Effects of an Enkephalin Analog on Pancreatic Endocrine Function and Glucose Homeostasis in Normal and Diabetic Dogs*

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Abstract
The effects of an iv infusion of an enkephalin analog, [D-met2, Pro5]enkephalin-amide (enkephalin*), on circulating insulin, glucagon, and glucose concentrations were examined in vivo in normal and alloxan-diabetic dogs. Dose-response experiments in normal conscious dogs demonstrated inhibition of glucagon release (maximal decrease, 19 ± 10 pg/ml) at an infusion rate of 1.6 μg kg-1 h-1. At a dose of 32 μg kg-1 h-1, an increase of 44 ± 12 pg/ml in the glucagon concentration was observed. Both the degree of inhibition and stimulation of glucagon secretion were statistically significant compared to those seen after the infusion of enkephalin* together with naloxone. There was minimal suppression of insulin secretion at the lowest infusion dose, but significant stimulation (maximum increase, 5.0 ± 1.4 μ/ml) at the highest dose. This change was also prevented by naloxone. Similar effects were observed in the peripheral circulation of anesthetized dogs at an infusion rate of 32 μg kg-1 h-1. However, greater increases in insulin (179 ± 49 μ/ml) and glucagon (294 ± 112 pg/ml) concentrations occurred in the pancreatic vein. Brisk stimulation of glucagon secretion from the gastric fundus was also noted. No significant changes in glucose concentrations were observed in either group of normal animals, whether conscious or anesthetized. To determine the potential pathophysiological significance of the enkephalin*-induced changes in insulin and glucagon secretion, alloxan-diabetic dogs were infused with enkephalin* at a rate of 32 μg kg-1 h-1. Enkephalin* infusion resulted in an increase of 56 ± 22 pg/ml in the glucagon concentration, associated with a rise in plasma glucose of 66 ± 15 mg/dl. This accentuation of hyperglycemia in diabetic animals indicates the importance of the enkephalin*-induced rise in insulin in maintaining euglycemia in normal dogs. When the rise in glucagon was prevented by a simultaneous infusion of somatostatin, the elevation of glucose levels was abolished. In addition, the increases in glucagon and glucose levels were significantly diminished by the opiate antagonist naloxone. These experiments suggest that both insulin and glucagon play an important role in the metabolic effects mediated by enkephalin*. We conclude that opioid peptides influence pancreatic endocrine function in vivo through specific opiate receptors and suggest that endogenous opioid peptides, by similar mechanisms, may contribute to the worsening of metabolic control in diabetes mellitus.