The Connection between Diabetes, Beta Endorphins and Obesity

Our bodies produce thousands of chemicals that control impulses necessary for everyday function and sensory navigation. Endorphins, a multi-functional chemical, are emitted to counteract and deal with sensations by transmitting electrical impulses through the body to the nervous system. One of their duties is to help combat pain, much in the same way as morphine or codeine does. Endorphins are also responsible for producing the euphoric feeling one usually experiences after sex, or after an intense work out (often referred to as runners-high). Rigorous work outs not only keep us in shape, but also decrease our stress level due to the endorphins released into the body during the exercise. Other ways to trigger the release of these hormones is through the practice of meditation, acupuncture, and massage therapy.

The common obesity of middle age presents as a set of features that strongly resembles the cardinal symptoms of Cushing's syndrome: obesity of the face (moon face), upper back (buffalo hump) and trunk (pot belly) accompanied by signs of protein-wasting. In non-obese individuals who remain at a constant weight throughout life, the proportion of adipose tissue increases with age at the expense of lean tissue loss. Thus, a mild version of Cushing's syndrome may be part of the normal aging process. A more intense version of this process may occur in overweight adults. Excess and chronic activity of two pituitary hormones may contribute to this adiposity. Both hormones are produced in the same pituitary cell by cleavage from a common large precursor known as pro-opiocortin. One hormone is adrenocorticotrophin (ACTH), which stimulates the release of the glucocorticoid hormones. These hormones promote the conversion of bodily proteins to glucose (gluconeogenesis). The other pituitary hormone is beta-endorphin, a stimulant of appetite that causes the release of insulin. This pancreatic hormone promotes the conversion of glucose and fatty acids to triglycerides (lipogenesis). Three different etiologies are suggested for the excessive and chronic action of these two pituitary hormones: tumors that increase the number of cells that synthesize pro-opiocortin: mutant strains such as the genetically obese mouse (ob/ob) and rat (fa/fa) that produce excessive amounts of ACTH and beta-endorphin: and an age-determined shift in the type of cleavage enzymes present in the pro-opiocortin cell that favors ACTH and beta-endorphin production. Lean body weight loss may be an important contributor to the increased medical problems and mortality of the obese.

Administration of human β-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 β-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 non diabetic subjects. These preliminary findings suggest that further studies to elucidate the role of pancreatic β-endorphin on glucose regulation may be rewarding.
Naltrexone, an opiate antagonist, was administered to young obese (ob/ob) and lean mice for five weeks. Animals had continuous access to food and received 10 mg/kg SC twice daily with equivalent volumes of saline given to controls. The effects on body weight, and pituitary and plasma levels of β-endorphin-like material were measured. Naltrexone-injected obese animals gained weight more slowly over the first three weeks while the weight gain of lean animals was not affected by naltrexone. Plasma levels of β-endorphin were shown to be significantly higher in untreated ob/ob mice and this difference increased with age (4–20 weeks). With naltrexone treatment, plasma levels in +/? mice rose and exceeded those in ob/ob. Saline treatment appeared to be a stress, and pituitary β-endorphins rose 4–6 fold in ob/ob compared with +/?. While naltrexone reduced the levels in ob/ob pituitary towards normal, no effect on β-endorphin levels in pituitary of lean mice was obtained. In vitro studies of effects of the opiate antagonists, naloxone, on insulin secretion by isolated islets provided additional evidence of resistance of lean mice to naloxone relative to ob/ob. (IRI secretion fell only in naloxone treated ob/ob islets.) These observations support the contention that this form of genetic obesity is characterized by elevated endogenous opiate levels and an increased sensitivity to opiate antagonists such as naltrexone or naloxone.

