Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin, encoded for by the mouse ob gene, regulates feeding behavior and energy metabolism. Its receptor (Ob-R) is encoded by the mouse diabetic (db) gene and is mutated in the db/db mouse so that it lacks the cytoplasmic domain. We show that the full-length leptin receptor (Ob-Rb), which is believed to transmit the leptin signal, is expressed in pancreatic islets of ob/ob and wild-type mice, as well as in hypothalamus, liver, kidney, spleen, and heart. Recombinant leptin inhibited basal insulin release in the perfused pancreas preparation from ob/ob mice but not in that from Zucker fa/fa rats. Leptin (1-100 nmol/l) also produced a dose-dependent inhibition of glucose-stimulated insulin secretion by isolated islets from ob/ob mice. In contrast, leptin at maximum effective concentration (100 nmol/l) did not inhibit glucose-stimulated insulin secretion by islets from db/db mice. These results provide evidence that a functional leptin receptor is present in pancreatic islets and suggest that leptin overproduction, particularly from abdominal adipose tissue, may modify directly both basal and glucose-stimulated insulin secretion.
Diabetes 1997 Feb
PMID:Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. 900 Jul 10

A brief review of the studies on the obese (ob) gene is given. The ob gene is a mouse gene, the mutations of which are associated with altered metabolism and increased lipid deposits in adipose tissue. Recessive ob gene mutations in homozygous mice result in obesity and diabetes mellitus. Both mouse and human ob cDNAs were cloned and sequenced using positional cloning, exon trapping, and PCR. Of ten tested tissues, the ob gene was expressed only in white adipose tissue. The ob gene cDNA has a region of the nucleotide sequence with an opening reading frame and encodes the ob protein consisting of 167 amino acid residues. Mouse and human ob proteins showed a 85% homology. The 145-amino acid peptide termed as leptin and derived from ob protein after cleavage of signal peptide is secreted in the blood and stimulates fat consumption in energy metabolism. The biologically active ob peptide has been obtained by gene engineering methods. Administration of the ob protein to ob/ob mice reduced body weight and abolished symptoms of diabetes. The ob protein lowered body weight also in healthy animals. It was biologically effective both upon parenteral and intravenous administration and also when injected into lateral ventricle of the brain. With a polyclonal antiserum against the peptide the ob protein was shown to be present in human and mouse plasma and mouse adipose tissue. Based on the data obtained, it is postulated that the ob gene protein product leptin, is a hormone, which is secreted by adipocytes in the blood in varying amounts and regulates the mass of adipose tissue by stimulating lipid metabolism. Similarly to adipocytes, many other organs and tissues are presumably endocrine and may secrete peptide hormones in the blood. This considerably extends the scope of endocrinology and makes it necessary to review the existing concepts and views.
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PMID:[ob protein--product of expressing an obesity gene and some aspects of modern-day endocrinology]. 901 Dec 50

Differences in fat cell size and function among adipose tissue depots are well known and may be important in the pathophysiology of the metabolic and cardiovascular complications of obesity. Since the newly discovered adipocyte hormone leptin is thought to be a central factor in the regulation of energy homeostasis, it may be interesting to know if there are regional differences in leptin production. The aim of this study was to compare the level of leptin expression in the omental and subcutaneous abdominal adipose tissue from obese humans. Adipose tissue samples were collected from 25 severely obese adults (mean BMI: 48.9 +/- 9.7 kg/m2) undergoing vertical gastric banding. Semi-quantitative determination of leptin mRNA by the RT-PCR technique showed significantly lower leptin expression in omental compared to subcutaneous abdominal adipose tissue (leptin/Sp1 ratio in omental vs. subcutaneous fat: 1.53 +/- 0.89 vs. 3.02 +/- 1.58, p < 0.01). Identical results were obtained when Northern blotting was applied in a subgroup. Leptin expression increased with age in omental adipose tissue (r = 0.42, p < 0.05), but not in subcutaneous tissue. No correlation was found between BMI or waist/hip ratio (WHR) and leptin expression in omental or subcutaneous adipose tissue. The regional difference in leptin expression was similar in the patients with impaired glucose tolerance/type-2 diabetes and those with normal glucose tolerance. In conclusion, the results of this study indicate that leptin expression is lower in omental than subcutaneous adipose tissue, possibly due to differences in fat cell size and/or sympathetic innervation.
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PMID:Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. 901 43

