Summary
To investigate the influence of opiates on insulin action in vivo, we induced mild physiological hyperinsulinaemia (15–20 mU/l) in five trained conscious dogs in the absence or presence of ongoing infusion with the opiate agonist D-met2-pro5-enkephalinamide (DMPE, 0.5 μg·kg-1· min-1), or the opiate antagonist naloxone (1.25 mg followed by 1 μg· kg-1·min-1). The effects on glucose production and glucose utilization were measured by isotope dilution using 3-3H-glucose. Glucose fell similarly over 30 min in response to insulin in controls (0.021±0.003 mmol·1-1· min-1), and both the DMPE and naloxone studies (0.016±0.002 mmol · 1-1 · min-1 and 0.017±0.003 mmol·1-1 ·min-1, respectively). In control dogs, insulin lowered glucose by transiently suppressing production by 0.028 ±0.006 mmol·kg-1·min-1 at 20–30 min without changing utilization. In contrast, in both the DMPE and naloxone studies insulin lowered glucose by markedly raising utilization at 20 min by 0.094 ±0.017 and 0.139±0.022 mmol·kg-1·min-1, respectively. Furthermore, insulin failed to suppress production in both DMPE and naloxone studies and, as plasma glucose fell, production rose in both treatment groups at 20 min by 0.045 ±0.012 and 0.089 ±0.022 mmol · kg-1 · min-1 respectively. The counter-regulatory hormone glucagon was transiently suppressed by insulin at 20 min in controls, but not in the treatment groups; cortisol and adrenaline rose at 30 and 45 min respectively in the naloxone group only. No other changes were noted in counterregulatory hormones. Thus hormonal changes do not appear to account for the early pronounced rise in glucose utilization leading to the fall in glucose in the DMPE and naloxone studies. We conclude that the morphine-like agent DMPE and high doses of the opiate antagonist naloxone modulate insulin-induced glucose fluxes in vivo, promoting both glucose utilization and production. These effects may be direct or indirect, and may serve a function in the redistribution of glucose during stress responses.
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Krieger DT, Martin JB (1981) Brain peptides. N Engl J Med 304: 944–951
Morley JE (1981) The endocrinology of the opiates and opioid peptides. Metabolism 30: 195–209
Felberg W, Gupta KP (1974) Morphine hyperglycaemia. J Physiol (Lond) 238: 487–502
Reid RL, Yen SSC (1981) β-endorphin stimulates the secretion of insulin and glucagon in humans. J Clin Endocrinol Metab 52: 592–594
Stubbs WA, Jones A, Edwards CRW, Delitalia G, Jeffcoate WJ, Jeffcoate SJ, Besser GM, Bloom SR, Alberti KGMM (1978) Hormonal and metabolic responses to an enkephalin analogue in normal man. Lancet 2: 1225–1227
Feldman M, Kiser RS, Unger RH, Li CH (1983) Beta endorphin and the endocrine pancreas: studies in healthy and diabetic human beings. N Engl J Med 308: 349–353
Ipp E, Dhorajiwala JM, Moossa AR, Rubenstein AH (1980) Enkephalin stimulates insulin and glucagon release in vivo and accentuates hyperglycaemia in diabetic dogs. Clin Res 28: 396 A (Abstract)
Ipp E, Dobbs R, Unger RH (1978) Morphine and β-endorphin influence the secretion of the endocrine pancreas. Nature 276: 190–191
Robinson RP, Williams PE, Gooch BR, Abumrad NN (1982) The effect of morphine and naloxone on plasma glucagon and glucose production in the diabetic dog. Diabetes 31 (Suppl 2): 161A (Abstract)
Morley JE, Baranetsky NG, Wingert TD, Carlson HE, Hershman JM, Melmed S, Levin SR, Jamison KR, Weitzman R, Chang RJ, Varner AA (1980) Endocrine effects of naloxone-induced opiate receptor blockade. J Clin Endocrinol Metab 50: 251–257
Jeanrenaud X, Maeder E, Del Pozo E, Felber JP (1981) Enkephalin-induced glucose-insulin dissociation in man. Diabetologia 21: 287 (Abstract)
Szekely JI, Ronai AZ, Dunai-Kovacs Z, Miglecz E, Berzetri I, Bajusz S, Graf L (1977) (D-met2,pro5)-Enkephalinamide: a potent morphine-like analgesic. Eur J Pharmacol 43: 293–294
Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA (1974) Spontaneous and amino acid-stimulated glucagon secretion in the immediate postnatal period. Relation to glucose and insulin. J Clin Invest 53: 1159–1166