In a double-blind study, eight patients with symptomatic myocardial ischemia and nine with asymptomatic myocardial ischemia were compared during physical exercise under naloxone (6 mg i.v.) or placebo. Plasma beta-endorphin, cortisol and catecholamines were measured before exercise, during maximal exercise, and 10, 20 and 60 min after exercise. A tourniquet pain test (on the forearm, under control of transcutaneous PO2), and an electrical pain test (intracutaneous electrode placed in the finger with the electrical stimulus under computer control and two-interval forced-choice psycho-physical technique) were performed before exercise as well as immediately after, and 60 min after exercise. Plasma beta-endorphin levels increased significantly (P < 0.01) during exercise in symptomatic and asymptomatic patient groups; every patient showed an increase on beta endorphins during and after exercise. However, the increase found in beta-endorphins during and after exercise was significantly larger (P < 0.01) in asymptomatic than in symptomatic patients. After naloxone, this difference was no longer evident. Angina pectoris during exercise was reported with less latency in symptomatic patients (P < 0.05) and occurred in two of nine asymptomatic patients following naloxone. The time course of plasma cortisol levels exhibited the same pattern as beta-endorphins with the same significant differences between symptomatic and asymptomatic groups. Electrical pain thresholds, though on average higher in asymptomatic patients (2.21 mA vs. 0.79 mA), were not affected by exercise or naloxone. Asymptomatic patients required more time to reach pain thresholds in the tourniquet pain test (P < 0.02). After exercise, tourniquet pain thresholds were significantly lower (P < 0.01) under naloxone compared with placebo. The results suggest that there are quantitative differences in the endorphinergic regulation of pain in patients with symptomatic and asymptomatic myocardial ischemia.

The infusion of synthetic human β-endorphin (4.5 ng/kg/min) produced the following:
(1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C- peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels;
(2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of β-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pre treatment did not induce any change of the flat glucose and hormonal responses to β-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma β-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.
Investigation has been carried out on 50 samples of fetal pancreata from the 10th to the 32nd week of gestation using the PAP technique. (3-Endorphin-reactive cells were morphometrically recorded by means of the point-counting method.
β-Endorphin reactivity occurred for the first time during the 15th week. During further development, β-endorphin cells were found inside and outside the islets. From the 18th to the 23rd week, these cells were primarily localized in the islet periphery. From the 24th week, they rearranged and occurred in irregular positions mixed with other islet cells. This rearrangement took place with a 4 week delay compared with the basic cell types of the islet organ.
The extrainsular portion of these cells in the exocrine parenchyma varied between 0.3 % in the 27th week and up to 10% in the 22nd week. Concerning the adult human pancreas, it has been suggested whether (3-endorphin cells may be a 6th basic cell type of the islet organ. Previous studies on the coexistence of somatostatin, glucagon and (3-endorphin in the same islet cell and the morphometric analysis would support this assumption.
Endogenous opioids have a tonic inhibitory effect on sympathetic tone and have been implicated in the pathophysiology of vasodepressor syncope. Plasma beta endorphin concentrations increase after vasodepressor syncope induced by exercise or by fasting. AIMS--To take frequent samples for plasma beta endorphin estimation during tilt testing, and to determine whether plasma beta endorphin increased before the start of syncope. PATIENTS--24 patients undergoing tilt testing for investigation of unexplained syncope. SETTING--Tertiary referral center. Blood samples were obtained during 70 degrees head up tilt testing. Plasma beta endorphin concentrations were estimated by radioimmunoassay (mean(SD) pmol/l). RESULTS--Patients with a positive test showed a rise in beta endorphin concentrations before syncope baseline 4.4(1.5) v start of syncope 8.5(3.1), p < 0.002). In contrast, patients with a negative test showed no change in beta endorphin concentrations (baseline 3.4(1.0) v end of test 4.5(2.3), NS). After syncope all patients showed a large secondary increase in beta endorphins (32.3(18.6)). An increase in plasma beta endorphins precedes vasodepressor syncope. This finding supports a pathophysiological role for endogenous opioids in diabetes, obesity and other related disorders.