Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identifying the role of the melanocortin system in regulating energy homeostasis has relied on both genetic and pharmacological studies. The key findings included 1) that the coat color phenotype in the lethal yellow (A(Y)/a) mouse is due to antagonism of the melanocortin-1 receptor (MC1R) by the agouti gene product; 2) the MC3R and MC4R are expressed in CNS centers involved in energy homeostasis, and 3) the combined results of pharmacological studies showing that agouti is an antagonist of the MC4R and transgenic studies showing that inhibition or loss of the MC4R recapitulate the lethal yellow phenotype. Pro-opiomelanocortin (POMC), MC3R, and MC4R knockouts are obese and are now being used to further analyze melanocortin receptor function. The obesity phenotype observed in the MC3R and MC4R knockouts (KO) differ markedly. MC4RKO mice are hyperphagic, do not regulate pathways that increase energy expenditure (diet-induced thermogenesis) and physical activity in response to hyperphagia, and can develop type 2 diabetes. In contrast, MC3R deficient mice are not hyperphagic, have a normal metabolic response to increased energy consumption, and do not develop diabetes. The mechanism underlying the increased adiposity in the MC3R knockout remains unclear, but might be related to changes in nutrient partitioning or physical activity.
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PMID:The melanocortin receptors: lessons from knockout models. 1235 99

The ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP) multigene family contains five members. NPP1-3 are type II transmembrane metalloenzymes characterized by a similar modular structure composed of a short intracellular domain, a single transmembrane domain and an extracellular domain containing a conserved catalytic site. The short intracellular domain of NPP1 has a basolateral membrane-targeting signal while NPP3 is targeted to the apical surface of polarized cells. NPP4-5 detected by database searches have a predicted type I membrane orientation but have not yet been functionally characterized. E-NPPs have been detected in almost all tissues often confined to specific substructures or cell types. In some cell types, NPP1 expression is constitutive or can be induced by TGF-beta and glucocorticoids, but the signal transduction pathways that control expression are poorly documented. NPP1-3 have a broad substrate specificity which may reflect their role in a host of physiological and biochemical processes including bone mineralization, calcification of ligaments and joint capsules, modulation of purinergic receptor signalling, nucleotide recycling, and cell motility. Abnormal NPP expression is involved in pathological mineralization, crystal depositions in joints, invasion and metastasis of cancer cells, and type 2 diabetes. In this review we summarize the present knowledge on the structure and the physiological and biochemical functions of E-NPP and their contribution to the pathogenesis of diseases.
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PMID:Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. 1275 29

Proopiomelanocortin (POMC) is expressed in the arcuate nucleus of the hypothalamus (ARC) and the commissural nucleus of the solitary tract (cNTS). Post-translational processing of POMC produces two melanocortin receptor ligands, alpha- and gamma-melanocyte-stimulating hormone (MSH). Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a population of ARC neurons that co-express neuropeptide Y (NPY) and the MC3R/MC4R antagonist agouti-related peptide (AgRP). MC4R haploinsufficient humans and MC4R knockout (MC4RKO) mice exhibit increased adiposity and linear growth. MC4RKO mice exhibit hyperleptinemia and hyperinsulinemia and sometimes, but not always, develop type 2 diabetes (T2D). Individually housed MC4RKO mice fed low-fat diets are not hyperphagic when food intake is corrected for lean mass, whereas hyperphagia is observed after the introduction of diets with increased fat content. POMC knockout (POMCKO) mice are similar in that the severity of hyperphagia increases with the introduction of high-fat diets. By contrast, targeted deletion of the MC3R in the mouse results in increased adiposity despite the absence of hyperphagia. MC3RKO mice also exhibit reduced linear growth and lean mass; while MC3RKO mice are hyperleptinemic and hyperinsulinemic, the development of T2D has not been reported. The MC4R, but not the MC3R, is required for the stimulation of energy expenditure in response to melanocortin agonists and voluntary hyperphagia. Evidence for altered physical activity has also been reported for both knockout models. Analysis of MC4RKO mice indicates that this receptor is involved in rapidly coordinating energy consumption with energy expenditure through diet-induced thermogenesis and activity.
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PMID:Knockout studies defining different roles for melanocortin receptors in energy homeostasis. 1285 22

The salt-inducible kinases (SIKs) are a family of related serine-threonine kinases. In cultured adrenocortical cells, SIK1 is rapidly but transiently induced by adrenocorticotropin (ACTH) treatment, suggesting that it contributes to ACTH-mediated induction of steroidogenic enzymes. However, ACTH treatment of Y1 mouse adrenocortical cells stimulates a rapid translocation of SIK1 from the nucleus to the cytoplasm, and SIK1 represses the transcription of a steroidogenic enzyme by inhibiting the action of cAMP-responsive elements in the promoter. These studies suggest that SIK1 has a role in the fine tuning of steroidogenic enzyme production during the initial phase of steroidogenesis. SIK2 is found in adipocytes and phosphorylates a specific serine residue in insulin receptor substrate-1. This finding, along with the fact that its expression is raised in the white adipose tissue of mice with type 2 diabetes mellitus, suggests that SIK2 might be involved in metabolic regulation in adipose tissue. Thus, members of the SIK family are emerging as important modulators of key processes such as steroid hormone biosynthesis by the adrenal cortex and insulin signaling in adipocytes.
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PMID:Salt-inducible kinase in steroidogenesis and adipogenesis. 1469 22

