beta-endorphin and Diabetes-Mellitus--Type-2

We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels.. This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid β-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma β-endorphin levels. Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use.

Topics: Analgesics, Opioid; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Epidemics; Humans; Obesity

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10 week old male db/db and db/ + mice, collected tissue at 24 and 72 h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1 mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48 h post HI, and collected brain tissue and blood at 72 h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.

Topics: Animals; beta-Endorphin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Ischemic Stroke; Male; Mice; Naltrexone; Neurons

In an attempt to clarify the role of endogenous opioid in peripheral I2-imidazoline receptors activation for improvement of insulin action, bilateral adrenalectomy was carried out in rats with insulin resistance induced by 4-week fructose-rich chow feeding. Single intravenous (i.v.) injection of agmatine (1mg/kg) for 30 min increased the plasma beta-endorphin-like immunoreactivity (BER) in a way parallel to the reduction of plasma glucose in sham-operated fructose chow-fed rats; this action of agmatine was totally abolished by BU224 at sufficient dosage (1mg/kg, i.v.) to block I2-imidazoline receptors. The plasma glucose lowering effect of agmatine was markedly reduced but not totally deleted by adrenalectomy in fructose chow-fed rats. A direct effect of agmatine on glucose homeostasis can thus be considered. The hyperinsulinemic-euglycemic clamp technique was performed to evaluate insulin sensitivity. The effect of agmatine on elevation of the average rate of glucose infusion at the glucose clamp steady state in sham-operated fructose chow-fed rats was lessen in adrenalectomized fructose chow-fed rats, but was completely abolished by BU224. The obtained results suggest that the improvement of insulin sensitivity by agmatine is produced by two mechanisms, stimulation of adrenal gland to enhance beta-endorphin secretion and a direct activation of peripheral I2-imidazoline receptor in tissues, for the amelioration of insulin action.

Topics: Adrenalectomy; Agmatine; Analysis of Variance; Animals; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fructose; Glucose Clamp Technique; Hypoglycemic Agents; Imidazoles; Imidazoline Receptors; Insulin; Insulin Resistance; Male; Rats; Rats, Wistar

Acupuncture at the Zhongwan acupoint has been widely used in traditional Chinese medicine to relieve symptoms of diabetes mellitus. Our study investigated the effect on plasma glucose of electroacupuncture applied at the Zhongwan acupoint in rat diabetic models. Plasma concentrations of insulin, glucagon and beta-endorphin- were also determined using radioimmunoassay. A decrease in plasma glucose was observed in rats after electroacupuncture (15 Hz, 10 mA) for 30 min at the Zhongwan acupoint. This was observed in normal rats and rat models with Type II (non-insulin-dependent) diabetes mellitus. No significant effect on plasma glucose was observed in rat models with Type I (insulin-dependent) diabetes mellitus: neither the streptozotocin (STZ)-induced diabetic rats nor the genetic (BB/W) rats. Further, the hypoglycaemic action of electroacupuncture stimulation disappeared in rats with insulin-resistance induced by an injection of human long-acting insulin repeated daily to cause the loss of tolbutamide-induced hypoglycaemia. An insulin-related action can thus be hypothesised. This hypothesis is supported by an increase in plasma insulin-like immunoreactivity after electroacupuncture stimulation in normal rats. Participation of glucagon was ruled out because there was no change in plasma glucagon-like immunoreactivity resulting from electroacupuncture stimulation. In addition to an increase in plasma beta-endorphin-like immunoreactivity, the plasma glucose lowering action of electroacupuncture stimulation at Zhongwan acupoint was abolished by naloxone in a sufficient dose to block opioid receptors. Thus we suggest that electroacupuncture stimulation at the Zhongwan acupoint induces secretion of endogenous beta-endorphin which reduces plasma glucose concentration in an insulin-dependent manner.

Topics: Acupuncture Points; Animals; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Electroacupuncture; Glucagon; Hypoglycemia; Insulin; Insulin Resistance; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Tolbutamide

Autoradiography was used to study the opioid receptors in soleus and extensor digitorum longus (EDL) muscles from normal mice and mice with type II diabetes. Binding sites for [125I]beta-endorphin were present on the surface membranes in muscles from normal mice. The density of receptors was higher in muscles from obese diabetic mice. The specific delta-opioid ligands DPDPE and [D-Ala2]deltorphin-II inhibited the binding of [125I]beta-endorphin whereas mu and kappa agonists did not. Therefore, the opioid receptor present in skeletal muscle fibers of the mouse is of the delta subtype and the number of these receptors is increased in type II diabetes in the mouse.

