Recurrent hypoglycemia inhibits the counterregulatory response by suppressing adrenal activity

Abstract

Hypoglycemia activates the counterregulatory response (CRR), a neural-endocrine reflex that restores euglycemia. Although effective if occasionally activated, repeated induction of the CRR leads to a decline in responsiveness and prolonged exposure to hypoglycemia. The mechanism underlying this impairment is not known. We found that the reduction in epinephrine release that characterizes a suppressed CRR involves a long-lasting form of sympatho-adrenal synaptic plasticity. Using optogenetically evoked catecholamine release, we show that recurrent hypoglycemia reduced the secretory capacity of mouse adrenal chromaffin cells. Single activation of the CRR increased the adrenal levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, but this was prevented by repeated activation. In contrast, the level of neuropeptide Y (NPY), an adrenal cotransmitter, remained elevated after recurrent hypoglycemia. Inhibition of NPY or Y1 signaling, either transgenically or pharmacologically, prevented the attenuation of both TH expression and epinephrine release. These results indicate that impairment of the CRR involves suppressed activity at the adrenal level. Interfering with the peripheral NPY-dependent negative feedback loop may provide a way to avoid the pathophysiological consequences of recurrent hypoglycemia which are common in the diabetic state.

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

“…The development of a peripheral defect at the level of epinephrine-secreting chromaffin cells after recurrent hypoglycemia contributes to the impaired counterregulatory secretion of epinephrine (28, 38). Ma et al (28) showed that in a rodent model of HAAF defects existed in the adrenal gland but not in the downstream hepatic components of the counterregulatory response.…”

“…The development of a peripheral defect at the level of epinephrine-secreting chromaffin cells after recurrent hypoglycemia contributes to the impaired counterregulatory secretion of epinephrine (28, 38). Ma et al (28) showed that in a rodent model of HAAF defects existed in the adrenal gland but not in the downstream hepatic components of the counterregulatory response. These results suggest that impaired sympathetic efferent neuronal signaling causes reduced activation of epinephrine-secreting cells in the adrenal gland, since cell death was not observed in the adrenal gland (28).…”

Use of a Continuous Glucose Monitor for Preoperative Monitoring and Treatment of Hypoglycemia in a Case of Pancreatic Neuroendocrine Tumor

“…Excessive compensation of brain glycogen levels during recurrent hypoglycemia could contribute to the development of hypoglycemia-associated autonomic failure in humans (15). Inhibition of the counterregulatory response by suppressed adrenal activity has been observed in animal models (16).…”

Synaptotagmin-7 participates in the regulation of acetylcholine release and short-term presynaptic facilitation in splanchnic nerve terminals

“…In the context of the sympatho-adrenal system, facilitation may have a role in amplifying epinephrine discharge from chromaffin cells during conditions that increase sympathetic tone, including hypoglycemia (13,53). The resulting increase in circulating epinephrine would then be expected to increase blood glucose via multiple metabolic pathways (13,53,54). Our data show that in Syt7 KO animals fed ad libitum, epinephrine content in the adrenal medulla, as well as in the blood, are not different from WT animals ( Figure 6).…”