The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.
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PMID:[Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome]. 1572 52

Abstract Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob / ob and db / db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob / ob and db / db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob / ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions.
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PMID:Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. 1598 91

In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine-phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is alpha-melanocyte-stimulating hormone (alpha-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the pro-opiomelanocortin (POMC) precursor protein. Recent results have shown that alpha-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. alpha-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. alpha-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with alpha-MSH suggest reciprocal effects: alpha-MSH appears to increase sensitivity to insulin when present in the CNS, while alpha-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, alpha-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.
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PMID:The role of melanocyte-stimulating hormone in insulin resistance and type 2 diabetes mellitus. 1639 14

Sexual dimorphisms in hypoglycemic counterregulation are well documented in young healthy and type 1 diabetic subjects. Here, we questioned whether sex differences in counterregulation are present also in type 2 diabetic patients who are in a postmenopausal state. In an attempt to answer this question, we examined hormonal responses to a single-step hypoglycemic clamp (50 mg/dL) in 15 postmenopausal women and 15 age-matched men. Patients were also matched for body mass index, HbA(1c), diabetes duration, and diabetes therapy. In addition to hormonal counterregulation, perception of symptoms as well as aspects of neurocognitive function (short-term memory of words and reaction time on an auditory vigilance task) was assessed at baseline and during the hypoglycemic clamp. Hypoglycemia induced a profound rise in almost all counterregulatory hormones, that is, epinephrine, norepinephrine, corticotropin, cortisol, and growth hormone (all P < .007), except for glucagon, which slightly decreased (P = .014). However, none of the responses differed between sexes (all P > .256). In addition, perceived symptoms (P < .001) as well as reaction time on the vigilance task (P < .001) increased, and short-term memory performance tended to deteriorate (P = .091) during hypoglycemia. Again these changes did not differ between the sexes (all P > .370). In sum, data suggest that, in contrast to previous observations in young, healthy, and type 1 diabetic subjects, sex does not represent an important determinant of hormonal, subjective, and neurocognitive responses to hypoglycemia in postmenopausal type 2 diabetic patients. However, the women in our study were all postmenopausal and not receiving hormone replacement therapy. Therefore, our results cannot be generalized to female patients with type 2 diabetes who are premenopausal or on hormone replacement therapy, that is, conditions characterized by increased blood estrogen levels.
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PMID:Hormonal, subjective, and neurocognitive responses to brief hypoglycemia in postmenopausal women and age-matched men with type 2 diabetes mellitus. 1648 76

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.
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PMID:Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects. 1652 11

Symptomatic diabetic neuropathy has been found to be associated with hypothalamus-pituitary-adrenal (HPA) axis hyperfunction, but no data are available about HPA activity in diabetic patients with asymptomatic autonomic imbalance. To evaluate HPA axis activity in patients with type 2 diabetes mellitus (T2DM) in relation to the presence or the absence of subclinical parasympathetic or sympathetic neuronal dysfunction, we performed an observational study on 59 consecutive type 2 diabetic patients without chronic complications and/or symptoms of neuropathy or hypercortisolism. The following were measured: serum cortisol at 08:00 am and at midnight (F8 and F24, respectively), post-dexamethasone suppression cortisol, 24-hour urinary free cortisol (UFC), and morning corticotropin (ACTH). Deep-breathing (DB) and LS (LS) autonomic tests were performed to assess the parasympathetic function; postural hypotension test was performed to evaluate sympathetic activity. Patients were subdivided into 4 groups: subjects with parasympathetic failure (group A), sympathetic failure (group B), both para- and sympathetic failure (group C), and without autonomic failure (group D). Hypothalamus-pituitary-adrenal activity was increased in group A compared with group D (UFC, 48.6 +/- 21.4 vs 21.6 +/- 9.8 microg/24 h, P < .0001; ACTH, 27.0 +/- 8.6 vs 15.7 +/- 5.7 pg/dL, P < .01; F8, 20.4 +/- 4.5 vs 13.6 +/- 3.8 microg/dL, P < .05; post-dexamethasone suppression cortisol, 1.2 +/- 0.4 vs 0.8 +/- 0.6 microg/dL, P < .05, respectively) and group B (UFC, 26.3 +/- 11.0 microg/24 h, P < .0001; ACTH, 19.9 +/- 8.0 pg/dL, P < .05). Regression analysis showed that UFC levels were significantly associated with the deep-breathing test (beta = -0.40, P = .004) and tended to be associated with the lying-to-standing test (beta = -0.26, P = .065), whereas body mass index, glycated hemoglobin, and duration of disease were not. Type 2 diabetic patients with asymptomatic parasympathetic derangement have increased activity of HPA axis, related to the degree of the neuronal dysfunction.
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PMID:Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance. 1683 52


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