Role of hyperglucagonemia in catabolism associated with type 1 diabetes: effects on leucine metabolism and the resting metabolic rate.

Abstract

The catabolic state of poorly controlled type 1 diabetes has largely been attributed to insulin deficiency. However, the role of hyperglucagonemia, which occurs concomitantly with insulin deficiency, has not been fully investigated. We studied the effects of hyperglucagonemia during insulin deprivation on energy expenditure (using indirect calorimetry) and protein metabolism (using L-[1-(13)C,15N]leucine and L-[1-(13)C]leucine as tracers) in 12 type 1 diabetic subjects. Five protocols were used: insulin treatment, insulin deprivation, insulin deprivation with suppression of endogenous glucagon with somatostatin (SRIH) and growth hormone replacement, insulin deprivation with endogenous glucagon suppression with SRIH (no growth hormone replacement), and insulin deprivation with SRIH and a high level of glucagon replacement (no growth hormone replacement). It was observed that leucine oxidation and the resting metabolic rate (RMR) were significantly lower during insulin treatment and insulin deprivation with concomitant SRIH infusion (lowering 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 also associated with a trend for decreased protein synthesis. Hyperglucagonemia did not affect leucine transamination. Insulin replacement decreased leucine flux and oxidation. Leucine oxidation (R2 = 0.79) and the RMR (R2 = 0.81) were seen, by multiple regression analysis, to correlate with glucagon levels and not with other hormones. We conclude that while insulin deficiency increases protein breakdown, hyperglucagonemia is primarily responsible for the increased leucine oxidation and RMR seen during insulin deprivation.

Effect of Insulin Deprivation on Muscle Mitochondrial ATP Production and Gene Transcript Levels in Type 1 Diabetic Subjects

“…The finding of increased oxygen consumption during insulin deprivation in type 1 diabetes is consistent with previous findings (14,15). The current study demonstrated that increased O 2 consumption at the whole-body level was associated with a decrease in MAPR.…”

“…Moreover, inhibition of glucagon secretion by somatostatin during insulin deprivation in type 1 diabetes reverses the increased O 2 consumption. Re-introduction of glucagon increased O 2 consumption in those subjects, demonstrating that high glucagon levels contributed to increased O 2 consumption during insulin deprivation (15). Glucagon has also been shown to increase O 2 consumption during insulin deficiency in nondiabetic healthy people (26).…”

“…An alternative explanation that we favor is that increased Vo 2 , which represents whole-body O 2 consumption, might have occurred in tissue (or tissues) other than skeletal muscle. Previous studies have shown that increased O 2 consumption during insulin deprivation is related to elevated glucagon levels (15). Moreover, inhibition of glucagon secretion by somatostatin during insulin deprivation in type 1 diabetes reverses the increased O 2 consumption.…”

“…A reduced MAPR during insulin deprivation in type 1 diabetic patients would suggest that reduced insulin action reduces muscle mitochondrial function. However, it has been observed that insulin deprivation in type 1 diabetes results in increased oxygen consumption, suggesting an increased rate of oxidative phosphorylation (14,15). Therefore, in the current study, we determined whether acute withdrawal of insulin treatment in C-peptide-negative people with type 1 diabetes results in reduced MAPR and alterations in transcript levels of genes involved in mitochondrial function.…”

Specific gene expression signature associated with development of autoimmune type-I diabetes using whole-blood microarray analysis

“…This observation was confirmed in different studies showing that insulin deprivation in T1D results in increased oxygen consumption, suggesting increased rate of oxidative phosphorylation. 32,33 The recent immunohistochemical analysis of a pancreatic gland from a patient with longstanding diabetes provided interesting clues to disease pathogenesis. 4 Interestingly, the remaining b-cells were detected in islets and within the exocrine pancreas in close vicinity of T-lymphocytes or macrophages This is consistent with the existence of a persistent autoimmune process and the inability of b-cells to regenerate from ductal cell precursors.…”