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

The recently cloned adipose tissue hormone leptin has been proposed to be involved in the neuroendocrine regulation of adiposity and its metabolic sequelae. Visceral fat is known to predict reduced insulin sensitivity and associated adverse metabolic profiles. In this study, we report the first evaluation of the relationships between leptin levels and total body fat, visceral fat, and insulin sensitivity in a cohort of premenopausal African-American women. Thirty-four subjects were analyzed for total fat mass and visceral fat by dual-energy X-ray absorptiometry and computerized axial tomography, respectively. Insulin sensitivity (SI) was assessed using Bergman's minimal model. Results showed that fasting leptin levels strongly correlated with total body fat mass (r = 0.797, P < 0.001). Correlations of leptin with visceral fat (r = 0.54, P < 0.001) and SI (r = -0.419, P = 0.02) were dependent on total body fat. In conclusion, leptin levels reflect total body fat mass, and although visceral fat is known to predict reduced insulin sensitivity independently, leptin did not. Our data thus suggest that diverse mechanisms are responsible for the regulation of total body versus visceral fat distribution, with its metabolic and health risks.
Diabetes 1996 Nov
PMID:Leptin: a significant indicator of total body fat but not of visceral fat and insulin insensitivity in African-American women. 886 72

Many hormones circulate bound to serum proteins that modulate ligand bioactivity and bioavailability. To understand the biology of leptin action, we investigated the presence of leptin binding proteins in serum. 125I-labeled leptin binds competitively to at least three serum macromolecules with molecular masses of approximately 85, approximately 176, and approximately 240 kDa in rodents and approximately 176 and approximately 240 kDa in humans. The ability to bind appears to involve sulfhydryl/disulfide interactions because it is inhibited under reducing conditions. When serum is added to recombinant 125I-leptin, there is a shift in sedimentation of 125I-leptin as analyzed by sucrose gradient centrifugation from approximately S1.9 to approximately S4.3. This shift is markedly attenuated in serum from obese mice (ob/ob, db/db, brown-fat ablated, gold-thioglucose treated, high-fat fed) compared with that from nonobese controls. The size distribution of endogenous serum leptin as determined by radioimmunoassay (RIA) after sucrose gradient centrifugation is also consistent with saturation of binding in hyperleptinemic obesity. In humans, free leptin increases with BMI. Thus, in lean rodents and humans a large proportion of leptin circulates bound to several serum proteins. Free leptin is increased in serum of obese subjects, which may alter leptin bioactivity, transport, and/or clearance.
Diabetes 1996 Nov
PMID:Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. 886 73

Neuropeptide Y (NPY) neurones in the arcuate nucleus of the rodent hypothalamus may play a key role in responding to reductions in body energy stores with appropriate changes in energy homeostasis, namely an increase in food-seeking behaviour and hyperphagia, together with a reduction in heat production by brown adipose tissue. These adaptive responses are mimicked by the injection of NPY into the main sites of projection of the NPY neurones, and animals that are threatened by energy deficits (e.g. through starvation or insulin-deficient diabetes) show increased activity of these neurones. Genetically obese rodents also show hyperactivity of the NPY neurones, which is inappropriate to their energy needs and may contribute to their hyperphagia, reduced energy expenditure and excessive weight gain. The NPY neurones may be inhibited by insulin and leptin, which may both serve as signals of peripheral fat mass. Ultimately, characterization of the specific "feeding' receptors which mediate NPY's central effects on energy homeostasis may provide opportunities for designing drugs to manipulate and appetite and energy balance in man, notably obesity and the cachexia commonly associated with malignancy and chronic infection.
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PMID:Neuropeptide Y, the hypothalamus and the regulation of energy homeostasis. 887 Nov 82

The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition.
Exp Clin Endocrinol Diabetes 1996
PMID:Regulation of energy balance by leptin. 888 45

Leptin, a recently identified hormone, is believed to reduce appetite and maintain body weight. The mRNA of leptin is expressed only in mature adipose cells. To clarify the regulation of leptin gene expression in adipocytes, 3T3-L1 adipocytes were treated for 16 h with various agents known to modulate lipid metabolism, and then the leptin mRNA was measured by the reverse transcription-polymerase chain reaction method. Interestingly, both norepinephrine and isoproterenol reduced the level of leptin mRNA to about 20% of that found in untreated control cells in a dose-dependent fashion. The maximum reduction occurred at 100 nmol/l of either norepinephrine or isoproterenol, and the half-maximal effect was observed at approximately 3 nmol/l norepinephrine and approximately 1 nmol/l isoproterenol. Propranolol reversed about 50% of the reduction by either norepinephrine or isoproterenol. In contrast, phentolamine did not inhibit the reduction by either norepinephrine or isoproterenol. Moreover, both cholera toxin and dibutyryl cAMP decreased the level of leptin mRNA to about 10% of that in control cells in a dose-dependent fashion. The maximum effect was elicited at 100 ng/ml cholera toxin and 100 micromol/l dibutyryl cAMP. The concentration producing the half-maximal effect was approximately 1 ng/ml cholera toxin and approximately 50 micromol/l dibutyryl cAMP. Dibutyryl cGMP, however, did not affect leptin gene expression. These results suggest that a signaling pathway that results in the activation of protein kinase A regulates leptin gene expression in 3T3-L1 adipocytes.
Diabetes 1996 Dec
PMID:Reduced expression of the leptin gene (ob) by catecholamine through a G(S) protein-coupled pathway in 3T3-L1 adipocytes. 892 60

