naloxone and Insulin-Resistance

Beta-endorphin were detected in the endocrine pancreas and seem able to influence insulin and glucagon release. Hence, endogenous opioids could have a role in glucoregulation and in the pathogenesis of obesity beyond the previously detected effects on appetite. Metabolic abnormalities, such as hyperinsulinemia, insulin-resistance and obesity, are common features of polycystic ovary syndrome (PCOS), and seem to have a pathogenetic role in this disorder. A link between opioids and PCOS-related hyperinsulinism is suggested by the finding of altered central opioid tone and elevated beta-endorphins levels, directly correlated with body weight, in these patients. Furthermore, naloxone and naltrexone significantly reduce the insulin response to glucose load only in hyperinsulinemic PCOS patients. This effect is obtained chiefly through an improvement of insulin clearance. Naltrexone is also able to ameliorate the abnormal gonadotrophins secretion and to improve the ovarian responsiveness in obese PCOS women undergoing ovulation induction with exogenous GnRH. Such effects are believed to be obtained through an amelioration of hyperinsulinemia. Gonadal steroids modulate the opioid system both centrally and in peripheral districts. Nevertheless, the decline of ovarian function does not abolish the opioidergic control of glucoregulation. Post-menopausal period is characterised by a high prevalence of hyperinsulinemia and insulin-resistance. In particular, an association between hyperinsulinemia and increased opioid activity was found in postmenopausal women showing a central body fat distribution. Both naloxone and naltrexone ameliorate the metabolic imbalance also when it appears in the climacteric period, and mainly by increasing insulin clearance. The benefits of naltrexone may represent in the future a useful tool for the treatment of women with hyperinsulinism in the clinical practice.

Topics: Clinical Trials as Topic; Endorphins; Female; Humans; Hyperinsulinism; Insulin Resistance; Menopause; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Polycystic Ovary Syndrome

We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.

Topics: Acanthosis Nigricans; Adolescent; Adult; Blood Glucose; Female; Humans; Insulin; Insulin Resistance; Naloxone; Naltrexone; Narcotic Antagonists; Polycystic Ovary Syndrome

Insulin resistance is a metabolic disorder which affects the diabetes mellitus pathophysiology and alters the cell excitability. This study has been designed to evaluate the anti-nociceptive and anti-inflammatory effects of chronic administration of Withania somnifera root (WSR) in fructose drinking water rats.. An experiment was carried out on 48 Wistar-Albino male rats, weighting 200±30 g, which were divided into six groups (n=8): control group (C), control morphine (CM), W. somnifera group (WS) which received WSR (62.5 mg/g diet), W. somnifera naloxone group (WSN) which received WSR and naloxone, fructose (F) group which received fructose drinking water and FWS group which received fructose-enriched drinking water and WSR during the trial period. A biphasic pain response was induced after intraplantar injection of formalin (50 μL, 1%). Pain behavior was measured using Dubuisson methods. The obtained data were analyzed by SPSS software V. 18, using ANOVA and Tukey test. Results were expressed as mean±SD. Statistical differences were considered significant at p<0.05.. The results showed that the insulin resistance index, blood sugar, insulin, IL-6, TNF-α, and acute and chronic pain score in the F group were significantly increased in comparison with the control group, but these parameters in the FWS group were significantly decreased compared with the F group (p<0.001).. Our findings indicated that chronic oral administration of WSR has analgesic and anti-inflammatory effects in fructose drinking water rats and causes improved insulin resistance index.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Diet; Fructose; Glucose Tolerance Test; Insulin; Insulin Resistance; Interleukin-6; Male; Naloxone; Pain; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Withania

