Effect of Stress on Glucoregulation in Physiology and Diabetes
To examine the glucoregulatory responses to stress and their impact on diabetes, we used the following models of stress: A) Hypoglycemia; B) Epinephrine infusion; C) Intracerebroventricular (ICV) injection of carbachol, an analog of acetylcholine.
Hypoglycemia induces release of all counterregulatory hormones. During acute hypoglycemia, glucose production increases initially mainly due to glucagon release but eventually also due to a very large increment in catecholamines. In newborn dogs, neither epinephrine nor glucagon respond to a decrease in plasma glucose. This lack of a safeguard against hypoglycemia may indicate that the brain in pups is less dependent on a normal supply of glucose as a fuel, than in adult dogs. Counterregulation is enhanced when the effects of endogenous opiates are blocked by naloxone, indicating that endogenous opiates play a regulatory role during hypoglycemia. However, beta-endorphins which can be released with epinephrine during various stress situations, potentiate the peripheral effect of epinephrine. Glucoregulatory responses, even to slight changes in plasma glucose, are greatly enhanced during glucocorticoid treatment. This apparently reflects the greater sensitivity of the liver to glucagon. In diabetic dogs, similar to human diabetics, the glucagon response is abolished and the response of the catecholamines is partially decreased. On the basis of histological studies, we proposed that the deficient glucagon response in diabetes could be related to an increase in the somatostatin-glucagon ratio in the diabetic pancreas. This ratio is further augmented when normoglycemia is maintained with insulin. In response to a decrease in plasma glucose, there is a biphasic increment in glucose production in normal dogs, which is missing in diabetes. When normoglycemia is restored in diabetic dogs with phlorizin treatment, the second but not the first increment in glucose production is restored. We postulated, therefore, that the toxic effect of hyperglycemia, in addition to the lack of glucagon response, is the main reason why in diabetes, glucose production cannot respond promptly to a decrease in plasma glucose. The low rate of metabolic clearance of glucose seen in diabetes in the post-absorptive state, also reflects, at least in part, the toxic effect of glucose, because with acute normalization of glucose with phlorizin, metabolic glucose clearance substantially improves. Hyperglycemia is the main reason for the decreased number of glucose transporters in diabetic muscle.
Epinephrine infusion in normal dogs mimics some effects of stress, in that it increases glucose production, inhibits metabolic glucose clearance and increases lipolysis. These metabolic effects of epinephrine are independent of glucagon release. In diabetes, however, epinephrine-induced hyperglycemia is exaggerated which is mainly due to glucagon. This occurs both because of excessive glucagon release, and increased hepatic sensitivity to the effects of glucagon related to hypoinsulinemia.
ICV injection of a small amount of carbachol induces a release of all counterregulatory hormones. Interestingly, insulin secretion is not affected, possibly because the alpha- and beta-adrenergic pancreatic inputs are balanced. Surprisingly, this release of counterregulatory hormones induces only a marginal change in plasma glucose, since increased glucose production is matched by a similar increase in glucose uptake. In contrast, in hyperglycemic diabetic dogs, the same carbachol injection induces a much larger increment in plasma glucose. This occurred because the metabolic clearance rate of glucose did not increase. We therefore postulated a neural mechanism which controls peripheral glucose uptake and requires a permissive effect of insulin. Somatostatin, injected ICV before carbachol, abolishes most counterregulatory responses as well as the increment in glucose turnover. Lipolysis is also decreased but FFA re-esterification is abolished, reflecting a decrease in glucose uptake in the adipocyte.
KeywordsPlasma Glucose Glucose Production Hepatic Glucose Production Plasma Glucagon Glucagon Release
Unable to display preview. Download preview PDF.
