ROLE OF HYPERGLUCAGONEMIA IN CATABOLISM ASSOCIATED WITH TYPE-1 DIABETES - EFFECTS ON LEUCINE METABOLISM AND THE RESTING METABOLIC-RATE

The catabolic state of poorly controlled type 1 diabetes has largely b een attributed to insulin deficiency. However, the role of hyperglucag onemia, which occurs concomitantly with insulin deficiency has not bee n fully investigated. We studied the effects of hyperglucagonemia duri ng insulin deprivation on energy expenditure (using indirect calorimet ry) and protein metabolism (using L-[1-C-13, N-15]leucine and L-[1-C-1 3]leucine as tracers) in 12 type 1 diabetic subjects. Five protocols w ere used: insulin treatment, insulin deprivation, insulin deprivation with suppression of endogenous glucagon with somatostatin (SRIH) and g rowth hormone replacement, insulin deprivation with endogenous glucago n suppression with SRIH (no growth hormone replacement), and insulin d eprivation with SRIH and a high level of glucagon replacement (no grow th hormone replacement). It was observed that leucine oxidation and th e resting metabolic rate (RMR) were significantly lower during insulin treatment and insulin deprivation with concomitant SRIH infusion (low ering glucagon) than during insulin deprivation alone. Replacement of glucagon at a high level during SRIH infusion in the insulin-deprived state increased leucine oxidation and the RMR. Hyperglucagonemia was a lso associated with a trend for decreased protein synthesis. Hypergluc agonemia did not affect leucine transamination. Insulin replacement de creased leucine flu and oxidation. Leucine oxidation (R-2 = 0.79) and the RMR (R-2 = 0.81) were seen, by multiple regression analysis, to co rrelate with glucagon levels and not with other hormones. We conclude that while insulin deficiency increases protein breakdown, hyperglucag onemia is primarily responsible for the increased leucine oxidation an d RMR seen during insulin deprivation.