Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation

Abstract

The relative contributions of the sympathetic nervous system and the adrenal medullae, the two components of the sympathoadrenal system, to the manifestations of hypoglycemia are largely unknown. We tested the hypothesis that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural activation. To do so, we quantitated neurogenic symptoms, as well as norepinephrine (NE) kinetics and selected hemodynamic changes, during hyperinsulinemic euglycemic and stepped hypoglycemic clamps in 15 healthy control subjects (Controls) and four bilaterally adrenalectomized patients (ADX). Plasma epinephrine responses to hypoglycemia were virtually absent in ADX, as expected. Neurogenic symptom scores increased to higher values during the hypoglycemic compared with the euglycemic clamps in both Controls (P < 0.0001) (e.g., final scores of 7.8 +/- 1.2 vs. 3.0 +/- 0.7) and ADX (P < 0.0001) (e.g., final scores of 10.8 +/- 4.1 vs. 2.5 +/- 1.0). Plasma NE concentrations (P < 0.0001) and systemic NE spillover (P = 0.0007) increased during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. Similarly, heart rate increased (P = 0.0104), diastolic blood pressure decreased (P = 0.0003), and forearm blood flow increased (P < 0.0001) during the hypoglycemic compared with the euglycemic clamps in Controls but not in ADX. These data indicate that the neurogenic symptoms of hypoglycemia are largely the result of sympathetic neural, rather than adrenomedullary, activation. They also suggest that the plasma NE and hemodynamic responses to hypoglycemia are largely the result of adrenomedullary, rather that sympathetic neural, activation.

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

“…The relative amounts of W, NREMS and REMS on the baseline day from 30-120 minutes after saline injection are comparable to a recent sleep study from our laboratory conducted from 1300-1500 hours that did not involve subcutaneous injections [26]. Although a hyperinsulinemic, euglycemic group was not included in this study, we believe that the effect of insulin treatment on arousal reported here is due to hypoglycemia, rather than hyperinsulinemia, for the following reasons: 1) Hyperinsulinemic euglycemic clamp studies in normal humans are not associated with significant autonomic activation or development of hypoglycemic symptoms [27]. 2) In the study of Banarer and Cryer, altered sleep efficiency during stepped hypoglycemic clamp was not reported for non-diabetic humans studied at the 85, 75, or 65 mg/dl steps, only during the 55 and 45 mg/dl steps [14].…”

Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An [11C]-3-O-methyl-d-glucose PET study

“…However, our data are consistent with other studies in which hormonal responses and awareness have not been concordant and provide further evidence that adrenaline responses per se do not define hypoglycaemia unawareness [e.g. 46,47].…”

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

“…The origin of hypoglycemic symptoms during hypoglycemia is complex. Previous studies demonstrated scenarios whereby discordant responses between autonomic symptoms and catecholamine responses can exist during hypoglycemia (17,(31)(32)(33). Generally, studies have determined that autonomic symptoms can be preserved despite reduced activity in other branches of the sympathetic nervous system.…”

“…Generally, studies have determined that autonomic symptoms can be preserved despite reduced activity in other branches of the sympathetic nervous system. For example, DeRosa et al (31) demonstrated that symptom responses are preserved in adrenalectomized subjects who have no measurable epinephrine levels during hypoglycemia. Additionally, Aftab-Guy et al (34,35) demonstrated that high levels of plasma epinephrine mimicking values observed during moderate hypoglycemia only produce minor increases in hypoglycemic symptoms.…”