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)

The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that fa and diabetes (db) are homologous loci in the rat and mouse genomes, respectively. It has been shown that db alleles carry mutations in the Lepr (leptin receptor) gene. This paper describes a point mutation in the fatty allele of Lepr. A nucleotide substitution at position 880 (A-->C) causes an amino acid substitution at position 269 (Gln-->Pro). The mutation generates a novel Msp I site that cosegregates with fa in 1,028 meioses examined in obese F2 progeny from two crosses (Bnx13M and WKYx13M) and is still segregating in three rat colonies. PCR-based mutagenesis was used to introduce the fa mutation into the mouse Lepr cDNA. Transient transfection studies indicate that the mutant Lepr cDNA has greatly reduced binding of leptin (Lep) at the cell surface. These data are strong evidence that the single nucleotide substitution in the fa allele of Lepr (Leprfa) is responsible for the obese phenotype.
Diabetes 1996 Aug
PMID:Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). 869 Jan 63

Leptin (Ob protein) is a recently isolated hormone produced by adipocytes and is a powerful regulator of satiety centers in the brain. A defect in either leptin production or transmission of the leptin signal in animal models, i.e. ob/ob and db/db mice, respectively, results in a syndrome of obesity and diabetes which closely resembles that which occurs in humans. Leptin release is regulated in part by nutritional status and its expression in adipose tissue is up-regulated by insulin. Since hyperinsulinemia is a primary defect in ob/ob and db/db mice which manifests early in the disease, we postulated that leptin may also regulate insulin release as part of a "adipoinsular' feedback loop. We demonstrate the expression of leptin receptor mRNA in primary rat pancreatic islets and in the insulinoma cell line beta TC-3. Furthermore, we find binding of 125I-leptin to beta TC-3 cells which is significantly displaced by leptin. These findings suggest the possibility that the binding of leptin to its receptor in beta-cells may modulate insulin expression in a negative feedback loop, and thereby may have an anti-obesity effect.
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PMID:Leptin receptors expressed on pancreatic beta-cells. 870 21

Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulin-sensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/l troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40-50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.
Diabetes 1996 Sep
PMID:Effect of troglitazone on leptin production. Studies in vitro and in human subjects. 877 34

We have cloned the rhesus monkey obese cDNA and have analyzed its expression in monkeys with a wide range of body weights (lean to very obese) and with or without non-insulin-dependent diabetes mellitus to examine the relationship of ob gene expression to obesity and non-insulin-dependent diabetes mellitus. The sequence of monkey ob protein, excluding the signal peptide, showed 91% identity with the human protein. We observed a significant correlation between the level of ob mRNA and body weight. We also found a significant relationship between ob mRNA and fasting plasma insulin concentration; however, insulin stimulation during a 100-140-min euglycemic/hyperinsulinemic clamp did not result in any changes in ob mRNA levels. Circulating levels of the ob gene product leptin were also significantly correlated with body weight. These results show that ob gene expression is related to body weight and is not acutely regulated by insulin.
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PMID:Regulation of obese (ob) mRNA and plasma leptin levels in rhesus monkeys. Effects of insulin, body weight, and non-insulin-dependent diabetes mellitus. 881 Feb 96

