Putative Hypothalamic Glucoreceptors Play No Essential Role in the Response to Moderate Hypoglycemia

Abstract

The response to insulin-induced hypoglycemia includes increased plasma levels of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. This integrated response is thought to be mediated via sympathetic afferent pathways emanating from the ventromedial hypothalamus. However, the precise loci of the receptors that sense glucopenia are not known. In this study, we investigated the importance of putative forebrain glucoreceptors to the systemic response to hypoglycemia. Three protocols were performed. Protocol 1: the systemic response was observed in conscious dogs to hypoglycemia induced by infusion of insulin at a high rate (150 mU/min). Protocol 2: the effect of concomitant bilateral, intracarotid glucose infusion on the response to intravenous insulin was examined. Intracarotid glucose infusion rates were chosen to yield central euglycemia in the face of systemic hypoglycemia. Protocol 3: as a control for protocol 2, glucose was infused at low rates into the systemic circulation, yielding hypoglycemia in both central and systemic blood. When insulin was infused at 150 mU/ min, without glucose replacement (protocol 1; N = 6), plasma insulin increased from 14 ± 3 to 335 ± 35 μU/ ml at 60 min (P < 0.001). Glucose fell from basal (104 ± 3 mg/dl) to 38 ± 3 mg/dl (P < 0.001). Significant increases were observed in epinephrine (basal, B: 63 ± 8; steady state, SS: 1762 ± 582 pg/ml; P < 0.007), norepinephrine (B: 209 ± 33, SS: 650 ± 133 pg/ml; P < 0.01), and glucagon (B: 256 ± 35, SS: 467 ± 35 pg/ml; P < 0.03). In addition, endogenous glucose production (Ra) increased from 72 ± 4 to 108 ± 9 mg/min (P < 0.02) despite frank hyperinsulinemia. Infusing glucose into the carotid arteries at 204 ± 10 mg/min (protocol 2; N = 7) during a 4-h systemic insulin infusion was sufficient to prevent jugular hypoglycemia [jugular glucose, Gj, B: 100 ± 3, SS (90–160 min): 101 ± 3 mg/ dl; P > 0.70], but not peripheral hypoglycemia (Gp, B: 102 ± 2, SS: 55 ± 3 mg/dl; P < 0.001). Despite carotid glucose replacement, counterregulatory responses were still observed in epinephrine (B: 98 ± 14, SS: 466 ± 127 pg/ml; P < 0.04) and norepinephrine (B: 213 ± 19, SS: 474 ± 133 pg/ml; P < 0.05). Moreover, the magnitude of counterregulatory responses was not different when the glucose was given peripherally rather than centrally [protocol 3: epinephrine (B: 84 ± 18, SS: 523 ± 105 pg/ml; P < 0.004), norepinephrine (B: 277 ± 65, SS: 445 ± 71 pg/ml; P < 0.02)]. Counterregulatory responses to modest systemic hypoglycemia are not altered by the concomitant prevention of central hypoglycemia. Apparently, hypothalamic glucoreceptors are not essential for the sympathetic response to hypoglycemia, implying that important glucose-sensitive receptors are located elsewhere in the body.