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

Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P < 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI)-31.103 in women; leptin = 0.534 (BMI)-8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat)-24.817 in women; leptin = 0.402 (% body fat)-3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = -0.57; P < 0.0001) and high waist to hip ratio (r = 0.75; P < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
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PMID:The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. 910 Jun 10

Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was approximately 20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an "indirect pathway" of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.
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PMID:Direct antidiabetic effect of leptin through triglyceride depletion of tissues. 911 73

Pediatric obesity is a chronic and growing problem for which new ideas about the biologic basis of obesity offer hope for effective solutions. Prevalence of pediatric and adult obesity is increasing despite a bewildering array of treatment programs and severe psychosocial and economic costs. The definition of obesity as an increase in fat mass, not just an increase in body weight, has profound influence on the understanding and treatment of obesity. In principle, body weight is determined by a balance between energy expenditure and energy intake, but this observation does not by itself explain obesity. There is surprisingly little evidence that the obese overeat and only some evidence that the obese are more sedentary. Understanding of the biologic basis of obesity has grown rapidly in the last few years, especially with the identification of a novel endocrine pathway involving the adipose tissue secreted hormone leptin and the leptin receptor that is expressed in the hypothalamus. Plasma leptin levels are strongly correlated with body fat mass and are regulated by feeding and fasting, insulin, glucocorticoids, and other factors, consistent with the hypothesis that leptin is involved in body weight regulation and may even be a satiety factor (Fig. 2, Table 1). Leptin injections have been shown to reduce body weight of primates, although human clinical trials will not be reported until summer 1997. So many peptides influencing feeding have been described that one or more may have therapeutic potential (Fig. 2, Table 1). Although the complexity of pathways regulating body weight homeostasis slowed the pace of understanding underlying mechanisms, these complexities now offer many possibilities for novel therapeutic interventions (Fig. 2). Obesity is a major risk factor for insulin resistance and diabetes, hypertension, cancer, gallbladder disease, and atherosclerosis. In particular, adults who were obese as children have increased mortality independent of adult weight. Thus, prevention programs for children and adolescents will have long-term benefits. Treatment programs focus on modification of energy intake and expenditure through decreased calorie intake and exercise programs. Behavior-modification programs have been developed to increase effectiveness of these intake and exercise programs. These programs can produce short-term weight loss. Long-term losses are more modest but achieved more successfully in children than in adults. Several drug therapies for obesity treatment recently have been approved for adults that produce sustained 5% to 10% weight losses but experience with their use in children is limited. Identification of the biochemical pathways causing obesity by genetic approaches could provide the theoretic foundation for novel, safe, and effective obesity treatments. The cloning of leptin in 1994 has already led to testing the efficacy of leptin in clinical trials that are now underway. Although novel treatments of obesity are being developed as a result of the new biology of obesity, prevention of obesity remains an important goal.
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PMID:Pediatric obesity. An overview of etiology and treatment. 913 Sep 24

Leptin is a signaling protein that in its mutant forms has been associated with obesity and Type II diabetes. The lack of sequence similarity has precluded analogies based on structural resemblance to known systems. Backbone NMR signals for mouse leptin (13C/15N -labeled) have been assigned and its secondary structure reveals it to be a four-helix bundle cytokine. Helix lengths and disulfide pattern are in agreement with leptin as a member of the short-helix cytokine family. A three-dimensional model was built verifying the mechanical consistency of the identified elements with a short-helix cytokine core.
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PMID:Leptin is a four-helix bundle: secondary structure by NMR. 916 7

The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10-1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 +/- 37% (mean +/- SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 +/- 134 vs. 410 +/- 157 nmol/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.
Diabetes 1997 Jul
PMID:Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. 920 Jun 62

Plasma leptin level is known to correlate with the degree of obesity. To determine the influences of renal function and insulin resistance on plasma leptin concentrations, we measured plasma leptin concentrations and performed the euglycaemic hyperinsulinaemic clamp studies in 57 patients with non-insulin-dependent diabetes mellitus with a wide range of renal function. In simple regression analyses, plasma leptin concentration showed significant positive correlations with percentage of body fat measured by dual energy X-ray absorptiometry, body mass index, waist to hip ratio and fasting plasma insulin. Leptin level was higher in females than males. Multiple regression analyses indicated that percent body fat, waist to hip ratio, plasma insulin, gender and renal function (1/creatinine), but not insulin sensitivity, were significant and independent determinants of plasma leptin level. These results suggest that plasma leptin level is regulated or affected by multiple factors including renal function. Insulin resistance appeared to increase leptin levels indirectly by raising plasma insulin.
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PMID:Renal function and insulin resistance as determinants of plasma leptin levels in patients with NIDDM. 922 47

Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although beta-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels.
Diabetes 1997 Aug
PMID:beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. 923 51

Leptin, an adipocyte-derived hormone that directly regulates both adiposity and energy homeostasis, decreases food intake and appears to partition metabolic fuels toward utilization and away from storage. Because skeletal muscle expresses the leptin receptor and plays a major role in determining energy metabolism, we studied leptin's effects on glucose and fatty acid (FA) metabolism in isolated mouse soleus and extensor digitorum longus (EDL) muscles. One muscle from each animal served as a basal control. The contralateral muscle was treated with insulin (10 mU/ml), leptin (0.01-10 microg/ml), or insulin plus leptin, and incorporation of [14C]glucose or [14C]oleate into CO2 and into either glycogen or triacylglycerol (TAG) was determined. Leptin increased soleus muscle FA oxidation by 42% (P < 0.001) and decreased incorporation of FA into TAG by 35% (P < 0.01) in a dose-dependent manner. In contrast, insulin decreased soleus muscle FA oxidation by 40% (P < 0.001) and increased incorporation into TAG by 70% (P < 0.001). When both hormones were present, leptin attenuated both the antioxidative and the lipogenic effects of insulin by 50%. Less pronounced hormone effects were observed in EDL muscle. Leptin did not alter insulin-stimulated muscle glucose metabolism. These data demonstrate that leptin has direct and acute effects on skeletal muscle.
Diabetes 1997 Aug
PMID:Leptin directly alters lipid partitioning in skeletal muscle. 923 63

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.
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PMID:Serum leptin levels are independently correlated with two measures of HDL. 924 70

Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors.
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PMID:[Leptin and its biological and clinical significance. Is leptin and insulin resistance in the X-5H hormonal metabolic syndrome a parallel or causally-linked phenomenon?]. 924 68


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