The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.
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PMID:Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. 917 44

The acute effects of hyperglycemia and hyperinsulinemia on plasma leptin levels were determined in 42 highly trained women athletes (18-69 yr) and 14 sedentary control women (18-50 yr, body mass index < 25 kg/m2), using the glucose clamp technique. The relationships of body composition, physical fitness, age, and plasma leptin levels were examined in all participants. In addition, the effect of weight loss and aerobic exercise and plasma leptin levels were examined in 4 Newly diagnosed untreated noninsulin-dependent diabetes mellitus patients. The time course of plasma leptin levels changed little from basal during hyperglycemic (approximately 10 mmol/L) or hyperinsulinemic-euglycemic (400-3000 pmol/L) clamp studies in either athletes, controls, or noninsulin-dependent diabetes mellitus patients. A strong correlation between plasma leptin levels and fasting insulin was present (r = 0.60, P < 0.001). Plasma leptin and percent fat were higher in controls than athletes (12.6 vs. 4.0 ng/mL and 33.2 vs. 20.8%; both P < 0.001). The relationships between percent fat (dual-energy x-ray absorptiometry) or intraabdominal adipose tissue (computed tomography) and leptin for the entire group were highly significant (r = 0.70, r = 0.52; P < 0.001). When percent fat was controlled, the relationship between fasting insulin and leptin remained (P < 0.002). There was not a significant association between age and plasma leptin levels in a univariate analysis in this population. However, after adjustment for percent fat, a significant inverse relationship between age and leptin appeared (P < 0.05). The weight loss and aerobic exercise program resulted in an average 6 +/- 0.8 kg wt loss. Leptin levels decreased > 28% in each patient (P < 0.01). In conclusion, neither acute hyperglycemia or hyperinsulinemia affects plasma leptin levels. Percent fat is the strongest predictor of leptin levels, even in lean, highly trained women athletes.
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PMID:The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationships with body fat, visceral adiposity, and age in women. 895 55

The ob/ob mouse is genetically deficient in leptin and exhibits both an obese and a mild non-insulin-dependent diabetic phenotype. To test the hypothesis that correction of the obese phenotype by leptin gene therapy will lead to the spontaneous correction of the diabetic phenotype, the ob/ob mouse was treated with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. The subsequent diminishment in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. These results not only demonstrated that the obese and diabetic phenotypes in the adult ob/ob mice are corrected by leptin gene treatment but also provide confirming evidence that body weight control may be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients.
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PMID:Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. 896 36

To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, guide cannulas were positioned stereotaxically into three brain regions--the ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal raphe nucleus (n = 3), and the lateral ventricle (n = 3)--of nonobese male rats (400-500 g). Daily food intake and body weight changes were measured during twice-daily injections of saline (0.1 microl) followed by recombinant human leptin (0.05 microg) for 3 days via the brain cannulas. VMH-injected rats also were followed during a postleptin saline recovery interval. This small dose of leptin did not change food intake or body weight from that during the preceding saline injection period in ventricle-injected or dorsal raphe-injected rats. In sharp contrast, VMH-injected rats ate much less food (56 +/- 8% basal) and lost 9 +/- 3 g/day or 5% of their body weight during 3 days of leptin administration. VMH-injected animals fully recovered from leptin-induced effects within 3 days. We conclude that small doses of leptin that do not effect eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food intake when injected into the VMH. These data suggest that the VMH or a brain region in close proximity to it is a key target for the biological actions of leptin.
Diabetes 1997 Jan
PMID:The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus. 897 Oct 96

Identification of the OB (leptin) receptor (OBR) as the gene that is defective in diabetes (Leprdb) mice and fatty (Leprfa) rats provides an important candidate gene for the study of the genetics of human obesity. We defined the boundaries of the 18 coding exons for the long form of OBR, and sequenced the immediately adjacent intronic regions. These sequences can be used to generate reagents for genetic analysis (e.g., direct sequencing, single-stranded conformational polymorphism analysis, etc.) of the possible role of OBR in the regulation of adiposity in humans. In addition, we have identified two highly polymorphic intronic microsatellites that can be scored with the polymerase chain reaction.
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PMID:Genomic structure of the human OB receptor and identification of two novel intronic microsatellites. 897 14


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