Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
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PMID:GAD2 on chromosome 10p12 is a candidate gene for human obesity. 1614 52

Several endocrine abnormalities are reported in obesity. Some of these abnormalities are considered as causative factors for the development of obesity, whereas others are considered to be secondary effects of obesity and usually are restored after weight loss. Thyroid hormones usually are normal in obesity, with the exception of T3 which is elevated. Prolactin is normal but prolactin response to different stimuli is blunted. GH is low and GH response to stimuli is blunted. IGF-I levels are normal or elevated. Cortisol, ACTH, and urine free cortisol levels are usually normal; however, a hyperresponsiveness of the HPA axis with increased cortisol and ACTH response to stimulatory tests is observed in centrally obese individuals. Total testosterone and SHBG levels are low, but free testosterone levels are usually normal in obese men. LH and FSH levels usually are normal and estrogens are elevated. Norepinephrine levels are elevated, whereas epinephrine levels are low or normal. Aldosterone levels are elevated but renin activity is usually normal. Parathyroid hormone levels are elevated with normal serum calcium levels and increased urine calcium levels. Monogenic mutations that result in severe obesity have been described in several individuals. Also, several endocrine diseases have obesity as one their clinical manifestations. Hypothyroidism, Cushing's syndrome, GH and testosterone deficiency, polycystic ovarian syndrome, insulinoma, hypothalamic lesions, and genetic syndromes often present with obesity. In most of these conditions, appropriate treatment of the primary disease results in weight loss. In addition, the fat cell has been found to be an endocrine organ that produces several peptides that are bioactive and participate in the regulation of adipocyte function.
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PMID:Obesity and endocrine disease. 1471 Oct 67

We describe six patients (five women and one man; median age, 47 years; range, 39 to 54) with postprandial symptoms of neuroglycopenia owing to endogenous hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass surgery. Except for equivocal evidence in one patient, there was no radiologic evidence of insulinoma. Selective arterial calcium-stimulation tests, positive in each patient, were used to guide partial pancreatectomy. Nesidioblastosis was identified in resected specimens from each patient, and multiple insulinomas were identified in one. Hypoglycemic symptoms diminished postoperatively. We speculate that hyperfunction of pancreatic islets did not lead to obesity but that beta-cell trophic factors may have increased as a result of gastric bypass.
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PMID:Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. 1638 76

In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.
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PMID:SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. 1614 4

We report two cases of insulinoma in advanced age patients considered unsuitable for surgery, in whom single daily doses of octreotide successfully improved hypoglycemia and hyperinsulinemia. The biological half-life of octreotide is about 100 min, hence it is customary to use two or three administrations per day to prevent hypoglycemia in insulinoma patients. The first case was a 76-year-old woman who presented with hyperinsulinemic hypoglycemia. Computed tomography (CT) and magnetic resonance imaging did not identify a tumor in the pancreas but a 1.5-cm tumor was found in the pancreatic body on abdominal angiography and selective arterial calcium stimulation and hepatic venous sampling (ASVS) were compatible with insulinoma. The patient refused surgery, but was successfully treated with octreotide at 50 microg subcutaneous injection once daily. Since the treatment was started (1 year), she has not suffered hypoglycemia. Case 2 was an 85-year-old woman who presented with hyperinsulinemic hypoglycemia. CT identified a 1.5-cm tumor in the pancreatic uncus, but she was considered unsuitable for surgery due to advanced age, obesity and cardiopulmonary dysfunction. Octreotide at 100 microg subcutaneous injection once daily prevented further hypoglycemic attacks, but two months later, postprandial plasma glucose was elevated. Octreotide was gradually reduced to 50 microg once daily. Three years have passed since the treatment without any hypoglycemic attack. Successful treatment with octreotide once daily could be due to old-age-related slow metabolism and could be potentially considered as the treatment of choice for elderly patients with insulinoma especially those considered unsuitable for surgery.
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PMID:Successful treatment of insulinoma by a single daily dose of octreotide in two elderly female patients. 1654 76

Sex-determining region Y-box (SOX) 6 negatively regulates glucose-stimulated insulin secretion from beta-cells and is a down-regulated transcription factor in the pancreatic islet cells of hyperinsulinemic obese mice. To determine the contribution of SOX6 to insulin resistance, we analyzed the effects of SOX6 on cell proliferation. Small interfering RNA-mediated attenuation of SOX6 expression stimulated the proliferation of insulinoma INS-1E and NIH-3T3 cells, whereas retroviral overexpression resulted in inhibition of cell growth. Quantitative real time-PCR analysis revealed that the levels of cyclin D1 transcripts were markedly decreased by SOX6 overexpression. Luciferase-reporter assay with beta-catenin showed that SOX6 suppresses cyclin D1 promoter activities. In vitro binding experiments showed that the LZ/Q domain of SOX6 physically interacts with armadillo repeats 1-4 of beta-catenin. Furthermore, chromatin immunoprecipitation assay revealed that increased SOX6 expression significantly reduced the levels of acetylated histones H3 and H4 at the cyclin D1 promoter. By using a histone deacetylase (HDAC) inhibitor and co-immunoprecipitation analysis, we showed that SOX6 suppressed cyclin D1 activities by interacting withbeta-catenin and HDAC1. The data presented suggest that SOX6 may be an important factor in obesity-related insulin resistance.
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PMID:SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation. 1741 98

