Recurrent hypoglycemia inhibits the counterregulatory response by suppressing adrenal activity
Yunbing Ma, Qian Wang, Debria Joe, Manqi Wang, Matthew D. Whim
Yunbing Ma, Qian Wang, Debria Joe, Manqi Wang, Matthew D. Whim
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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 4

Recurrent hypoglycemia does not lead to widespread peripheral impairment of the CRR.

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Recurrent hypoglycemia does not lead to widespread peripheral impairment...
(A) PCNA-immunoreactive cells were mainly found in the region of the zona glomerulosa (black arrowheads), not the medulla (white arrows). (B) Caspase-3–immunoreactive cells (black arrowheads) were present in the cortex. Occasional cells were found in the medulla (boxed area). (C and D) PCNA and caspase-3 immunoreactivity in the adrenal medulla after single or recurrent episodes of IIH (n = 6 and 4, respectively). (E and F) Blood glucose levels during pyruvate tolerance tests. (G and H). Quantification of the area under the glucose response curves (n = 5–6 per group). (I and J). Hepatic glycogen levels in WT and NPY-KO mice, respectively (n = 4). (K) Periodic acid-Schiff staining in hepatic cryosections. (L) Model of adrenal plasticity during the CRR. Epinephrine (Epi) and NPY are released from chromaffin cells during hypoglycemia (Hypogly) as a part of the CRR. NPY subsequently inhibits the expression of TH, which delays the refilling of the depleted epinephrine-releasable pool; therefore, epinephrine stores are functionally related to the level of NPY release [Epi = f(NPY)]. If hypoglycemia is reexperienced, less epinephrine is available for release, and the magnitude of the CRR is reduced (i.e., HAAF). The inhibition may be further magnified by a hypoglycemia-induced increase in NPY expression. *P < 0.05, by 1-way ANOVA. Scale bars: 100 μm.