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 are largely unknown. Here, we determined the effects of KD-induced ketosis on the sympathoadrenal response to a single insulin-induced hypoglycemic challenge. We investigated how a 3 week KD feeding regimen affected the main components of the sympathoadrenal counterregulatory response: adrenal sympathetic nerve activity (ASNA), adrenal gland activity, plasma epinephrine, and brainstem glucose-responsive C1 neuronal activation in anesthetized, nondiabetic male Sprague-Dawley rats. Rats on KD had similar blood glucose (BG) levels and elevated ketone body β-hydroxybutyrate (BHB) levels compared to the control Chow diet group. All KD rats responded to hypoglycemia with a robust increase in ASNA, which was initiated at significantly lower BG levels compared to Chow-fed rats. The delay in hypoglycemia-induced ASNA increase was concurrent with rapid disappearance of BHB from cerebral and peripheral circulation. Adrenal gland activity paralleled epinephrine and ASNA response. Overall, 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.
Highlights
Published: 29 July 2021Insulin therapy is the gold standard of treatment for type 1 diabetes and patients with advanced type 2 diabetes, but maintaining consistent blood glucose levels is challenging.Hypoglycemia frequently results from inadvertent excessive administration of insulin [1]and, if untreated, can lead to serious neurological consequences, such as mental confusion, seizures, and coma
The fact that glucagon injections are less effective in patients who follow a low-carbohydrate diet [22], our study focused on the role of the sympathoadrenal system and epinephrine, which are expected to be the major contributors to the counterregulatory response (CRR) in the setting of type 1 diabetes
This appears to be the case in studies investigating the CRR to hypoglycemia; previous human studies showed that acute infusion of exogenous ketones causes a reduction in epinephrine levels [11,49], which contrasts with our findings in Ketogenic diets (KD)-fed rats. This discrepancy might be explained by the stimulatory effects of acute ketone administration on cerebral blood flow [50], which is associated with significantly reduced perception of hypoglycemia symptoms and blunted sympathoadrenal response in healthy humans [51]. These findings suggest that attenuated CRR to hypoglycemia in the settings of acute administration of ketones, as opposed to KD-induced sustained ketosis, might be due to the direct effects of ketones on cerebral blood flow, the elevation of which allows a faster delivery of all energy substrates, including glucose, to the brain rather than preferential neuronal metabolism of ketones
Summary
Published: 29 July 2021Insulin therapy is the gold standard of treatment for type 1 diabetes and patients with advanced type 2 diabetes, but maintaining consistent blood glucose levels is challenging.Hypoglycemia frequently results from inadvertent excessive administration of insulin [1]and, if untreated, can lead to serious neurological consequences, such as mental confusion, seizures, and coma. Hypoglycemia is initially counteracted by increased glucagon secretion and suppression of endogenous insulin release [3]. If blood glucose levels continue to fall (
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