Effect of functional adrenalectomy on glucagon secretion and circulating catecholamines during insulin hypoglycemia in the dog

Abstract

The present study was carried out to determine whether an increase in the pancreatic immunoreactive glucagon (IRG) secretion during the acute phase of insulin-induced hypoglycemia depends on circulating catecholamines of adrenal origin. Hypoglycemia was induced by a bolus insulin injection (0.15 IU/kg, i.v.) in dogs anesthetized with sodium pentobarbital (35 mg/kg, i.v.). Plasma aortic epinephrine (E) and norepinephrine (NE) concentrations increased significantly 30 min after the injection of insulin. At this time point, a functional adrenalectomy (diversion of bilateral adrenal venous blood from the systemic circulation) was performed for 5 min. The increased aortic E and NE concentrations significantly decreased reaching, within 5 min, a level below the corresponding preinjection control value. The basal output of pancreatic IRG (6.58 +/- 1.12 ng/min, n = 6) significantly increased (24.93 +/- 2.77 ng/min, p less than 0.05, n = 6) 30 min after insulin injection. During the functional adrenalectomy, the increased pancreatic IRG output diminished rapidly, within 5 min, to approximately 50% (11.73 +/- 3.19 ng/min, p less than 0.05, n = 6) of the value observed 30 min after insulin administration. In the other group of dogs receiving sham adrenalectomy, the increased aortic E and NE concentrations and pancreatic IRG output following insulin injection remained elevated above the levels observed immediately before the sham adrenalectomy. The net decrease in IRG output during the adrenalectomy was significant (p less than 0.05) compared with the corresponding net IRG output observed in the sham group.(ABSTRACT TRUNCATED AT 250 WORDS)

The Relationship of Glucokinase Activator–induced Hypoglycemia with Arteriopathy, Neuronal Necrosis, and Peripheral Neuropathy in Nonclinical Studies

“…Hence, just like the neuronal and axonal lesions, these cardiovascular lesions might also be related to hypoglycemia rather than a direct effect of GKAs. These lesions bear some morphological similarities with catecholamine stimulation/administration (fibrinoid necrosis of coronary arteries, myocardial inflammation/necrosis, subendocardial hemorrhage; Jellinek et al 1966;Khullar et al 1989;Szakacs and Mehlman 1960) and strongly suggest that the vascular/heart lesions seen with our GKAs may be related to a counterregulatory catecholamine response to hypoglycemia in these species (Havel and Valverde 1996;Molina and Abumrad 2001;Yamaguchi, Briand, and Gaspo 1990), rather than a direct effect of GK activators. Therefore, these cardiovascular changes (myocardial necrosis and hemorrhage and arteriopathy) could be the direct manifestation of marked severe hypoglycemia and/or indirectly the consequence of a transient catecholamine surge or a combination of both.…”