THE EFFECTS OF INSULIN ON THE COUNTERREGULATORY RESPONSE TO EQUIVALENT HYPOGLYCEMIA IN PATIENTS WITH INSULIN-DEPENDENT DIABETES-MELLITUS

We previously demonstrated that hyperinsulinemia can amplify the count erregulatory response to hypoglycemia in normal subjects. The aim of t he present study was to determine if differing concentrations of insul in can modify the counterregulatory response to equivalent fixed hypog lycemia in insulin-dependent-diabetic subjects (IDDM). Experiments wer e carried out in seven lean, overnight-fasted, moderately controlled ( hemoglobin A(1c), 10.9%; normal range, 5-9) IDDM subjects with a disea se duration of 13 +/- 3 yr. All were maintained normoglycemic overnigh t so that basal plasma glucose (5.6 +/- 0.2 and 5.4 +/- 0.2 mmol/L) an d insulinemia (63 +/- 18 and 48 +/- 10 pmol/L) were similar at the sta rt of each study. Insulin was infused for 120 min in two separate rand omized protocols, so that steady state levels (mean +/- SE) of 742 +/- 212 pmol/L (low) and 3360 +/- 710 pmol/L (high) were obtained. Glucos e was infused during both protocols to ensure that the rate of fall of plasma glucose (0.09 mmol/L.min) and the hypoglycemic plateau (2.8 +/ - 0.1 mmol/L) were similar. In response to hypoglycemia, plasma levels of epinephrine, norepinephrine, cortisol, GH, and pancreatic polypept ide increased similarly during both insulin infusions. During the fina l 30 min, despite similar levels of counterregulatory hormones, hepati c glucose production was significantly reduced in the presence of high compared to low insulin levels (1.7 +/- 2.8 vs. 8.3 +/- 1.7 mu mol/kg .min; P < 0.05). Similarly, plasma nonesterified fatty acids (472 +/- 94 vs. 787 +/- 105 mu mol/L) and blood 3-hydroxybutyrate levels (30 +/ - 12 vs. 106 +/- 29 mu mol/L) were significantly reduced (P < 0.05) du ring high compared to low dose infusions. Cardiovascular parameters (h eart rate and systolic, diastolic, and mean arterial pressures) respon ded similarly during both infusions. We conclude that 1) insulin per s e does not amplify the counterregulatory response to equivalent hypogl ycemia in individuals with moderately controlled, long duration IDDM; and 2) there may be a relative autonomic adrenomedullary deficit in so me IDDM subjects that prevents the amplified epinephrine response to h yperinsulinemia during hypoglycemia.