naloxone and Diabetes-Mellitus

The role of endogenous opioids on the reflex cardiovascular control of chronic uraemic patients was investigated. The opiate antagonist naloxone administered intravenously caused a significant increase in the abnormal Valsalva manoeuvre ratio in nine chronic uraemic patients, but it had no effect in six diabetic patients with normal renal function, whose response to the Valsalva manoeuvre was similar to that of chronic uraemic patients. Naloxone had no effect in eight normal subjects. The increase in the Valsalva ratio observed in uraemic patients was due to restoration of the parasympathetically mediated reflex bradycardia of the release phase of the manoeuvre. Naloxone did not modify supine and standing blood pressure and heart rate in any group. Endogenous opioids may be involved in the defective autonomic control of heart rate in uraemic patients.

Topics: Adult; Autonomic Nervous System Diseases; Blood Pressure; Chronic Disease; Diabetes Mellitus; Drug Evaluation; Heart Rate; Humans; Male; Middle Aged; Naloxone; Reflex, Abnormal; Uremia; Valsalva Maneuver

The aim of the present study was to establish whether the persistence of residual beta-cell activity after long-term diabetes mellitus (DM) exerts a protective role on luteinizing hormone (LH) secretion.. The LH responses to stimulation with gonadotropin-releasing hormone (Gn-RH) (100 microg in an i.v. bolus) or naloxone (4 mg injected in an i.v. bolus, followed by the constant infusion of 8 mg in 2 h) were measured in C-peptide-positive (CpP) and C-peptide-negative (CpN) normally menstruating women with short-term (group 1 < 3 years, CpP n = 11, CpN n = 11) or long-term (group 2 > 10 years, CpP n = 11, CpN n = 11) DM and in age-matched normal control subjects (n = 11).. Gn-RH induced significant increments in LH secretion in all groups. Significant LH responses to naloxone were observed in all groups, except in group 2 CpN patients. However, the LH response to either Gn-RH or naloxone was significantly lower in group 1 CpN, group 2 CpP and group 2 CpN patients than in the normal control subjects. Furthermore, the LH response was significantly lower in group 2 CpP than in group 1 CpP patients and in group 2 CpN than in group 1 CpN subjects.. These results indicate a role for both deficiency in residual endogenous insulin secretion and duration of diabetes in the derangement of LH secretory control. The data suggest that the protective role exerted by residual beta-cell activity on LH secretion during the early years of DM diminishes with time elapsed after the onset of diabetes mellitus.

Topics: Adult; C-Peptide; Diabetes Mellitus; Female; Gonadotropin-Releasing Hormone; Humans; Insulin; Insulin Secretion; Luteinizing Hormone; Naloxone; Time Factors

Modulation of feeding by opiates, putative satiety peptides, and dopamine was explored in the Chinese hamster, an animal that develops diabetes mellitus in certain inbred strains. Diabetic hamsters were hyperphagic relative to their nondiabetic controls, but both groups exhibited natural circadian variation in feeding. Starvation provoked hyperphagia of about 1-h duration in both groups. Naloxone and butorphanol had no effects on Chinese hamster feeding. Opiate receptor binding on Chinese hamster brains demonstrated no specific binding of naloxone or ethylketocyclazocine, but IR-dynorphin concentrations were comparable with that in rats. N-allylnormetazocine, a sigma-opiate receptor agonist, appeared to stimulate diabetic hamster feeding. Peptides reputed to have satiety effects in rats were without effect in Chinese hamsters: cholecystokinin, bombesin, somatostatin, and pancreatic polypeptide. Calcitonin limited feeding in both groups but may be nonspecific. Dopaminergic blockade by haloperidol also limited feeding, and diabetic hamsters were more sensitive to this. Although Chinese hamsters clearly can modulate their food intake when diabetic, we conclude that the opiatergic and peptidergic influences on feeding are very different from those in rats and may be of little importance.

Topics: Animals; Brain; Calcitonin; Circadian Rhythm; Cricetinae; Cyclazocine; Diabetes Mellitus; Dynorphins; Eating; Endorphins; Ethylketocyclazocine; Feeding Behavior; Haloperidol; Mesocricetus; Naloxone; Peptide Fragments; Phenazocine; Sincalide; Starvation

Beta-endorphin is present in the endocrine pancreas, suggesting that endorphins may have a role in islet-cell function. To evaluate this possibility, we infused synthetic human beta-endorphin intravenously in healthy volunteers and in insulin-dependent diabetic patients. In both groups, beta-endorphin increased plasma glucagon concentrations, and this rise was accompanied by a significant increase in plasma glucose concentrations. In nondiabetic subjects, beta-endorphin also increased plasma insulin concentrations. The threshold dose of beta-endorphin for producing increased plasma concentrations of glucose and glucagon was 0.005 mg--a dose that acutely increased plasma concentrations of beta-endorphin by approximately 40-fold. Glucose, glucagon, and insulin responses to beta-endorphin could not be blocked by intravenous naloxone. These studies suggest that endorphins may be involved in gluco-regulation, that their hyperglycemic action is mediated at least in part by glucagon, and that the effect of beta-endorphin on islet-cell function is relatively resistant to naloxone.

