beta-endorphin and Insulin-Resistance

Metformin has been widely used in clinical type 2 diabetes treatment and prevention. The present study was designed to explore the effect on people with a sedentary lifestyle at therapeutic doses. Twenty-two physically-inactive volunteers with normal glucose tolerance were studied. Escalating doses of metformin in low-dose (250 mg), intermediate-dose (500 mg), and high-dose (750 mg) treatment three times per day were administrated into each subject for a three-week treatment period. Fasting plasma glucose, A1C, HOMA-IR for insulin resistance, lipid profile, and plasma beta-endorphin-like immunoreactivity (BER) were measured before treatment and weekly at the end of each dosing period. Metformin significantly reduced fasting plasma glucose and HOMA-IR in healthy humans after receiving this treatment at therapeutic doses including low-dose (5 %, 17 %), intermediate-dose (6 %, 25 %) and high-dose treatment (6 %, 21 %). Plasma BER was also increased from 135.46 +/- 61.73 pg/ml to 137.52 +/- 66.11 pg/ml by low-dosing (p = 0.39), to 139.17 +/- 64.08 pg/ml by intermediate-dosing (p = 0.32), and to 149.59 +/- 63.32 pg/ml by high-dosing (p < 0.05). Also, serum cholesterol decreased significantly using metformin at therapeutic doses including low-dose (4 %), intermediate-dose (8 %) and high-dose treatment (7 %). However, metformin failed to modify levels of serum HDL-cholesterol and C-reactive protein (CRP) in healthy subjects. Also, the reduction of serum cholesterol by metformin did not correlate to the increase in insulin sensitivity. In conclusion, metformin causes a significant parallel increase in insulin sensitivity and plasma beta-endorphin level in human subjects.

Topics: Adult; beta-Endorphin; Blood Glucose; C-Reactive Protein; Cholesterol, HDL; Dose-Response Relationship, Drug; Fasting; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Metformin; Middle Aged

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, β-endorphin (β-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF β-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and β-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and β-EP declined in CSF, whereas acutely, only β-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Topics: Adult; Agouti-Related Protein; beta-Endorphin; Brain; Caloric Restriction; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Melanocortins; Middle Aged; Obesity; Pro-Opiomelanocortin; Radioimmunoassay; Young Adult

This pilot study describes a relationship between insulin resistance and μ-opioid neurotransmission in limbic appetite and mood-regulating regions in women with polycystic ovary syndrome (PCOS), suggesting that insulin-opioid interactions may contribute to behavioral and reproductive pathologies of PCOS. We found that [1] patients with PCOS who are insulin-resistant (n = 7) had greater limbic μ-opioid receptor availability (nondisplaceable binding potential) than controls (n = 5); [2] receptor availability was correlated with severity of insulin resistance; and [3] receptor availability normalized after insulin-regulating treatment.

Topics: Adult; beta-Endorphin; Binding Sites; Brain; Carbon Radioisotopes; Case-Control Studies; Female; Fentanyl; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Magnetic Resonance Imaging; Metformin; Michigan; Pilot Projects; Polycystic Ovary Syndrome; Positron-Emission Tomography; Receptors, Opioid, mu; Time Factors; Treatment Outcome; Young Adult

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

In an attempt to probe the effect of beta-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and beta-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of beta-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid mu-receptors. Opioid mu-receptors may therefore be activated by beta-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of beta-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. beta-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of beta-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after beta-endorphin infusion. Infusion of beta-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.

Topics: Animals; beta-Endorphin; Diet; Fructose; Glucose; Glucose Transporter Type 4; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor, Insulin; Serine; Signal Transduction; Tyrosine

In this study, the authors assessed the endocrine system and glucose tolerance in obese and non-obese women chronically treated with typical antipsychotic drugs (AP). In particular, we tested the hypotheses that these subjects display hypogonadism and increased insulin resistance compared to healthy weight-matched controls, as these abnormalities create a tendency towards excessive body weight gain. Twenty-six AP-treated women were matched with 26 healthy women by age, body mass index and day of the menstrual cycle. The following serum variables were evaluated in each subject: glucose tolerance after an oral glucose overload, insulin, leptin, beta-endorphin, reproductive hormones, adrenal steroids and lipids. Compared to controls, AP-treated women displayed significantly higher levels of basal glucose, insulin after 60 min of the glucose overload, prolactin, thyroid stimulating hormone and beta-endorphin, with lower levels of C-Peptide, progesterone, 17-OH progesterone, androstenedione and high-density lipoprotein cholesterol. The levels of estradiol, estrone and leptin did not differ between the groups. Thus, women treated with typical AP appeared to display more insulin resistance than healthy controls, predisposing them to excessive weight gain. Insulin sensitivity might be further impaired when the subject switches to atypical AP administration. Metformin and related agents may reduce body weight in these subjects. The high levels of the opiate beta-endorphin suggest that opiate antagonists such as naloxone and naltrexone might be useful as well. Even though the luteal phase of the menstrual cycle appears to be severely disturbed, the normal serum levels of estradiol and estrone do not support the proposal derived from animal experimental studies about the use of estrogens or tamoxifen to counteract AP-induced obesity.