In insulinoma cell lines proliferation and insulin gene transcription are stimulated by growth hormone and prolactin, which convey their signals through the transcription factors Stat5a and 5b (referred to as Stat5). However, the contribution of Stat5 to the physiology of beta-cells in vivo could not be assessed directly since Stat5-null mice die perinataly. To explore the physiological role of Stat5 in the mouse, the corresponding gene locus targeted with loxP sites was inactivated in beta-cells using two lines of Cre recombinase expressing transgenic mice. While the RIP-Cre transgene is active in pancreatic beta-cells and the hypothalamus, the Pdx1-Cre transgene is active in precursor cells of the endocrine and exocrine pancreas. Mice carrying two floxed Stat5alleles and a RIP-Cre transgene developed mild obesity, were hyperglycemic and exhibited impaired glucose tolerance. Since RIP-Cre transgenic mice by themselves display some glucose intolerance, the significance of these data is unclear. In contrast, mice, in which the Stat5 locus had been deleted with the Pdx1-Cre transgene, developed functional islets and were glucose tolerant. Mild glucose intolerance occurred with age. We conclude that Stat5 is not essential for islet development but may modulate beta-cell function.
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PMID:The transcription factors Stat5a/b are not required for islet development but modulate pancreatic beta-cell physiology upon aging. 1759 54

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.
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PMID:Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. 1770 23

Guggulsterone has been used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on pancreatic beta cells is unknown. Therefore, in this study, the effect of guggulsterone on IL-1beta- and IFN-gamma-induced beta-cell damage was investigated. Treatment of RINm5F (RIN) rat insulinoma cells with IL-1beta and IFN-gamma induced cell damage, and this damage was well correlated with nitric oxide (NO) and prostaglandin E2 (PGE2) production. However, guggulsterone completely prevented cytokines-mediated cytotoxicity, as well as NO and PGE2 production, and these effects were correlated with reduced levels of the inducible form of NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein expressions. The molecular mechanism by which guggulsterone inhibits iNOS and COX-2 gene expressions appeared to involve the inhibition of NF-kappaB activation. The cytoprotective effects of guggulsterone were also mediated through the suppression of the JAK/STAT pathway. Cells treated with the cytokines downregulated the protein level of SOCS-3, however pretreatment with guggulsterone attenuated this decrease. Additionally, in a second set of experiments in which rat islets were used, the findings regarding the beta-cell protective effects of guggulsterone were essentially the same as those observed when RIN cells were used; guggulsterone prevented cytokines-induced NO and PGE2 production, iNOS and COX-2 expressions, JAK/STAT activation, NF-kappaB activation, downregulation of SOCS-3, and impairment of glucose-stimulated insulin secretion. Collectively, these results suggest that guggulsterone may be used to preserve functional beta-cell mass.
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PMID:Guggulsterone, a plant sterol, inhibits NF-kappaB activation and protects pancreatic beta cells from cytokine toxicity. 1834 24

The total pancreatic beta cell mass is reduced in individuals with type 2 diabetes. We analyzed the islets of leptin receptor-deficient (Lepr-/-) mice, a model animal for type 2 diabetes with obesity. The plasma insulin levels in Lepr-/- mice peaked at approximately 7 weeks, an age at which the animals manifest normoglycemia to moderate hyperglycemia. Consistent with this, the beta cell mass was enlarged as compared with Lepr+/- mice, and it decreased thereafter. Thus, we focused on the islets of Lepr-/- mice at 7 weeks to elucidate the mechanism underlying beta cell failure. Endoplasmic reticulum (ER) stress was enhanced in beta cells of Lepr-/- mice at 7 weeks, as indicated by the increase in c-Jun and eIF2 alpha phosphorylation. Lepr-/- mice also exhibited a reduction in insulin signaling in beta cells at 7 weeks, as indicated by the decrease in Akt phosphorylation. These results indicate that both augmented ER stress and reduced insulin signaling occur before the onset of frank diabetes. Next, to examine the mutual effect of ER stress and insulin signaling in beta cells in vitro, we used MIN6 insulinoma cells. Tunicamycin induced ER stress as well as inhibited insulin signaling. Conversely, the PI-3 kinase inhibitor, LY294002, enhanced ER stress. Furthermore, the reduction in insulin signaling by LY294002 facilitated the induction of ER stress with tunicamycin. Taken together, we concluded that both ER stress and reduced insulin signaling might synergistically affect pancreatic beta cell dysfunction.
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PMID:Reduced insulin signaling and endoplasmic reticulum stress act synergistically to deteriorate pancreatic beta cell function. 1877 13


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