Topics: Adult; beta-Endorphin; Blood Glucose; Diabetes Mellitus; Endorphins; Female; Glucagon; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Naloxone; Sodium Chloride

Serum insulin and blood metabolite responses to oral glucose with and without intravenous naloxone were measured in 24 chlorpropamide-alcohol flush positive and negative Type 2 (non-insulin dependent) diabetic patients with and without retinopathy. In the chlorpropamide-alcohol flush positive patients with retinopathy, fasting blood glucose was increased greater than 40% and the serum triglycerides were increased over twofold compared with each of the other three groups. Following oral glucose (50 g), the chlorpropamide-alcohol flush positive diabetic patients with complications had a lower serum insulin and higher blood glycerol than the other three groups. Thus, chlorpropamide-alcohol flush positive subjects with retinopathy showed distinct metabolic differences from the other three groups. There was no evidence that opiate-receptors influenced the metabolic response to oral glucose in the Type 2 diabetic patients since the infusion of intravenous naloxone produced no effect on the serum insulin or blood metabolites.

Topics: Aged; Blood Glucose; Chlorpropamide; Diabetes Mellitus; Diabetic Retinopathy; Drug Interactions; Ethanol; Face; Female; Glucose Tolerance Test; Glycerol; Humans; Insulin; Male; Middle Aged; Naloxone; Triglycerides

Plasma insulin and glucose concentrations were examined in man in a basal state from central venous samples taken at 1-min intervals for up to 2.5 h. Normal subjects have insulin oscillations of mean period 14 min (significant autocorrelation, p less than 0.0001) with changes in concentration of 40% over 7 min. The pulsation frequency was stable through cholinergic, endorphin, alpha-adrenergic or beta-adrenergic blockade, or small perturbations with glucose or insulin. Stimulation of insulin secretion by intravenous glucose, tolbutamide or sodium salicylate increased the amplitude of the insulin oscillations while the frequency remained stable. Patients with a truncal vagotomy or after Whipple's operation had longer-term oscillations of 33 and 37 min periodicity (autocorrelation: p less than 0.0001), with insulin-associated glucose swings four times larger than those of normal subjects. Type 2 (non-insulin-dependent) diabetic patients had a similarly increased insulin-associated glucose swing of six times that seen in normal subjects. The hypothesis is proposed that the 14-min cycle of insulin production is controlled by a 'pacemaker' which assists glucose homeostasis. The longer 33-37-min oscillations, seen in those with denervation, may arise from a limit-cycle of the feedback loop between insulin from the B cells and glucose from the liver. The vagus may provide hierarchical control of insulin release.

Topics: Adult; Aged; Atropine; Blood Glucose; Diabetes Mellitus; Female; Glucose; Humans; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Naloxone; Phentolamine; Propranolol; Sodium Salicylate; Tolbutamide; Vagotomy

Human diabetes mellitus is characterized by impaired insulin response to intravenous glucose. In search of possible factors which impair insulin release, we have investigated the effect of naloxone, a specific opiate receptor blocker, on insulin responses to glucose in subjects with non-insulin-dependent diabetes, as well as in normal subjects. Naloxone was given as a priming dose of 0.4 mg followed by a constant infusion of either 0.4 mg (N = 7), 2 mg (N = 7), or 4 mg (N = 8) for 90 min. Acute insulin response to glucose (mean change 3-10 min insulin), second phase insulin secretion (change 10-60 min), as well as glucose disappearance rates (%/min) were significantly increased in the diabetics receiving the two higher doses of naloxone (2 and 4 mg, respectively). None of these effects were seen in diabetics receiving saline or in normal subjects receiving naloxone. These results seem to suggest that sensitivity to endogenous opiates may play some part in non-insulin-dependent diabetes.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Naloxone; Receptors, Opioid

Topics: Adult; Blood Glucose; Blushing; Chlorpropamide; Diabetes Mellitus; Drug Interactions; Ethanol; Glucose Tolerance Test; Humans; Insulin; Middle Aged; Naloxone

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Eating; Male; Mice; Mice, Inbred C57BL; Naloxone

Non-insulin-dependent diabetes is associated with facial flushing after alcohol in patients on chlorpropamide (chlorpropamide alcohol flushing, C.P.A.F.) especially when there is a family history of diabetes. C.P.A.F. in three subjects (two diabetics, one non-diabetic) was blocked by the specific opiate antagonist naloxone. In nine subjects (six diabetics) C.P.A.F. was reproduced by the enkephalin analogue with opiate-like activity [D-Ala2, MePhe4, Met (O)-ol] enkephalin (DAMME). C.P.A.F. thus may be due to increased sensitivity to endogenous opiates. DAMME and other substances with opiate-like activity, such as morphine and beta-endorphin, affect carbohydrate metabolism and insulin secretion. Increased sensitivity to endogenous opiates such as enkephalin may thus give rise to non-insulin-dependent diabetes associated with C.P.A.F.

Topics: Alcoholic Beverages; Chlorpropamide; Diabetes Mellitus; Drug Antagonism; Endorphins; Enkephalins; Face; Hormones; Humans; Hypersensitivity; Naloxone; Skin Temperature