Topics: Adrenal Glands; Adult; Antipsychotic Agents; beta-Endorphin; Blood Glucose; C-Peptide; Endocrine System; Female; Gonadal Steroid Hormones; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Lipids; Multivariate Analysis; Obesity; Prolactin; Sex Hormone-Binding Globulin; Thyroid Hormones

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

To study the associations of obesity (as body mass index (BMI)), of body fat distribution (as waist to hip ratio (WHR)) and of beta-endorphinaemia (beta-EP-aemia) with fasting insulin and glucose concentrations, with insulin secretion (as first phase insulin response (FPIR)) and with insulin sensitivity (SI) in obese women.. a cross-sectional study of insulin sensitivity in obese women.. 45 obese women (age: 20-70 y, BMI: 27-50).. Frequently sampled intravenous glucose tolerance test (FSIGTT), FPIR, fasting glucose, fasting insulin, BMI, body fat topography (WHR), beta-EP-aemia, plasma ACTH.. In univariate analysis the following positive associations were observed: fasting glucose with age and WHR, fasting insulin with BMI and WHR, beta-EP plasma concentration with WHR; SI was negatively associated with BMI, WHR and beta-EP plasma concentrations. This pattern of associations remained unaltered in multivariate analysis including age, BMI and WHR as independent variables. The contribution of beta-EP plasma concentrations to SI variability was corroborated by a stepwise multiple regression analysis: 53.8% of SI variation could be explained by BMI (30.7%), by beta-EP plasma concentrations (17.2%) and by WHR (5.9%). Finally, women were divided into two groups according to whether they had a peripheral (P-BFD, WHR < or = 0.80, n = 24) or an abdominal (A-BFD, WHR > or = 0.85, n = 16) body fat distribution. After adjustment for age and BMI, SI values were lower while beta-EP and ACTH plasma concentrations were higher in the A-BFD compared to the P-BFD group. In this latter group, 54.8% of SI variation was explained by the same variables as in the whole group. In the A-BFD group, higher WHR was associated with lower FPIR.. 1) The major finding of this study is that, in non-diabetic obese women (especially those with a P-BFD), higher beta-EP plasma concentrations are associated with lower insulin sensitivity. This association is independent of both the magnitude of obesity and the pattern of fat distribution, although these two parameters are strong predictors of SI. 2) The major reduction in SI observed in women with A-BFD probably results from the additive effects of obesity, of elevated beta-EP plasma concentrations and of metabolic and endocrine alterations in relation with the central pattern of fat distribution.

Topics: Adult; Aged; beta-Endorphin; Body Constitution; Cross-Sectional Studies; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Middle Aged; Obesity; Regression Analysis

We examined the effects of an oral glucose load on plasma insulin, androgens, and beta-endorphin (beta EP) concentrations in patients carefully selected as having polycystic ovary syndrome (PCOS) and normal glucose tolerance. Our aim was to verify whether insulin resistance is a common feature of PCOS and to differentiate the metabolic abnormalities related to PCOS from those associated with obesity. Plasma immunoreactive insulin (IRI), C-peptide (C-PR), testosterone, androstenedione, dehydroepiandrosterone sulfate, ACTH, and beta EP responses to a 3-h oral glucose tolerance test (OGTT) were evaluated in 10 obese (OB-PCOS) and 10 nonobese (NO-PCOS) patients with PCOS and in 7 obese and 7 nonobese ovulatory controls. OB-PCOS and NO-PCOS did not differ significantly from weight-matched controls in the IRI response, but had a significantly higher C-PR response in terms of mean postglucose load levels and mean incremental areas. During OGTT, mean plasma levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate declined in both PCOS groups as well as in controls, and no significant correlation between the plasma androgen and IRI or C-PR responses was found. The ACTH response in OB-PCOS and NO-PCOS was similar to that in controls, with a progressive decrease until 180 min. A similar decline in plasma beta EP was found in controls, whereas no change in plasma beta EP was observed in OB-PCOS and NO-PCOS. These findings indicate that independently of the presence of obesity, PCOS patients have enhanced insulin secretion in response to OGTT and show a peculiar pattern of changes in plasma beta EP.

Topics: Administration, Oral; Adult; Androgens; Androstenedione; beta-Endorphin; C-Peptide; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Obesity; Polycystic Ovary Syndrome; Radioimmunoassay; Testosterone

It is speculated that endogenous opioid peptides are involved in glucose metabolism and that their homeostasis might be disturbed in obesity. Despite a different response of the pancreatic beta-cells after beta-endorphin and naloxone injections between obese patients and normal weight controls, there is little knowledge concerning the direct influence of a glucose load on beta-endorphin plasma levels, especially with respect to various nutrition states. During exploration of this topic we gained further insight on the difference of basal beta-endorphin plasma levels between normal and overweight persons. We compared beta-endorphin plasma levels during an oral glucose load in 60 obese, non-diabetic patients and in 20 normal weight controls. We also studied 40 of the obese patients after a weight reduction of 2.1 kg/m2. The following results were obtained: (1) Normal weight females have significantly lower (P less than 0.05) basal beta-endorphin levels compared to the male controls. This difference in gender is abolished in obesity where female and male patients do not differ in basal beta-endorphin plasma levels. Therefore, the difference between normal and overweight persons in beta-endorphin plasma levels was restricted to the subgroup of females. We suppose that former neglect of this difference in gender explains most of the so far reported discrepant results. (2) During the oral glucose tolerance test the beta-endorphin plasma values remained constant in the obese group. Despite improved insulin sensitivity after weight reduction there was still no change of beta-endorphin plasma levels both during the OGTT and when compared to the values before weight reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; beta-Endorphin; Blood Glucose; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Sex Characteristics; Weight Loss