Ketogenic Diet‐Induced Ketosis Delays the Onset, but Preserves the Magnitude of The Sympathoadrenal Response to Hypoglycemia in Rats

Abstract

The sympathoadrenal counterregulatory response to hypoglycemia is critical for individuals with type 1 diabetes due to impaired ability to produce glucagon. Ketogenic diets (KD) are an increasingly popular diabetes management tool, however the effects of KD on the sympathoadrenal response to hypoglycemia, and hence safety, are largely unknown. We propose that the KD could delay the sympathoadrenal response to hypoglycemia due to the availability of an additional energy substrate to the brain in the form of ketone bodies, but the magnitude of the response will not be affected. The aim of this study was to investigate the effects of KD on the main peripheral components of the sympathoadrenal counterregulatory response: adrenal sympathetic nerve activity (ASNA), adrenal gland activity and plasma epinephrine in non-diabetic male rats. Methods Male Sprague-Dawley rats fed KD or chow diet (CHOW) for 3 weeks were anaesthetised and ASNA recorded. Insulin (5 U/kg; iv) induced hypoglycemia and the sympathoadrenal counterregulatory response. Blood glucose and β-hydroxybutyrate (BHB, ketone body) were measured every 15 min post-insulin for 2 hours. Plasma epinephrine was determined via ELISA. Adrenal gland activity was assessed by immunohistochemistry for Fos. Results Rats on KD, compared to the control chow diet (CHOW) group, had similar blood glucose (BG) levels, and had elevated ketone body β-hydroxybutyrate (BHB) levels. None of the KD rats developed clonic convulsions post-insulin, while >40% of the CHOW rats did. CHOW rats had either a strong ASNA response without convulsions, or a failed ASNA response with convulsions. All KD rats responded to hypoglycemia with a robust increase in ASNA, which was initiated at lower BG levels compared to convulsion-free CHOW rats. Both adrenal gland activity and epinephrine levels positively correlated with ASNA response. Conclusions KD-induced ketosis was associated with initiation of the sympathoadrenal response at lower blood glucose levels, however the magnitude of the response was not diminished. Furthermore, KD appeared to be protective against sympathoadrenal failure and severe hypoglycemia-induced neuroglycopenia.