Walter RM, Dudl RJ, Palmer JP, Ensinck JW (1974) The effect of adrenergic blockade on the glucagon responses to starvation and hypoglycemia in man. J Clin Invest 54: 1214–1220
Peuler DJ, Johnson GA (1977) Simultaneous single isotope radio-enzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 21: 625–636
Radziuk J, Norwich KH, Vranic M (1978) Experimental validation of measurements of glucose turnover in nonsteady state. Am J Physiol 234: E84-E93
Altszuler N, Barkai A, Bjerknes C, Gottlieb B, Steele R (1975) Glucose turnover values in the dog obtained with various species of labeled glucose. Am J Physiol 229: 1662–1667
Sacca L, Sherwin R, Hendler R, Felig P (1979) Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. J Clin Invest 63: 849–857
Pyke DA (1979) Diabetes: the genetic connections. Diabetologia 17: 333–343
Mason JS, Heber D (1982) Endogenous opiates modulate insulin secretion in flushing non-insulin-dependent diabetics. J Clin Endocrinol Metab 54: 693–697
Gerich J, Cryer P, Rizza R (1980) Hormonal mechanisms in acute glucose counterregulation: the relative roles of glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. Metabolism 29: 1164–1175
Chiasson JL, Liljenquist JE, Finger FE, Lacy WW (1976) Differential sensitivity of glycogenolysis and gluconeogenesis to insulin infusions in dogs. Diabetes 25: 283–291
Liljenquist JE, Keller U, Chiasson JL, Cherrington AD (1979) Insulin and glucagon actions and consequences of derangements in secretion. In: De Groot LJ (ed) Endocrinology. Grune and Stratton, New York, pp 981–996
Wilson SP, Klein RL, Chang KJ, Gasparis MS, Viveros OH, Yang WH (1980) Are opioid peptides co-transmitters in noradrenergic vesicles of sympathetic nerves? Nature 288: 707–709
Amir S, Brown ZW, Amit Z (1979) The role of endorphins in stress: evidence and speculations. Neurosci Biobehav Rev 4: 77–86
Ono T, Oomura Y, Nishino H, Sasaki K, Muramoto K, Yano I (1980) Morphine and enkephalin effects on hypothalamic glucoresponsive neurons. Brain Res 185: 208–212
Van Loon GR, Appel NM (1981) β-endorphin-induced hyperglycemia is mediated by increased central sympathetic outflow to adrenal medulla. Brain Res 204: 236–241
North RA, Egan TM (1982) Electrophysiology of peptides in the peripheral nervous system. Br Med Bull 38: 291–296
Werther GA, Joffe S, Artal R, Banach W, Sperling M (1981) Is the autonomic nervous system involved in the recovery of glucose output during physiologic hyperinsulinemia. Diabetes 30 (Suppl): 108 A (Abstract)
Sawynok J, Pinsky C, LaBella FS (1979) On the specificity of naloxone as an opiate antagonist. Life Sci 25: 1621–1632
Wakabayashi I, Demura R, Miki N, Ohmura E, Miyoshi H, Shizume K (1980) Failure of naloxone to influence plasma growth hormone, prolactin, and cortisol secretion induced by insulin hypoglycaemia. J Clin Endocrinol Metab 50: 597–599
Serri O, Rasio E, Somma M (1981) Effects of naloxone on insulininduced release of pituitary hormones. J Clin Endocrinol Metab 53: 206–208
Pert BC, Pasternak G, Snyder SH (1973) Opiate agonists and antagonists discriminated by receptor binding in brain. Science 182: 1359–1361
Wolfe RR, Miller HI, Spitzer JJ (1977) Glucose and lactate kinetics in burn shock. Am J Physiol 232: E415-E418
Wilmore DW, Mason AD, Jr Pruitt BA, Jr (1976) Insulin response to glucose in hypermetabolic burn patients. Ann Surg 183: 314–320
Richter EA, Garetto LP, Goodman MN, Ruderman NB (1982) Muscle glucose metabolism following exercise in the rat. Increased sensitivity to insulin. J Clin Invest 69: 785–793
Ahlborg G, Felig P (1982) Lactate and glucose exchange across the forearm, legs and splanchnic bed during and after prolonged leg exercise. J Clin Invest 69: 45–54
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Werther, G.A., Joffe, S., Artal, R. et al. Opiates modulate insulin action in vivo in dogs. Diabetologia 26, 65–69 (1984). https://doi.org/10.1007/BF00252266
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DOI: https://doi.org/10.1007/BF00252266