Systemic and Local Adrenergic Regulation of Muscle Glucose Utilization During Hypoglycemia in Healthy Subjects

Abstract

Adrenergic responses are crucial for hypoglycemic recovery. Epinephrine increases glucose production, lipolysis, and peripheral insulin resistance as well as blood flow and glucose delivery. Sympathetic activation causes vasoconstriction and reduces glucose delivery. To determine the effects of ␣-and ␤-adrenergic activity on muscle glucose uptake during hypoglycemia, we studied forearm blood flow (FBF) (plethysmography), arteriovenous glucose difference (AV-diff), and forearm glucose uptake (FGU) during insulin infusion with 60 min of euglycemia followed by 60 min of hypoglycemia. Twelve healthy subjects (27 ؎ 5 years of age) were randomized to intravenous propranolol (IV PROP, 80 g/min), intravenous phentolamine (IV PHEN, 500 g/min), intra-arterial propranolol (IA PROP, 25 g/min), intra-arterial phentolamine (IA PHEN, 12 g/min per 100 ml forearm tissue), and saline (SAL). FBF increased during hypoglycemia with SAL (P < 0.001) but not with IA or IV PROP. FGU (P ‫؍‬ 0.015) and AV-diff (P ‫؍‬ 0.099) fell during hypoglycemia with IA PROP but not with IV PROP. FBF increased during hypoglycemia with IA and IV PHEN (P < 0.005). AV-diff fell during hypoglycemia with IA and IV PHEN (P < 0.01), but FGU was unchanged. Blood pressure fell (P < 0.001), and adrenergic and neuroglycopenic symptoms increased with IV PHEN (P < 0.01). Thus, systemic but not local propranolol prevents a decrease in forearm glucose extraction during hypoglycemia, suggesting that epinephrine increases peripheral muscular insulin resistance through systemic effects. ␣-Adrenergic activation inhibits vasodilation and helps maintain brain glucose delivery. Diabetes 51:734 -742, 2002 H ypoglycemia is the limiting factor in achieving good glycemic control in patients with type 1 diabetes. Discovering the physiologic mechanisms by which the body normally protects itself from hypoglycemia and how these mechanisms are altered in diabetes will increase our understanding of the pathophysiology and treatment of diabetes. We have demonstrated that during insulin-induced hypoglycemia, forearm blood flow (FBF) increases (1). The increase in flow augments glucose delivery and maintains normal glucose uptake despite a fall in glucose extraction. Local ␤-adrenergic blockade inhibits the vasodilation and leads to decreased forearm glucose uptake (FGU) during hypoglycemia, whereas local ␣-adrenergic blockade increases flow and increases FGU. In contrast to this, other authors have demonstrated that systemic combined ␣-and ␤-blockade and ␤-blockade alone lead to increased peripheral glucose uptake during hypoglycemia (2-6). The metabolic mechanisms by which increases in ␣-and/or ␤-adrenergic activity decrease peripheral glucose uptake during hypoglycemia are not clearly defined.Peripheral glucose uptake is dependent on two factors, fractional cellular glucose uptake and the amount of glucose delivered to the tissues (7,8). It is unclear whether the sympathetic activation that accompanies hypoglycemia is associated with decreased glucose transport or decreased glucose d...

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