In rodents, food intake and insulin increase ob gene expression and circulating leptin concentrations, but it is unknown whether insulin regulates plasma leptin concentrations in humans. We measured plasma leptin concentrations in 27 normal subjects (16 men, 11 women; age, 24 +/- 1 years; BMI, 22.6 +/- 0.5 kg/m2; body fat, 18 +/- 1%) during a 6-h euglycemic hyperinsulinemic clamp (sequential insulin infusions of 1, 2, and 5 mU.kg-1.min-1 for 2 h each). During these insulin infusions, plasma leptin increased from a basal concentration of 7.4 +/- 1.6 ng/ml by -2 +/- 2, 17 +/- 4, and 50 +/- 6% to 7.2 +/- 1.5 (NS vs. basal), 8.5 +/- 1.7 (P < 0.001), and 10.4 +/- 2.0 ng/ml (P < 0.001), respectively. Of the subjects, eight also participated in a control study where saline was infused for 6 h. In these subjects, plasma leptin increased by 5 +/- 4, 26 +/- 10, and 62 +/- 10% during the insulin infusions, and decreased by 9 +/- 4 (P = 0.07 for change during saline vs. insulin), 13 +/- 4 (P < 0.01), and 17 +/- 4% (P < 0.001) after 2, 4, and 6 h of the saline infusion, respectively. Women had higher plasma leptin concentrations basally and during hyperinsulinemia (P < 0.001) than men, but this difference was entirely accounted for by greater adiposity in women (22 +/- 2 vs. 14 +/- 1%, P < 0.001). These data provide evidence for the insulin regulation of plasma leptin concentrations in humans. This effect requires hours of high insulin concentrations, implying that postprandial satiety is not regulated via changes in plasma leptin concentrations. Insulin may, however, be of importance in the long-term or diurnal regulation of plasma leptin concentrations.
Diabetes 1996 Oct
PMID:Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. 882 72

The aim of this study was to investigate the regulation of leptin expression and production in cultured human adipocytes using the model of in vitro differentiated human adipocytes. Freshly isolated human preadipocytes did not exhibit significant leptin mRNA and protein levels as assessed by reverse transcriptase (RT)-polymerase chain reaction (PCR) and radioimmunoassay (RIA). However, during differentiation induced by a defined adipogenic serum-free medium, cellular leptin mRNA and leptin protein released into the medium increased considerably in accordance with the cellular lipid accumulation. In fully differentiated human fat cells, insulin provoked a dose-dependent rise in leptin protein. Cortisol at a near physiological concentration of 10(-8) mol/l was found to potentiate this insulin effect by almost threefold. Removal of insulin and cortisol, respectively, was followed by a rapid decrease in leptin expression, which was reversible after readdition of the hormones. These results clearly indicate that both insulin and cortisol are potent and possibly physiological regulators of leptin expression in human adipose tissue.
Diabetes 1996 Oct
PMID:Insulin and cortisol promote leptin production in cultured human fat cells. 882 83

The effect of different doses of leptin, given as an intracerebroventricular (ICV) bolus, on body weight gain and food intake was investigated during refeeding, following a 24-h fast in lean (FA/fa) rats. It was observed that ICV leptin resulted in a dose-dependent decrease in body weight gain, compared with vehicle injection, a difference that persisted for at least 6 days. This was associated with a transient reduction in food intake over the first 2 days after leptin injection. More importantly, the effect of leptin was also observed in genetically obese fa/fa rats but at the expense of two to ten times higher leptin concentrations, indicating the presence of decreased leptin sensitivity. Furthermore, ICV leptin injections were able to decrease neuropeptide Y (NPY) levels in the arcuate and paraventricular hypothalamic nuclei in both lean and genetically obese fa/fa rats, although a higher leptin dose was again needed in the obese group. These observations provide further evidence for the implication of NPY and leptin in a regulatory loop controlling body homeostasis. This loop is functional in lean and genetically obese fa/fa rats, provided that leptin levels in the central nervous system are high enough in the obese group, in particular. Since human obesity is frequently associated with elevated circulating leptin levels, a state of decreased leptin sensitivity (i.e., leptin resistance), similar to that described here in fa/fa rats, could possibly occur in human syndromes as well.
Diabetes 1996 Oct
PMID:The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats. Reduced sensitivity compared with lean animals. 882 85

Insulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with noninsulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51 +/- 3 years, BMI 26.3 +/- 0.6 kg/m2, fasting plasma glucose 5.6 +/- 0.2 mmol/l) and seven patients with NIDDM (age 54 +/- 2 years, 27.0 +/- 0.9 kg/m2, 11.1 +/- 0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r = 0.72, p < 0.005), even after adjusting for the percentage of body fat (p < 0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37 +/- 14%; 5.2 +/- 0.8. vs 3.9 +/- 0.6 ng/ml, 6 vs 0 h, p < 0.05) in the normal subjects and after 8.5 h (38 +/- 11%; 7.1 +/- 1.0 vs 5.5 +/- 0.9 ng/ml, 8.5 vs 0 h, p < 0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11 +/- 1% (p < 0.005) and in the patients with NIDDM by 14 +/- 1% (p < 0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32 +/- 13 (p < 0.05), 53 +/- 14 (p < 0.001), 106 +/- 15 (p < 0.001) and 165 +/- 21 (p < 0.001) % higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11 +/- 9 (p < 0.05), 27 +/- 10 (p < 0.05), 58 +/- 7 (p < 0.001) and 106 +/- 13 (p < 0.001) % higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.
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PMID:Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. 885 24

We investigated the response of leptin to short-term fasting and refeeding in humans. A mild decline in subcutaneous adipocyte ob gene mRNA and a marked fall in serum leptin were observed after 36 and 60 h of fasting. The dynamics of the leptin decline and rise were further substantiated in a 6-day study consisting of a 36-h baseline period, followed by 36-h fast, and a subsequent refeeding with normal diet. Leptin began a steady decline from the baseline values after 12 h of fasting, reaching a nadir at 36 h. The subsequent restoration of normal food intake was associated with a prompt leptin rise and a return to baseline values 24 h later. When responses of leptin to fasting and refeeding were compared with that of glucose, insulin, fatty acids, and ketones, a reverse relationship between leptin and beta-OH-butyrate was found. Consequently, we tested whether the reciprocal responses represented a causal relationship between leptin and beta-OH-butyrate. Small amounts of infused glucose equal to the estimated contribution of gluconeogenesis, which was sufficient to prevent rise in ketogenesis, also prevented a fall in leptin. The infusion of beta-OH-butyrate to produce hyperketonemia of the same magnitude as after a 36-h fast had no effect on leptin. The study indicates that one of the adaptive physiological responses to fasting is a fall in serum leptin. Although the mediator that brings about this effect remains unknown, it appears to be neither insulin nor ketones.
Diabetes 1996 Nov
PMID:Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. 886 54

It has previously been demonstrated that plasma leptin correlates to body fat content. Increased body fat content is accompanied by low insulin sensitivity, which is compensated with increased insulin secretion. We therefore studied whether plasma levels of leptin also correlate to insulin secretion and sensitivity in humans. Therefore, we examined insulin sensitivity by the euglycemic-hyperinsulinemic clamp technique and measured the insulin response to intravenous arginine (5 g) at fasting and 14 mmol/l glucose in postmenopausal women. Percent body fat content was determined with impedance measurements. Log plasma leptin significantly correlated to percent body fat (r = 0.84, P < 0.001). In women with normal glucose tolerance (n = 36), partial correlation studies controlling for body fat content revealed significant correlations between log plasma leptin and fasting insulin levels (r = 0.39, P = 0.029), the insulin response to arginine at both glucose levels (r = 0.38 and r = 0.37, P < 0.036 for both), and the glucose potentiation of arginine-stimulated insulin secretion (r = 0.40, P = 0.025). In contrast, in women with impaired glucose tolerance (n = 17), these correlations were not significant. Plasma leptin did not correlate with insulin sensitivity independently of body fat content. To study whether the correlation between leptin and insulin would be explained by insulin stimulating leptin secretion, we examined plasma leptin during hyperinsulinemic conditions (689 +/- 41 pmol/l), under both euglycemia (5.0 mmol/l, n = 10) and hypoglycemia (2.5 mmol/l, n = 7). However, under both these conditions, plasma leptin was unaltered. In conclusion, plasma leptin 1) reflects body fat content and 2) correlates to insulin secretion independently of percent body fat in postmenopausal women with normal glucose tolerance.
Diabetes 1996 Nov
PMID:Plasma leptin levels correlate to islet function independently of body fat in postmenopausal women. 886 64


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