Effect of Acute and Antecedent Hypoglycemia on Sympathetic Neural Activity and Catecholamine Responsiveness in Normal Rats

Abstract

Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days ؊2 and ؊1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 ؎ 12 vs. 118 ؎ 21 spikes/s [P < 0.05]; or to 138 ؎ 8 vs. 114 ؎ 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 ؎ 11 vs. 130 ؎ 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 ؎ 17 vs. 171 ؎ 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 ؎ 5% vs. 140 ؎ 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness. Diabetes 50:1119 -1125, 2001 I mpaired hypoglycemic counterregulation and hypoglycemia unawareness are well-recognized complications of long-standing diabetes (1,2). Hypoglycemia unawareness has also been observed as a reversible consequence of transient prior hypoglycemic events (3-5) and has been observed even in individuals without diabetes (6). However, the pathophysiology of hypoglycemic counterregulation and hypoglycemia unawareness is still unclear. Although much has been learned of catecholamine and other hormonal responses to hypoglycemia, the role of sympathetic neural activity per se to adrenal and other tissues has received only limited study.Peripheral sympathetic nerve activity (SNA) originating in hypothalamic centers may be important in the counterregulatory response to hypoglycemia. Hoffman et al. (7) found that skeletal muscle SNA in type 1 diabetic and nondia...

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

“…In this condition, recurrent hypoglycemic events evoke progressively less and less epinephrine release, increasing the risk of severe hypoglycemia. Although the cause is not known, there is evidence for both central and peripheral defects (1,5,48). Because the phenomenon is activity-dependent, it is likely to involve the synaptic plasticity we have described here.…”

“…7A). To confirm the involvement of Y5 receptors, we incubated adrenal slices in the selective Y5 receptor agonist [cPP [1][2][3][4][5][6][7] ,NPY [19][20][21][22][23] ,Ala ]-hPancreatic Polypeptide (cPP, 1 μM, 3-6 h). EPSCs recorded from chromaffin cells in these slices had a significantly smaller PPR compared with control cells from fed mice (Fig.…”

“…The importance of sympathetic activity, and in particular circulating epinephrine in the CRR, is illustrated by the poor recovery from insulin-induced hypoglycemia when the release of this hormone is suppressed during hypoglycemia-associated autonomic failure (5,6), and by recent work showing that deletion of melanocortin 4 receptors from preganglionic sympathetic neurons leads to elevated levels of blood glucose (7).…”

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

“…Despite the fact that we only exposed the rats to one episode of hypoglycemia and we waited 48 h for recovery, we still found significant blunting of epinephrine responses to hypoglycemia after a single episode of moderate hypoglycemia. This rodent model of HAAF is unique in that suppressed epinephrine responses are seen after a single episode of moderate hypoglycemia, rather than multiple episodes used in other models (Evans et al, 2001;Sivitz et al, 2001;Inouye et al, 2002;Flanagan et al, 2003).…”

From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease

“…The finding of blunted hypoglycemia-induced epinephrine secretion in rats subjected to prior hypoglycemia has been confirmed by several other research groups. In one such study, rats were given 1.5 U insulin subcutaneously on 2 consecutive days to reduce blood glucose to 26 mg/dl (average on day 1) and 32 mg/dl (average on day 2) (Sivitz et al, 2001). However, in this study, blood glucose was only measured 150 min after insulin injection; thus, the depth and duration of hypoglycemia was not closely monitored and corticosterone and glucagon were not measured.…”