Effects of Long-Term Optimization and Short-Term Deterioration of Glycemic Control on Glucose Counterregulation in Type I Diabetes Mellitus

Abstract

To assess the effects of glycemie control on glucose counterregulation, rates of plasma glucose recovery from hypoglycemia and counterregulatory hormonal responses were studied in 18 C-peptide-negative patients with insulin-dependent diabetes mellitus (IDDM) before and after either improvement, no change, or deterioration in glycemic control. Hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 · min for 1 h) after maintenance of euglycemia overnight with i.v. insulin. In 13 patients with long duration of IDDM (9 ± 0.5 yr, mean ± SEM) and initially poor glycemic control (mean diurnal blood glucose, MBG 199 ± 8 mg/dl, ketoamine-HbA1 12.4 ± 0.2%; nondiabetic subjects 104 ± 4 mg/dl and 6.8 ± 0.09%, respectively), rates of plasma glucose recovery from hypoglycemia (0.30 ± 0.01 versus 0.60 ± 0.01 mg/dl · min in nondiabetic subjects, P < 0.001) and plasma glucagon (AUC 0.56 ± 0.09 versus 6.3 ± 0.50 ng/ml ·150 min in non-diabetic subjects, P < 0.01) and epinephrine (AUC 16.9 ± 0.2 versus 25.7 ± 0.2 ng/ml 150 min in nondiabetic subjects, P < 0.001) responses to hypoglycemia were impaired. Intensive therapy (three daily injections of insulin) instituted in 7 out of 13 IDDM patients for up to 9 mo improved MBG (124 ± 6 mg/dl, P < 0.01) and ketoamine-HbA1 (7.9 ± 0.02%, P < 0.01) but not rates of plasma glucose recovery (0.31 ± 0.01 mg/dl · min) and plasma glucagon (AUC 0.69 ± 0.07 ng/ml · 150 min) and epinephrine (AUC 14.9 ± 0.17 ng/ml ·150 min) responses. Similarly, no changes in glucose counterregulation were observed in the six IDDM patients in whom glycemic control was poorly maintained for 6–8 mo (MBG 201 ± 7 mg/dl, ketoamine-HbA112.3 ± 0.2%). In five patients with short duration of IDDM (11 ± 0.5 mo) and optimized glycemic control (MBG 131 ± 8 mg/dl, ketoamine-HbA1 7.9 ± 0.2%), rates of plasma glucose recovery, as well as counterregulatory responses of plasma glucagon and epinephrine, were normal. Neither deterioration of glycemic control for 2 wk (MBG 229 ± 12 mg/dl, ketoamine-HbA1 9.1 ± 0.2%) nor its improvement over the 2 subsequent wk (MBG 120 ± 8 mg/dl, ketoamine-HbA1 8.5 ± 0.2%) resulted in any significant change in glucose counterregulation. It is concluded that near-normalization of glycemic control for up to 9 mo is insufficient to reverse the impairment in glucose counterregulation found in long-term IDDM. Short-term deterioration in glycemic control, when not accompanied by alterations in counterregulatory hormone secretion, does not impair glucose counterregulation.