EFFECT OF CONTINUOUS SUBCUTANEOUS INSULIN INFUSION WITH LISPRO ON HEPATIC RESPONSIVENESS TO GLUCAGON IN TYPE-1 DIABETES

OBJECTIVE - People with type 1 diabetes frequently develop a blunted c ounterregulatory hormone response to hypoglycemia coupled with a decre ased hepatic response to glucagon, and consequently, they have an incr eased risk of severe hypoglycemia. We have evaluated the effect of ins ulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabet ic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS - Ten subjects on CSII were neared for 3 months with lispro and 3 months with regular i nsulin in a double-blind randomized crossover study. After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was meas ured in each subject. The test consisted of a 4-h simultaneous infusio n of somatostatin (450 mu g/h) to suppress endogenous glucagon, regula r insulin (0.15 mU.kg(-1).min(-1)), glucose at a variable rate to main tain plasma glucose near 5 mmol/l, and D-[6,6-H-2(2)]glucose to measur e HGP. During the last 2 h, glucagon was infused at 1.5 ng.kg(-1).min( -1). Eight nondiabetic people served as control subjects. RESULTS - Du ring the glucagon infusion period, free plasma insulin levels in the d iabetic subjects were 71.7 +/- 1.6 vs. 74.8 +/- 0.5 pmol/l after lispr o and regular insulin treatment, with plasma glucagon levels of 88.3 /- 1.8 and 83.7 +/- 1.5 ng/l for insulin:glucagon ratios of 2.8 and 3. 0, respectively (NS). However, plasma glucose increased to 9.2 +/- 1.1 mmol/l after lispro insulin compared with 7.1 +/- 0.9 mmol/l after re gular insulin (P < 0.01), and the rise in HGP was 5.7 +/- 2.8 mu mol.k g(-1).min(-1) after lispro insulin versus 3.1 +/- 2.9 mu mol.kg(-1).mi n(-1) after regular insulin treatment (P = 0.02). In the control subje cts, HGP increased by 10.7 +/- 4.2 mu mol.kg-1.min(-1) under glucagon infusion. CONCLUSIONS - Insulin lispro treatment by CSII was associate d with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensiti vity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.