- 4.R. A. Rizza, P. E. Cryer, and J. E. Gerich, Role of glucagon, catecholamines and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha-and beta-adrenergic blockade in plasma glucose recovery and glucose flux rate after insulin-induced hypoglycemia. J Clin Invest, 64:62–70 (1979).PubMedCrossRefGoogle Scholar
- 6.A. J. Garber, I. E. Karl, and D. M. Kipnis, Alanine and glutanine synthesis and release from skeletal muscle. IV. Beta-adrenergic inhibition of amino acid release, J Biol Chem, 251:1851–1857 (1976).Google Scholar
- 11.A. Klip, T. Ramlal, D. Dimitrakoudis, P. J. Bilan, G. Cartee, E. Gulve, J. O. Holloszy, and M. Vranic, The subcellular distribution of glucose transporters (GTs) in normal and diabetic rat skeletal muscle is regulated by hyperglycemia and insulin, Endocrine Society, p. 47, (Abstract 89). (1990).Google Scholar
- 25.S. Caprio, G. Gerety, M. Diamond, W. V. Tamborlane, and R. S. Sherwin, Naloxone enhances the hepatic response to hypoglycemia in diabetics with defective counterregulation, Diabetes, 38(suppl.2):4A, (Abstract) (1989).Google Scholar
- 35.G. Bolli, P. De Feo, P. Campagnucci, M. G. Cartechini, G. Angeletti, F. Santeusanio, P. Brunetti, and J. E. Gerich, Abnormal glucose counterregulation in insulin dependant diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion, Diabetes, 32:134–141 (1983).PubMedCrossRefGoogle Scholar
- 36.P. E. Cryer, Hypoglycemic glucose counterregulation in patients with insulin dependant diabetes mellitus, J Clin Lab Med, 99:451–456 (1982).Google Scholar
- 42.F. G. McDaniel, Acute suppression of hepatic gluconeogenesis by glucose in the intact animal Am J Physiol, 229:E569–E575 (1975).Google Scholar
- 45.K. S. Rastogi, L. Lickley, M. Jokay, S. Efendic, and M. Vranic, Paradoxical reduction in pancreatic glucagon with normalization of somatostatin and decrease in insulin in normoglycemic alloxan diabetic dogs: A putative mechanism of glucagon irresponsiveness to hypoglycemia, Endocrin, 126:1096–1104 (1990).CrossRefGoogle Scholar
- 47.M. Vranic, H. L. A. Lickley and J. K. Davidson, Exercise and stress in diabetes mellitus. In: Clinical Diabetes Mellitus: A problem oriented approach. (ed J. K. Davidson). Thieme-Stratton Inc., New York, pp. 172– 205 (1986).Google Scholar
- 50.E. Simatirakis, P. D. G. Miles, M. Vranic, R. Hunt, R. Gougen-Rayburn, C. J. Field and E. B. Marliss, Glucoregulation during single and repeated bouts of intense exercise and recovery in man Clin Invest Med 13(4), Abstract 134 (1990).Google Scholar
- 52.R. N. Bergman, Integrated control of hepatic glucose metabolism in the dog Ann NY Acad Sci, 148:441–468 (1977).Google Scholar
- 55.L. Kepinov, and S. Petit-Dutaillis, Action hyperglycemiate du sang du chien diabetique, Arch Int Physiol, 34:48–100 (1931).Google Scholar
- 57.R. H. Linger, and L. Orci, Hypothesis: The essential role of glucagon in the pathogenesis of diabetes mellitus, Lancet, 1:14–16 (1975).Google Scholar
- 62.J. E. Gerich, M. Lorenzi, E. Tsalikian, and J. H. Karam, Studies on the mechanism of epinephrine-induced hyperglycemia in man, Diabetes, 25:67–71 (1976).Google Scholar
- 64.F. W. Kemmer, A. Sirek, O. V. Sirek, G. Perez, and M. Vranic, Glucoregulatory mechanisms following hypophysectomy in diabetic dogs with residual insulin secretion, Diabetes, 23:26–34 (1983).Google Scholar
- 77.P. S. Sebel, in: Hazards and complications of anaesthesia, T. H. Taylor and E. Major, eds. New York, NY, Churchill Livingston (1987).Google Scholar
- 78.P. Miles, K. Yamatani, L. Lickley, and M. Vranic, Mechanism of glucoregulatory responses to stress and their deficiency in diabetes. Proc. Natl. Acad. Sci. U.S.A.. (1990) (in press).Google Scholar
- 81.P. D. G. Miles, K. Yamatani, H. L. A. Lickley, and M. Vranic, The intracerebroventricular injection of a somatostatin analog (ODT8-SS) suppresses the stress response in normal and diabetic dogs, Program of International Symposium on Somatostatin, Montreal, Canada. Abstract 68, (1989).Google Scholar