386-P: Chronic and Acute Consumption of a Ketogenic Diet Leads to Deficits in Hypoglycemic Counterregulation in Mice

Background: Due to their metabolic benefits, ketogenic diets (KDs) are growing increasingly popular as a dietary strategy for augmenting treatment of type 1 and type 2 diabetes. Although much is known regarding the metabolic benefits of KDs, little is known about their effect on hypoglycemic counter-regulation. We tested whether mice fed a KD have normal hypoglycemic counter-regulation.

Methods: B6 mice were fed a KD (Bio-Serv; F3666) ad lib for either 28 days (chronic) or 7 days (acute). On the final day of the diet, hypoglycemic counter-regulation was assessed via glucoprivic challenge (ICV 2DG, 1 mg/mouse, or saline) in the chronic KD group or via a hypoglycemic insulin tolerance test (ITT) in the acute KD group. Deficits in the counter-regulatory response were determined by comparing glucose and glucagon levels to control mice simultaneously fed a standard chow diet (LabDiet; 5001). ITTs consisted of a variable dose of IP insulin which produced equivalent hypoglycemia in all groups (∼45 mg/dL).

Results: As expected, mice fed a KD either acutely or chronically had lower fasting blood glucose levels relative to controls (chronic KD: 132.4 and 167.5mg/dL respectively, p = 0.0011, n= 12-17/group; Acute KD: 167.3 and 200.7 mg/dL respectively, p = 0.026; n = 7-10/group). In response to glucoprivic challenge, chronic KD mice had a blunted rise in both glucose and glucagon relative to chow fed mice (Delta glucose: 84.2 and 135.8 mg/dL respectively, p = 0.017; Glucagon: 32.7 and 73.8 pg/mL respectively, p = 0.027; n = 5-8/group). Acute KD mice also had reduced serum glucagon levels in response to the ITT (28.8 and 50.1 pg/mL respectively, p = 0.044).

Conclusions: We show that consuming a KD reduces glucose counter-regulation in mice. If a similar effect exists in persons with diabetes it could blunt a homeostatic response which is critical for counteracting treatment-induced hypoglycemic crises. Further characterization of the effects of KDs on glucose counter-regulation is warranted.