Glucoregulation in alloxan-diabetic dogs

Abstract

In order to establish whether a prolonged subnormal secretion of insulin may affect glucoregulation against hypoglycemic stimuli, the level of plasma glucose was decreased in alloxan-diabetic dogs by the infusion of either 50 μg/kg · min phlorizin (PHL), ie, reducing the concentration of plasma glucose without hyperinsulinemia; or with 7 mU/kg · min insulin (combined hyperinsulinemia and hypoglycemia). The concentration of glucose, immunoreactive glucagon (IRG), and insulin (IRI) and catecholamines were followed in the plasma. Hepatic glucose production (Ra) and the overall rate of glucose removal from the circulation were calculated by a tracer method. During a 200-minute infusion of PHL plasma glucose fell from 328 ± 29 to 114 ± 16 mg/dL, while IRG rose from a mean of 470 ± 123 to 623 ± 200 pg/mL, however this increase was significant only in 3 out of 6 dogs. There was no change in the plasma level of epinephrine. Plasma IRI decreased significantly, the IRI IRG ratio remained low, and Ra did not increase. When the animals were treated with insulin for one week, plasma glucose was restored to normal, while plasma IRI and the IRI IRG ratio were raised above the normal level. Under these circumstances the infusion of PHL increased plasma IRG significantly from 59 ± 5 to 110 ± 32 pg/mL, decreased IRI slightly, and increased Ra by an average of 50 ± 16%. No measurable change in plasma glucose was observed indicating the restoration of nonhypoglycemic glucoregulation. In diabetic dogs during a 95-minute infusion of insulin, plasma glucose dropped from a mean of 338 ± 5 to 74 ± 24 mg/dL. Plasma IRG fell from 379 ± 151 to 151 ± 33 pg/mL, and there was a small increase in plasma epinephrine. Ra was decreased significantly from 5.1 ± 0.4 to 4.1 ± 0.7 mg/kg · min. Conclusions: ( A) In alloxan-diabetic dogs the absence of a regulatory increase in hepatic glucose production in response to a decrease of plasma glucose (as distinct from hyperinsulinemia) is due to the absence of, or only marginal increase in glucagon secretion and/or a reduced sensitivity of the liver to a decrease in the ambient concentration of glucose. ( B) The regulatory response is restored by a one-week long treatment with insulin. ( C) During simultaneous hyperinsulinemia and hypoglycemia the plasma concentration of glucagon decreases together with the rate of hepatic glucose production. ( D) Insulin deprivation for a few days significantly interferes with the regulatory response to a decreasing concentration of plasma glucose both in the presence or absence of simultaneous hyperinsulinemia.