Beta-endorphin inhibits glucose production in the conscious dog.

The effect of human beta-endorphin (h beta E) infusion (0.2 mg/h) on glucose homeostasis was studied in 10 conscious overnight fasted dogs in which endocrine pancreatic function was fixed at basal levels with somatostatin plus intraportal replacement of basal insulin and glucagon. h beta E caused a fall in plasma glucose from 107 +/- 5 to 76 +/- 6 mg/dl by 3 h (P less than 0.01). This was due to a 25% fall in tracer-determined glucose production (Ra; P less than 0.01). A significantly larger fall in Ra was observed in four dogs in which hypoglycemia was prevented by use of an exogenous glucose infusion (45 vs. 25%, P less than 0.05). These changes occurred in the absence of changes in circulating levels of insulin, glucagon, epinephrine, norepinephrine, and cortisol. We conclude that the naturally occurring opioid peptide, beta-endorphin, inhibits glucose production by the liver in vivo. This appears to be a direct effect of the opioid on the liver, since the inhibition took place in the absence of changes in the other hormones measured. These results suggest that endorphins act on glucose homeostasis in a complex way, both by affecting other glucoregulatory hormones as demonstrated elsewhere, and by directly modulating hepatic glucose production as shown here.

Effects of morphine on glucose homeostasis in the conscious dog.

This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma glucose, P less than 0.05) that is due to inhibition of glucose production (by 25-43%, P less than 0.05). The hypoglycemia was independent of detectable changes in insulin, glucagon, epinephrine and cortisol, and was not reversed by concurrent infusion of a slight molar excess of naloxone. Therefore, we postulate that the hypoglycemic effect of morphine results from the interaction of the opiate with non-mu receptors either in the liver or the central nervous system.

Prostaglandin E2 metabolite levels during diabetic ketoacidosis.

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.

Dropout and relapse during diabetes care.

OBJECTIVE: To determine factors associated with dropout and relapse during chronic diabetes care. RESEARCH DESIGN AND METHODS: Private practice outpatient treatment-education program for adult diabetes was surveyed. Retrospective analysis was done, involving 422 patients for up to 3 yr. RESULTS: Of the patients in the study, 12% dropped out after the initial visit, and 33% of the residual cohort dropped out during each subsequent 6-mo period. Factors associated with dropout included distance from home to clinic > 100 miles, lack of insulin treatment, and cigarette smoking. In patients who remained in follow-up, a significant decrease in HbA1C occurred during the first 6 mo, but 40% of the patients relapsed between 6 and 12 mo. Frequency of relapse declined as time passed. Relapse was more frequent in women. CONCLUSIONS: Dropout from treatment and relapse after temporary improvement account for a substantial amount of uncontrolled diabetes, and overcoming the obstacles of dropout and relapse has potential for significant improvement in diabetes care.

A role for endogenous prostaglandins in defective glucose potentiation of nonglucose insulin secretagogues in diabetics.

Noninsulin dependent diabetics have insulin responses to nonglucose secretagogues that are subnormal for their plasma glucose levels. Since endogenous prostaglandins have been implicated in the abnormal insulin responses to glucose in diabetics, the present study was performed to explore whether prostaglandins might also play a role in the defective insulin responses to nonglucose stimuli. We examined the effects of infusions of either prostaglandin E2 (PGE2) or sodium salicylate (SS), a PG synthesis inhibitor, on the acute insulin responses (AIR's) to arginine and isoproterenol and on the glucose potentiation of the insulin response to arginine in both normal and diabetic subjects. The AIR to arginine was augmented by SS in diabetics (SS = 61 +/- 12 microunits/ml, control = 37 +/- 5 microunits/ml, n = 11, p less than .01). SS, however, had no effect on the AIR to arginine in normal subjects (SS = 39 +/- 4 microunits/ml. control = 34 +/- 4 microunits/ml, n = 6, p = ns). Similarly, SS augmented the AIR to an isoproterenol pulse in diabetics (SS = 38 +/- 9 microunits/ml, control = 18 +/- 3, n = 9, p less than .05) but not in normal subjects (SS = 19 +/- 4 microunits/ml, control = 21 +/- 4 microunits/ml, n = 8, p = ns), suggesting a SS-sensitive defect in the insulin response to these nonglucose stimuli in diabetics. Conversely, PGE2 inhibited the AIR to arginine in diabetics (PGE = 28 +/- 5 microunits/ml, control = 39 +/- 7 microunits/ml, n = 7, p less than .05), but not in normal subjects (PGE = 74 +/- 7 microunits/ml, control = 80 +/- 14 microunits/ml, n = 5, p = ns). The effect of SS on glucose potentiation of the AIR to arginine was studied by measuring the AIR to arginine at two different levels of plasma glucose, one before and one after an insulin infusion, with glucose potentiation defined as the ratio delta AIR/delta prestimulus glucose. Glucose potentiation was significantly less in diabetics than in normals and SS significantly improved glucose potentiation toward normal values in diabetics but did not change glucose potentiation in normals. These findings suggest that endogenous PG's may play a role in the defective glucose potentiation of the AIR to nonglucose secretagogues in diabetics resulting in impaired insulin responses to these stimuli. This defect is partially reversible by an inhibitor of PG synthesis.

Hypothesis: prostaglandins mediate defective glucose recognition in diabetes mellitus.

The glucoreceptor hypothesis proposes that diabetics have a selective defect in both pancreatic and extra-pancreatic tissues in the recognition of, and hormonal responses to glucose. Many of these defective or even paradoxical responses to hyperglycemia and hypoglycemia can be mimicked by known actions of prostaglandins, particularly PGE, in normal subjects. Inhibition of PGE synthesis in diabetics partially reverses several abnormal responses. We propose that excessive production of, or sensitivity to, prostaglandins may play a role in some of the metabolic abnormalities associated with defective glucose recognition in diabetes mellitus.

Up-regulation of hepatic prostaglandin E receptors in vivo induced by prostaglandin synthesis inhibitors.

Up-regulation in vivo of liver plasma membrane receptors for prostaglandin E (PGE) was studied in Sprague-Dawley rats using the prostaglandin synthesis inhibitors, acetylsalicylic acid (ASA) and indomethacin (Indo). Following 4 days of treatment with ASA, the concentration of receptors and the affinity for binding were both significantly increased (Ro - +37%, KA = +62%). Following 4 days of treatment with Indo, the number of receptors was increased but the binding-site affinity was decreased (Ro = +40%, KA = -71%). Animals were then examined after treatment with either ASA or Indo for 1 day, a time when there was no significant decrease in PGE. After 1 day of treatment, the opposite changes in binding-site affinity were again observed, but there were no changes in the number of receptors with either drug, suggesting that the changes in affinity resulted from non-prostaglandin-related effects of the drugs. To ascertain the physiologic consequences of up-regulation, adenylate cyclase activity was measured in control and up-regulated membranes. There were no significant changes in basal or in PGE-stimulated adenylate cyclase activity. These data demonstrate that decreased endogenous PGE causes up-regulation of PGE receptors, but that this is not accompanied by increased adenylate cyclase activity. These data may indicate that PGE-stimulated adenylate cyclase operates maximally under normal receptor concentrations and that therefore its activity cannot be increased by regulatory changes in receptor density.