Topics: Analgesics; Animals; Autoradiography; beta-Endorphin; Binding, Competitive; Cell Membrane; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Iodine Radioisotopes; Mice; Mice, Obese; Muscle, Skeletal; Obesity; Oligopeptides; Receptors, Opioid, delta; Reference Values

The possible influence of both beta-endorphin and insulin secretion on diabetes development in pregnant women was studied by means of radioimmunoassay technique (RIA-Nichols Institute). The study was carried out by determination of beta endorphins in peripheral blood samples of 28 pregnant women with gestational diabetes. They consisted of two subgroups: 14 women with insulin independence, and 14 with insulin-dependent disease. Beta endorphin increase was found in both groups, according to the progression of gestation, and the rise was significantly higher in the insulin-dependent group. At the same time, insulin application caused a marked growth of beta-endorphins in insulin-dependent group. Beta-endorphins, inhibiting insulin secretion, can influence gestational diabetes development.

Topics: beta-Endorphin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Pregnancy; Time Factors

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hydrocortisone; Male

A lipolytic activity for beta-endorphin (beta EP) has been recently suggested both in vitro and in vivo. In our study we evaluated the relationship between beta EP and blood lipid pattern in Type 2 (non-insulin dependent) diabetic patients. Plasma beta EP, together with plasma beta-lipotropin (beta LPH), ACTH, cortisol and plasma insulin (IRI), was measured by RIA after silicic acid plasma extraction and Sephedex G-75 column chromatography. Although reduced beta EP (7.12 +/- 3.8 fmol/ml) and increased beta LPH (9.3 +/- 3.7 fmol/ml) levels were found in diabetic patients, compared to controls (8.53 +/- 3.3 fmol/ml, p less than 0.05 and 8.34 +/- 2.6 fmol/ml, p less than 0.05, respectively), higher plasma beta EP concentrations were demonstrated in hyperlipidemic diabetic patients (10.3 +/- 3.9 fmol/ml) than in patients with normal blood lipid pattern (4.85 +/- 1.45 fmol/ml, p less than 0.001). Several positive correlations between beta EP, plasma free fatty acids (r = 0.75, p less than 0.001), triglycerides (r = 0.84, p less than 0.001) and VLDL (r = 0.80, p less than 0.001) were found in our patients independently of overweight, hypoglycemic treatment, plasma IRI levels and of the degree of metabolic control. A higher prevalence of micro- and macrovascular complications was demonstrated in hyperlipidemic than in normolipidemic patients. Blood lipid disorders might therefore be associated with increased plasma beta EP levels in Type 2 diabetes.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Humans; Hydrocortisone; Hyperlipidemias; Insulin; Lipids; Male; Middle Aged; Radioimmunoassay

Topics: Adult; beta-Endorphin; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Islets of Langerhans; Male; Middle Aged

Topics: Adult; beta-Endorphin; Diabetes Mellitus, Type 2; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin

To address the possibility that an abnormality in pancreatic beta-endorphin activity might contribute to abnormal insulin secretion in diabetes mellitus, we studied the effects of beta-endorphin infusion on islet function in diabetic patients. The iv infusion of human beta-endorphin at a dose of 0.5 mg/h for 2 h in type-2 non-insulin-dependent diabetic patients (n = 12) raised plasma insulin and glucagon levels and slightly but significantly lowered plasma glucose concentrations. beta-Endorphin infusion also resulted in reappearance of a clear-cut acute insulin response to glucose, while second phase insulin release was increased and glucose disposal accelerated. Acute insulin and glucagon responses to arginine were not increased by beta-endorphin, suggesting that the effect of the opioid on the B cells of the diabetic patients is specific for glucose. An intraislet abnormality of opioid peptides action and/or secretion may play a role in the disturbances of insulin secretion in patients with type-2 diabetes mellitus.

Topics: Arginine; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Endorphins; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged

The effect of human beta-endorphin on plasma glucose, insulin, and glucagon concentrations was studied in patients with noninsulin-dependent diabetes mellitus and in normal subjects. The subjects were divided according to their body weight into lean (body mass index, less than 25) and obese (body mass index, greater than 29.5) groups. In lean subjects, infusion of 0.5 mg/h beta-endorphin caused significant increases in peripheral plasma glucose and glucagon levels, but no change in plasma insulin. In obese subjects, there was an immediate marked increase in both plasma insulin and glucagon concentrations during the beta-endorphin infusion, but the plasma glucose response was lower than that of lean subjects. In lean diabetic patients, beta-endorphin produced significant simultaneous increments in both insulin and glucagon concentrations and significantly decreased plasma glucose levels. These hormonal responses to beta-endorphin were amplified in the obese diabetic patients. There was a significant correlation (r = 0.61; P less than 0.01) between fasting plasma glucose levels and the integrated insulin area in response to beta-endorphin. The infusion of a lower dose of beta-endorphin (0.05 mg/h) in diabetic patients produced similar increments in both insulin and glucagon levels and also decreased plasma glucose concentration. These results indicate that beta-endorphin may have important glucoregulatory effects in man depending on the dose administered, the presence of obesity, and the prevailing plasma glucose concentration.

