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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.
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PMID:The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. 928 46

Recent research suggests that leptin may control body weight by regulating energy expenditure and energy intake in mice. To explore the possible role of leptin in the regulation of energy expenditure in humans, we used doubly-labeled water methodology to determine whether fasting plasma leptin concentrations were related to total daily energy expenditure (TEE) and its components, resting energy expenditure (REE) and physical activity energy expenditure (PAEE), in free-living older African-American men (n = 21) and women (n = 25). Plasma leptin concentrations were higher in women than men, even after the adjustment for differences in fat mass (28 +/- 3 ng/ml for women vs. 17 +/- 3 ng/ml for men; P < 0.01). The logarithm of plasma leptin concentrations correlated with fat mass in both women (r = 0.80) and men (r = 0.78) (P < 0.0001). After statistical adjustment for sex differences in fat-free mass and fat mass, women had lower TEE (22%) and REE (15%) (P < 0.01) and a trend (P = 0.08) toward lower PAEE, compared with men. After controlling for the effects of fat-free mass on energy expenditure, plasma leptin concentrations were related to REE (r = 0.68, P < 0.001) and tended to be related to TEE (r = 0.37, P = 0.07) in African-American women but not men (r = 0.18 and -0.03, respectively). Plasma leptin concentrations were not related to PAEE in either men or women. These results suggest that leptin may contribute to the regulation of TEE in older African-American women through its effects on resting energy metabolism, but the role of leptin in the regulation of energy expenditure is less apparent in older African-American men.
Diabetes 1997 Sep
PMID:Daily energy expenditure is related to plasma leptin concentrations in older African-American women but not men. 928 36

Tumor necrosis factor-alpha (TNF-alpha), acting as a modulator of gene expression in adipocytes, is implicated in the development of insulin resistance and obesity. The aim of this study was to investigate whether the Nco I polymorphism of the TNF-alpha gene influences the relationship among insulin resistance, percent body fat, and serum leptin levels. A sample of 38 subjects (19 men, mean age 36.2 +/- 1.9 years, BMI 28.8 +/- 1.2 kg/m2, range 22.2-35.7; and 19 women, age 34.9 +/- 1.4 years, BMI 28.1 +/- 0.8 kg/m2, range 19-37.9) was divided into two groups on the basis of the Nco I genotype. Twenty-three subjects were (+/+) homozygotes for the presence of the Nco I restriction site that is associated with a guanine at position -308 of the TNF-alpha promoter. Of the other subjects, 12 were (+/-) heterozygotes and 3 (-/-) homozygotes for the absence of the restriction site, resulting from a guanine-to-adenine substitution at position -308 of the TNF-alpha promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-alpha than the wild-type allele TNF-1 in vitro. TNF-1 (+/+) and TNF-2 (+/- and -/-) groups of subjects were comparable in sex, age, BMI, waist-to-hip ratio, and several skinfold measurements. Basal serum insulin was greater (14.2 +/- 2 vs. 9.2 +/- 0.9 mU/l, P = 0.041) in the TNF-2 group in the presence of comparable serum glucose concentration. The integrated area under the curve of serum insulin concentrations, measured in response to a 75-g oral glucose challenge, and the percent body fat, measured by bioelectric impedance, were significantly increased in TNF-2 subjects (226.8 +/- 33 vs. 139.4 +/- 17.8 mU/l, P = 0.032; 33.6 +/- 2.8 vs. 24.9 +/- 2%, P = 0.01). TNF-2 subjects also showed a decreased insulin sensitivity index, as determined by the frequently sampled intravenous glucose tolerance test with minimal model analysis (1.9 +/- 0.4 vs. 3.05 +/- 0.3 min(-1) x mU(-1) x l(-1), P = 0.03). These differences were more marked among women. Paralleling the known relationship between insulin and leptin levels, serum leptin concentration was clearly increased in the TNF-2 group (19.6 +/- 3.4 vs. 11.1 +/- 1.5 ng/ml, P = 0.03). Therefore, (+/-) heterozygotes and (-/-) homozygotes may be more susceptible to developing insulin resistance and increased percent body fat. Results of the present study suggest that TNF-alphaNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.
Diabetes 1997 Sep
PMID:The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. 928 48

Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity.
Diabetes 1997 Sep
PMID:Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice. 928 57

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
Diabetes 1997 Sep
PMID:Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. 928 59

Interleukin 1beta (IL-1beta)-induced beta cell cytotoxicity has been implicated in the autoimmune cytotoxicity of insulin-dependent diabetes mellitus. These cytotoxic effects may be mediated by nitric oxide (NO). Since long-chain fatty acids (FFA), like IL-1beta, upregulate inducible nitric oxide synthase and enhance NO generation in islets, it seemed possible that islets might be protected from IL-1beta-induced damage by lowering their lipid content. We found that IL-1beta-induced NO production varied directly and islet cell viability inversely with islet triglyceride (TG) content. Fat-laden islets of obese rats were most vulnerable to IL-1beta, while moderately fat-depleted islets of food-restricted normal rats were less vulnerable than those of free-feeding normal rats. Severely lipopenic islets of rats made chronically hyperleptinemic by adenoviral leptin gene transfer resisted IL-1beta cytotoxicity even at 300 pg/ml, the maximal concentration. Troglitazone lowered islet TG in cultured islets from both normal rats and obese, leptin-resistant rats and reduced NO production and enhanced cell survival. We conclude that measures that lower islet TG content protect against IL-1beta-induced NO production and cytotoxicity. Leptin or troglitazone could provide in vivo protection against insulin-dependent diabetes mellitus.
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PMID:Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity. 931 73

