(DCP013) KETOGENIC DIET INTERVENTION IMPROVES HEPATIC STEATOSIS BUT NOT GLUCOSE TOLERANCE OR INSULIN SECRETION IN OBESE MICE

Background: The ketogenic diet (KD) is an extremely carbohydrate restricted diet that has re-emerged for the management of glycemia. In 2020, Diabetes Canada joined other international organizations in approving its use in the management of type 2 diabetes (T2D) based on short term studies showing weight loss, improved glycemic control, and reduced requirement of diabetes medications in people living with T2D. However, the longer-term impact of extreme fat consumption (>70% kcal), restricted carbohydrates ( < 50 g/day), and maintenance of elevated ketone bodies in circulation on insulin secretion and T2D is not well characterized. Insulin secretion can be modulated by many factors including G-protein coupled receptors that can amplify (incretin receptors) or inhibit (some fatty acid receptors) glucose stimulated insulin secretion. Additionally, whole body glucose homeostasis is reliant on tissue response to insulin, and insulin desensitization on the liver due to hepatic steatosis and inflammation is common.

METHODS AND RESULTS: To assess the impact of KD intervention on metabolically compromised mice, we fed male and female C57BL6J mice a high fat diet (HFD) for 10 weeks and then mice either maintained the HFD or underwent diet intervention with a KD or our chow diet for 12 weeks. Male and female mice on KD intervention had significantly higher fed blood ketones than chow and HFD-fed mice, confirming ketosis. After 6 weeks, glucose tolerance was not different improved by KD compared to HFD, however, KD intervention mice had higher active incretins post-glucose gavage. Male HFD-fed mice also had higher post-glucose plasma insulin than both intervention groups. Insulin tolerance test glycemia was also not different between diet groups. At sacrifice, male and female KD intervention mice had significantly lower liver weight than HFD continuers; however, only female intervention mice had lower total body weight. Unsurprisingly, KD intervention increased fed plasma triglycerides and increased mRNA expression of Cpt1α, a marker of fatty acid beta oxidation. Plasma markers of liver function were improved with KD in both sexes and gene expression of Itgax, associated with inflammatory macrophages, was reduced in male mice. However, during dynamic perifusion of isolated islets, glucose stimulated insulin secretion was not changed by diet intervention in male or female mice. But glucagon was lower at low (2.8 mM) glucose than both other diet groups, consistent with previous findings.

Conclusion: Together, while KD intervention was effective at improving total body mass and liver health (females) or liver health alone (males), it was unable to improve insulin secretion.