Recurrent hypoglycemia inhibits the counterregulatory response by suppressing adrenal activity
Yunbing Ma, … , Manqi Wang, Matthew D. Whim
Yunbing Ma, … , Manqi Wang, Matthew D. Whim
Published August 31, 2018; First published August 6, 2018
Citation Information: J Clin Invest. 2018;128(9):3866-3871. https://doi.org/10.1172/JCI91921.
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Concise Communication Neuroscience

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.

Authors

Yunbing Ma, Qian Wang, Debria Joe, Manqi Wang, Matthew D. Whim

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Figure 1

Recurrent episodes of hypoglycemia suppress catecholamine release from adrenal chromaffin cells.

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Recurrent episodes of hypoglycemia suppress catecholamine release from a...
(A) Schematic of glycemic protocols. Red: recurrent saline (Control); green: recurrent saline plus insulin (One hypo); blue: recurrent insulin (Rec hypo); gray: saline injection; white: insulin injection. I, insulin; S, saline. (B) Hypoglycemia-induced epinephrine release in vivo was blunted after recurrent insulin injection (n = 10). (C) Insulin injection evoked a reproducible fall in blood glucose levels (n = 9–10). (D) Cre immunoreactivity (Cre-ir) was restricted to the adrenal medulla in TH-Cre+ mice. (E) In TH-ChR(tdTomato) mice, RFP fluorescence was present on the cell membrane of chromaffin cells. TH-ir, TH immunoreactivity. (F) Catecholamine release was evoked from chromaffin cells in vitro using ChR-mediated depolarization and detected using carbon fiber amperometry. (G) Example of optogenetically evoked amperometric events. (H) Catecholamine secretion was detected from TH-Cre+ chromaffin cells that also expressed ChR (n = 12–13 cells). (I) Examples of amperometric events from mice exposed to glycemic protocols. (J) Cumulative amplitude of amperometric events (control: 554 events; 1 hypoglycemia: 1,008 events; recurrent hypoglycemia: 597 events; n = 21–33 cells per condition from 4 animals per treatment; plot was normalized to the number of recorded cells). (K) Cumulative number of amperometric events (from experiments in J). Scale bars: 100 μm (D), 10 μm (E). *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (B), Wilcoxon rank-sum test (H), Kolmogorov-Smirnov test (J and K).