To assess the therapeutic effects of naloxone and yohimbine on polycystic ovary syndrome (PCOS) in a rabbit model in terms of body weight and endocrinological parameters (luteinizing hormone, insulin, and estradiol).. A total of 50 adult, reproductively mature female rabbits (Oryctolagus cuniculus) were divided into five groups (n = 10/group). In the control group PCOS was not induced (negative control group), whereas in the remaining four groups (n = 40) PCOS was induced with a single i.m. injection of testosterone daily and were designated as follows: positive control, naloxone-treated (NalT), yohimbine-treated (YohT), and naloxone+yohimbine-treated (NalYT) groups.. A steadily ascending trend was noted in all of the studied parameters in the PCOS-induced group as compared to the negative control group. All the parameters showed a descending trend in the NalT group as compared to the positive control. Regarding the YohT and NalYT groups, all parameters showed a descending trend as compared to the positive control group except for estradiol.. Naloxone therapy either alone or combined with yohimbine improves a wide range of the clinical manifestations of PCOS. Furthermore, we suggest this therapy as an alternative to the conventional therapy with insulin-lowering agents in vogue.

Topics: Animals; Body Mass Index; Female; Follicle Stimulating Hormone; Insulin; Insulin Resistance; Luteinizing Hormone; Naloxone; Polycystic Ovary Syndrome; Rabbits; Testosterone; Yohimbine

In the current study we investigated the effect of mu-opioid receptor activation on insulin sensitivity. In obese Zucker rats, an intravenous injection of loperamide (18 microg/kg, three times daily for 3 days) decreased plasma glucose levels and the glucose-insulin index. Both effects of loperamide were subsequently inhibited by the administration of 10 microg/kg of naloxone or 10 microg/kg of naloxonazine, doses sufficient to block mu-opioid receptors. Other metabolic defects characteristic of obese Zucker rats, such as defects in insulin signaling, the decreased expression of insulin receptor substrate (IRS)-1, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase), and the glucose transporter subtype 4 (GLUT 4), and the reduction of phosphorylation in IRS-1 or Akt serine, were also studied. These defects were all reversed by loperamide treatment in a dose which overcame mu-opioid receptor blockade. Moreover, loss of tolbutamide-induced plasma glucose lowering action (10 mg/kg) in wild-type mice given a fructose-rich diet was markedly delayed by repeated treatment with loperamide; however, this delay induced by loperamide did not occur in mu-opioid receptor knockout mice. These results indicate an important role of peripheral mu-opioid receptors in the loperamide-induced improvement of insulin sensitivity. Our results suggest that activation of peripheral mu-opioid receptors can ameliorate insulin resistance in animals, and provide a new target for therapy of insulin resistance.

Topics: Analysis of Variance; Animals; Blood Glucose; Immunoblotting; Immunoprecipitation; Insulin Resistance; Loperamide; Mice; Mice, Knockout; Naloxone; Rats; Rats, Zucker; Receptors, Opioid, mu

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

This paper has tested the hypothesis that patients with hypothalamic obesity have altered mechanisms controlling insulin secretion when compared to obese patients without hypothalamic injury. Fasting glucose and insulin values were significantly higher in the morning than in the afternoon in the six control obese patients, but there was no diurnal difference in the six patients with hypothalamic obesity (n=6). The control obese subjects showed a diurnal variation in glucose-stimulated insulin secretion, whereas the patients with hypothalamic obesity did not, suggesting that hypothalamic injury had destroyed diurnal rhythms. Naloxone, an opioid antagonist, acutely suppressed fasting insulin in the six patients with essential obesity but had little effect on fasting insulin in the three patients with hypothalamic obesity or in five normal-weight controls. Naloxone increased insulin sensitivity in the obese control patients, but did not affect either insulin secretion or insulin sensitivity in patients with hypothalamic obesity or in normal weight subjects. Our results support the conclusion that hypothalamic obesity disrupts diurnal rhythms, with the suggestion that opioid peptides affect insulin secretion differently in patients with essential obesity as compared to normal weight subjects or those with hypothalamic obesity.

Topics: Adolescent; Adult; Blood Glucose; Body Height; Body Mass Index; Body Weight; Carbohydrates; Case-Control Studies; Circadian Rhythm; Female; Glucose; Glucose Tolerance Test; Humans; Hypothalamic Diseases; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Male; Naloxone; Narcotic Antagonists; Obesity; Time Factors