Human leptin, which is encoded by the obese (ob) gene, is secreted specifically from adipocytes and is involved in the regulation of satiety and energy consumption. We developed a radioimmunoassay for the determination of leptin in human serum using polyclonal antibodies generated in rabbits against a C-terminal fragment of leptin, leptin(126-140), coupled to hemocyanin. The sensitivity of the assay was app. 5 pmol/l leptin(126-140) equivalent to 0.5 fmol/tube. The intra-assay variation at 100 pmol/l was less than 4.8% and the interassay variation less than 8.3%. Dilution curves of serum samples containing high levels of leptin(126-140) were parallel to the standard curve. Following G-50 Sephadex chromatography a single specific peak was detected at app. 16 kd. The assay procedure compared well to a commercially available assay (Linco, St. Louis, USA) using polyclonal antibodies directed against the intact recombinant protein (R = 0.96; p < 0.0001). Serum levels were significantly higher than plasma levels (app.20%) over a wide range of the standard curve. Levels of serum leptin126-140 immunoreactivity were not altered by meals and no day-to-day variation was found. In a group of 148 healthy female and 108 healthy male subjects with a BMI between 18.2 and 40 kg/m2 there was a significant difference between sexes with higher circulating serum levels in female than in male subjects when tested for identical BMI (p < 0.001). Serum leptin levels in both male and female subjects were positively related to BMI (p < 0.001) when analysed for lean and obese subjects whereas in lean subjects this relation was not apparent. No relation of serum leptin levels and age was detectable in subjects with a BMI up to 30 kg/m2. These data support an important role of leptin in the regulation of body fat stores and BMI which is modulated by gender specific factors.
Exp Clin Endocrinol Diabetes 1996
PMID:Radioimmunoassay for the detection of leptin in human serum. 902 46

The known association between smoking cessation and weight gain, and the suggested role of leptin in the control of body weight, led to the present study which examined the association between smoking and serum leptin concentrations. Mean serum leptin levels, independent of body mass index (BMI), were calculated in male smokers and non-smokers from Nauru, Western Samoa and Mauritius. Smokers were generally leaner than non-smokers, and of similar ages. Levels of physical activity and glucose tolerance status were similar for smokers and non-smokers in Nauru and Western Samoa, while in Mauritius smokers were more active and less likely to be diabetic. Leptin concentrations in smokers were significantly lower than in non-smokers, even after adjusting for BMI, waist/hip ratio (WHR) or waist girth (P < or = 0.04). This association was independent of diabetes status. Smoking, via nicotinic mechanisms, may modify the sensitivity of hypothalamic leptin receptors and consequently modulate leptin synthesis and reduce body weight.
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PMID:Is leptin sensitivity the link between smoking cessation and weight gain? 902 1

Insulin stimulates ob gene expression and increases serum leptin concentrations in mice and in noninsulin-dependent diabetes mellitus patients. Obese women have higher ob gene messenger ribonucleic acid levels than obese men, suggesting that sex hormones are involved in the regulation of leptin synthesis. We studied the relationship among leptin, insulin, and testosterone in 15 men with insulin-dependent diabetes mellitus (IDDM; age, 29 +/- 2 yr; body mass index, 22.7 +/- 0.5 kg/m2; body fat, 9.5 +/- 1.0%; insulin dose, 44 +/- 4 U/day; hemoglobin A1c, 8.1 +/- 0.3%; diabetes duration, 12.7 +/- 2.0 yr) and 15 healthy control subjects (age, 27 +/- 1 yr; body mass index, 22.6 +/- 0.4 kg/m2; body fat, 9.6 +/- 0.5%) in the fasting state. In addition, the effect of a 4-h euglycemic hyperinsulinemia (approximately 600 pmol/L) on the plasma leptin concentration was determined. The fasting leptin concentration was negatively correlated to plasma testosterone (r = -0.55; P < 0.05) in IDDM patients. The fasting plasma leptin level rose 25% in healthy subjects (from 1.0 +/- 0.2 to 1.3 +/- 0.3 ng/mL; P < 0.05). The leptin levels were higher in IDDM subjects (P < 0.01) and remained unchanged (2.7 +/- 0.2 vs. 2.7 +/- 0.2 ng/mL) during hyperinsulinemia. We reached the following conclusions. 1) In nonobese IDDM patients, leptin synthesis is resistant to the acute effect of insulin. 2) Serum testosterone may contribute to the regulation of leptin synthesis in IDDM patients.
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PMID:Leptin synthesis is resistant to acute effects of insulin in insulin-dependent diabetes mellitus patients. 902 22

Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8-79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin's sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.
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PMID:Sexual dimorphism in plasma leptin concentration. 902 58

Leptin acts on the brain to inhibit feeding, increase thermogenesis, and decrease body weight. Neuropeptide Y (NPY)-ergic neurons of the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) are postulated to control energy balance by stimulating feeding and inhibiting thermogenesis, especially under conditions of energy deficit. We investigated whether leptin's short-term effects on energy balance are mediated by inhibition of the NPY neurons. Recombinant murine leptin (11 microg) injected into the lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline-treated controls (P < 0.05). Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01). A second study examined changes in leptin during 5 days' intracerebroventricular NPY administration (10 microg/day), which induced sustained hyperphagia and excessive weight gain. In NPY-treated rats, leptin mRNA levels in epididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma leptin levels were significantly higher (4.88 +/- 0.66 vs. 2.85 +/- 0.20 ng/ml; P < 0.01). Leptin therefore acts centrally to decrease NPY synthesis and NPY levels in the ARC-PVN projection; reduced NPY release in the PVN may mediate leptin's hypophagic and thermogenic actions. Conversely, NPY-induced obesity results in raised circulating leptin concentrations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a homeostatic loop to regulate body fat mass and energy balance.
Diabetes 1997 Mar
PMID:Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat. 903 86

Obese subjects with excess intra-abdominal fat deposition suffer greater adverse metabolic consequences than do similarly overweight subjects with a predominantly subcutaneous distribution of adiposity. Little is known about the factors regulating the regional distribution of body fat. Leptin is a recently characterized protein secreted by adipocytes that appears to provide a long-term hormonal feedback signal regulating fat mass. No systematic evaluation of site-related differences in human adipocyte leptin expression has been reported to date. Levels of leptin mRNA were examined by quantitative reverse transcription-polymerase chain reaction in adipocytes isolated from omental and subcutaneous adipose depots of nonobese and mildly obese individuals undergoing elective surgery. In all individuals studied (n = 24), leptin mRNA levels were higher in subcutaneous than in omental adipocytes (P < 0.0001). In contrast, there were no consistent site-specific differences in the expression of glycerol-3-phosphate dehydrogenase mRNA. The subcutaneous-to-omental ratio of leptin mRNA expression was markedly higher in women (5.5 +/- 1.1-fold) than in men (1.9 +/- 0.2-fold) (P < 0.02). A significant relationship between BMI and leptin mRNA expression was demonstrable in the subcutaneous adipocytes of women (P < 0.006). Thus, leptin mRNA appears to be expressed predominantly by subcutaneous adipocytes, particularly in women. These findings suggest a possible role for leptin in the control of adipose tissue distribution and mass.
Diabetes 1997 Mar
PMID:Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. 903 87

The obese phenotypes of the diabetes (db) mouse and fatty fa) rat are due to functional null mutations of the leptin receptor (Lepr). The recessive mutation in the Koletsky (f) obese rat maps to the same genetic intervals as db and fa and fails to complement the fa mutation. Comparison of the sequence of brain Lepr cDNA from +/+ and f/f animals reveals a T2349A transversion resulting in a Tyr763Stop nonsense mutation in the gene just before the transmembrane domain. Virtual absence of Lepr mRNA in whole brain from f/f animals is consistent with the presence of a null mutation. The predicted reduced cerebrospinal fluid (CSF) transport of leptin in both f/f and fa/fa mutants is reflected in the approximately 10-fold lower ratio of CSF/plasma leptin concentration in the obese versus lean animals. However, equivalent CSF leptin concentration between lean and obese rats (fa/fa, f/f) indicates that leptin can enter the CSF through a non-Lepr-mediated mechanism, which may be saturated at normal physiological plasma leptin concentration.
Diabetes 1997 Mar
PMID:Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat. 903 11


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