Topics: Adult; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endorphins; Glucagon; Humans; Hyperglycemia; Infusions, Intravenous; Middle Aged; Obesity

Topics: Animals; beta-Endorphin; Diabetes Mellitus, Type 2; Dogs; Endorphins; Glucose; Humans; Hyperglycemia; Islets of Langerhans; Stress, Physiological

Topics: beta-Endorphin; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endorphins; Humans

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endorphins; Humans; Middle Aged

Successive epinephrine infusions were used as a partial model to examine hormonal and metabolic responses to repeated stress stimuli. As both the endogenous opiates and epinephrine are released in response to stress, we have also studied interactions between epinephrine and B-endorphin. Epinephrine (0.1 microgram/kg . min) was infused for 60 min, followed by a 60-min recovery, in nine normal, conscious dogs. In a similar study, B-endorphin (0.06 microgram/kg . min) was given 30 min before epinephrine, then continuously infused throughout the study (N = 4 dogs). When epinephrine was infused, levels rose to 600-800 pg/ml. The changes in glucagon, B-endorphin, FFA, and hepatic glucose production were similar during both epinephrine infusions, but there was a diminished insulin response, a greater decrease in glucose metabolic clearance, and a greater increase in plasma glucose with the second epinephrine infusion. When B-endorphin was given, plasma levels increased to 5.3 ng/ml. Compared with the infusion of epinephrine alone, there was a much greater rise in plasma glucose due to greater suppression of glucose metabolic clearance. With the second epinephrine infusion, however, the changes in glucose concentration were not substantially different from those seen during the second infusion of epinephrine alone, as both hepatic glucose production and glucose metabolic clearance were suppressed. B-endorphin diminished the insulin and glucagon responses during the first epinephrine infusion and abolished them during the second, but did not alter the FFA, ACTH, or cortisol responses to epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Dogs; Endorphins; Epinephrine; Fatty Acids, Nonesterified; Glucose; Humans; Hydrocortisone; Insulin; Islets of Langerhans; Rabbits

Levels of methionine-enkephalin immunoreactivity (MEI) and beta-endorphin immunoreactivity (BEI) were measured by means of a specific RIA in pituitary, hypothalamus, pancreas, and adrenal glands of db/db and control mice. We found significantly higher levels of MEI in the pituitaries of db/db mice than in either littermate or background strain controls. There was no significant difference in MEI levels in pancreas, adrenal glands, and hypothalamus. There was a significant difference in the BEI levels in the pituitaries of db/db mice compared with those in controls. No significant difference in BEI levels was observed between db/db and control mice in any of the other regions examined. We conclude from the above data that the opiate peptide system in the hypophyseal-hypothalamic axis of the db/db mouse is abnormal and warrants further investigation. The significance of this finding with respect to the possible etiology of diabetes mellitus is discussed.

Topics: Adrenal Glands; Animals; beta-Endorphin; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Endorphins; Enkephalin, Methionine; Hypothalamus; Insulin; Mice; Mice, Mutant Strains; Pancreas; Pituitary Gland

Administration of human beta-endorphin (2.5 mg IV bolus) to three subjects with non-insulin-dependent diabetes mellitus (type II) induced prompt and simultaneous increments in the plasma concentrations of insulin and glucagon lasting up to 90 minutes. In contrast to the hyperglycemic response previously observed in normal subjects following beta-endorphin, these diabetics showed a progressive decline in plasma glucose throughout the study period. This disparity may be related to a relatively greater release of insulin and lesser rise in glucagon observed in diabetic subjects than in nondiabetic subjects. These preliminary findings suggest that further studies to elucidate the role of pancreatic beta-endorphin on glucoregulation may be rewarding.

Topics: Aged; beta-Endorphin; Blood Glucose; Diabetes Mellitus, Type 2; Endorphins; Female; Glucagon; Humans; Insulin; Male; Middle Aged