Adrenergic Mediation of Hypoglycemia-Associated Autonomic Failure

Abstract

OBJECTIVEWe tested the hypothesis that adrenergic activation, cholinergic activation, or both, mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.RESEARCH DESIGN AND METHODSSeventeen healthy adults were studied on 2 consecutive days on three occasions. Day 1 involved hyperinsulinemic euglycemic (90 mg/dL × 1 h), then hypoglycemic (54 mg/dL × 2 h) clamps, in the morning and afternoon on all three occasions with 1) saline infusion, 2) adrenergic blockade with the nonselective α-adrenergic and β-adrenergic antagonists phentolamine and propranolol, or 3) adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine in random sequence. Day 2 involved similar morning euglycemic and hypoglycemic clamps, with saline infusion, on all three occasions.RESULTSCompared with the responses to hypoglycemia during saline infusion on day 1, the plasma epinephrine and norepinephrine responses to hypoglycemia were reduced on day 2 (351 ± 13 vs. 214 ± 22 pg/mL for epinephrine and 252 ± 4 vs. 226 ± 7 pg/mL for norepinephrine during the last hour; both P < 0.0001). However, the plasma epinephrine and norepinephrine responses to hypoglycemia were not reduced on day 2 when adrenergic or adrenergic plus cholinergic blockade was produced during hypoglycemia on day 1.CONCLUSIONSAdrenergic blockade prevents the effect of hypoglycemia to reduce the plasma catecholamine responses to subsequent hypoglycemia. Thus, adrenergic activation mediates the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.

Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia

“…The PPR of EPSCs (10-90 events per cell) was calculated by dividing the amplitude of the second EPSC by that of the first (PPR = EPSC 2 /EPSC 1 ). For experiments involving the application of Y receptor agonists and antagonists, adrenal slices were incubated in ACSF containing 0.5 mM Ca 2+ with NPY (1 μM; American Peptide Company), [cPP [1][2][3][4][5][6][7] ,NPY [19][20][21][22][23] ,Ala In Vitro and in Situ Amperometric Recordings. For in vitro amperometry recordings, littermate paired experimental and control animals were killed by decapitation and chromaffin cells were isolated, as previously described (26).…”

“…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).…”

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…Combined α-adrenergic and β-adrenergic blockade prevents the attenuation of sympathoadrenal responses the day after hypoglycemia in humans. 69 If that were shown to be predominantly an effect of β 1 -adrenergic blockade, a trial of a β 1 -adrenergic antagonist for the prevention of hypoglycemia in patients with type 1 diabetes would be reasonable and might reduce mortality. 74 β 1 -adrenergic blockade would not impair the β 2 -adrenergic actions of catecholamines, such as their glucose-raising and symptom-generating effects.…”

“…Five potential treatments for reversing glucose counterregulatory defects 66 -selective serotonin-reuptake inhibitors (SSRIs), 67,68 adrenergic antagonists, 69 an opiate-receptor antagonist, 70,71 fructose, 72 and a selective ATP-sensitive potassium (K ATP )-channel agonist 73 -are of particular interest. All enhance counterregulatory responses to falling glucose concentrations.…”