements. However, the effects of intervention with strict dietary regimes on the progression of cardiovascular disease and glucoregulatory processes, like the incretin effect, have not been fully elucidated. The incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), potentiate insulin secretion postprandially to control glycemia but are rapidly inactivated by dipeptidyl peptidase-4 (DPP4) cleavage. In this study, we used atherosclerosis-susceptible mice with diet-induced obesity and dysglycemia to investigate the effect of intervention with extreme carbohydrate restriction. PCSK9 overexpressing mice were fed a high fat, high cholesterol diet (HFD) for 10 weeks, followed by a 12-week continuation or intervention with a KD or chow diet. Mice fed a KD diet had elevated free fatty acids and ketone bodies in the fed state and lower circulating DPP4. Elevated GIP and hyperinsulinemia were also reversed. KD mice had increased insulin secretion in response to 10 mM glucose supplemented with GLP-1 and GIP than HFD mice during ex-vivo perifusion analysis. Additionally, liver triglycerides, cholesterol, and aortic sinus atherosclerosis significantly improved with ketogenic and chow interventions. Nanostring analysis of the aorta demonstrated differentially expressed inflammatory genes and pathways in KD versus HFD feeding. Understanding how dietary regimens drive the metabolic milieu and surrounding pathologies will advance personalized nutrition advice for glycemic control.