New Zealand Obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, hyperinsulinemia, and hyperglycemia similar to that observed in young diabetes mutant mice on the C57BLKS/J background (C57BLKS/J-Lepr(db)/Lepr(db)). Here we show that in NZO this syndrome is accompanied by a marked elevation of the leptin protein in adipose tissue and serum. The promoter region and the complementary DNA of the ob gene of NZO mice, including its 5'-untranslated region, are identical with the wild-type sequence (C57BL, BALB/c), except that the transcription start is located 5 bp upstream of the reported site. In contrast to C57BLKS/J+/+ and C57BL/6J-Lep(ob)/Lep(ob) mice, NZO mice failed to respond to recombinant leptin (7.2 microg/g) with a reduction of food intake. Leptin receptor messenger RNA as detected by PCR appears as abundant in hypothalamic tissue of NZO mice as in tissue from lean mice. Ten nucleotide polymorphisms are found in the complementary DNA of the leptin receptor, resulting in two conservative substitutions (V541I and V651I) in the extracellular part of the receptor and one nonconservative substitution (T1044I) in the intracellular domain between the presumed Jak and STAT binding boxes. However, these mutations are also present in the related lean New Zealand Black strain (body fat at 9 weeks: New Zealand Black, 6.2 +/- 1.3%; NZO, 17.0 +/- 1.7%). Thus, the polymorphic leptin receptor seems to play only a minor, if any, role in the obesity and hyperleptinemia of the NZO mouse. It is suggested that the main defect in NZO is located distal from the leptin receptor or at the level of leptin transport into the central nervous system.
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PMID:Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse. 932 35

Leptin, the product of the human OB gene, is increased in obese individuals, suggesting resistance to its effect. However, there is variability in leptin levels at each level of body mass index, suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. Leptin concentrations are higher in women relative to men, a difference that is only partially explained by the increased fat depots in women. The authors hypothesized that higher estrogen levels in women might be responsible for the sexual dimorphism in leptin concentrations. To test this hypothesis, they measured leptin concentrations in premenopausal women not on oral contraceptives (PRE) (n = 53), postmenopausal women on hormone replacement therapy (POSTY) (n = 28), and postmenopausal women not on hormone replacement therapy (POSTN) (n = 28) in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Analyses were restricted to nondiabetic Mexican Americans. Subjects were well matched on obesity as assessed by body mass index (kg/m2): PRE = 31.0, POSTY = 29.8, and POSTN = 31.6. Leptin concentrations (ng/ml) were not significantly different among the three groups (PRE = 27.6, POSTY = 28.3, and POSTN = 27.8). The authors conclude that differences in estrogen levels are not likely to explain the sexual dimorphism in leptin concentrations.
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PMID:Leptin concentrations in women in the San Antonio Heart Study: effect of menopausal status and postmenopausal hormone replacement therapy. 932 36

Lipoatropic diabetes (LD) is a rare recessive autosomal disorder, mainly characterized by lipoatrophy with alterations in lipid metabolism and extreme insulin resistance. To identify molecular defects responsible for this disease, we tested the implication of 14 candidate genes coding for proteins involved either in insulin action, i.e. insulin receptor, insulin receptor substrate 1, insulin-like growth factor I receptor, diabetes-associated ras-like protein (Rad), and glycogen synthase, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CII, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the beta 3-adrenergic receptor; leptin; and fatty acid-binding protein 2. To this end, haplotype and linkage analyses using genotyping with microsatellites in 10 consanguineous families provided us with powerful genetic tools. Our results show that in most families, lod scores at a null recombination fraction were less than -2. Haplotype analysis also argues against the involvement of these genes in LD. This implies that mutations in these genes are unlikely to make a major genetic contribution to LD.
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PMID:Genetic exclusion of 14 candidate genes in lipoatropic diabetes using linkage analysis in 10 consanguineous families. 932 83

The Israeli Sand Rat (Psammomys obesus) is an excellent polygenic model for the study of obesity and diabetes. The metabolic characteristics and the heterogeneous development of these defects, including elevated leptin levels, mimic those found in susceptible human populations. Interestingly, only animals that develop metabolic abnormalities demonstrate hyperleptinemia and, in these animals, leptin administration at the same dose that is effective in ob/ob mice is ineffective in reducing food intake or body weight. Perhaps leptin resistance needs to develop in Israeli Sand Rats to allow the development of obesity and, in fact, leptin resistance may be the "thrifty gene" that predisposes individuals to the development of obesity and subsequent metabolic abnormalities. However, there remain many unanswered questions about the physiological actions of leptin. The widespread tissue location of receptors and the actions of leptin independent of food intake highlight the need for further research aimed at determining the major physiological action of this newly discovered and exciting hormone.
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PMID:Development of obesity and insulin resistance in the Israeli sand rat (Psammomys obesus). Does leptin play a role? 932 41


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