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

Although it is well-recognized that non-insulin-dependent diabetes-mellitus (NIDDM) shown a strong genetic component the search for candidate genes has been very difficult since NIDDM is a complex, heterogeneous, multifactorial syndrome resulting from both genetic susceptibility and environmental risk factors. Therefore, the use of inbred animal models is an essential component of genetic investigations in this field. As these lines are genetically homogeneous, it is possible to direct mating for optimal genetic crosses and control environmental factors. Strains with spontaneous NIDDM may be constituted from animals with one or several genetic mutation(s) transmitted generation to generation or selected from non-diabetic outbred animals by repeated breeding. The ob/ob and db/db mice, which are rodent models of NIDDM and obesity, belong to the first category. Recent studies using the positional cloning approach allowed the mapping of ob gene and identification of its product, leptin, which is a protein secreted by white adipose tissue and involved in the control of food intake. The db gene encodes the leptin receptor. The search for genetic linkage was undertaken in polygenic models, especially the Goto-Kakisaki (GK) rat which was obtained by selective breeding of individuals with glucose intolerance from a non-diabetic Wistar rat colony. Though precise definition of sub-phenotypes of glucose tolerance and insulin secretion, the mapping of microsatellite markers and QTL analysis, it has proved possible to identify many independent loci containing genes regulating glucose homeostasis and insulin secretion. In another polygenic model, the OLETF rat, a locus present on chromosome X was identified. Many complementary approaches in different strains may lead to the identification of candidate genes for NIDDM and help direct the search for candidate genes in humans who show synteny relationships with rodents.
Diabetes Metab 1997 Mar
PMID:Are animal models of diabetes relevant to the study of the genetics of non-insulin-dependent diabetes in humans? 910 82

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

Mutations in the obese gene (OB) or in the gene encoding the OB receptor(OB-R) result in obesity, infertility and diabetes in a variety of mouse phenotypes. The demonstration that OB protein (also known as leptin) can normalize body weight in ob/ob mice has generated enormous interest. Most human obesity does not appear to result from a mutant form of leptin: rather, serum leptin concentrations are increased and there is an apparent inability to transport it to the central nervous system (CNS). Injection of leptin into the CNS of overfed rodents resistant to peripheral administration was found to induce biological activity. Consequently, for the leptin to act as a weight-lowering hormone in human obesity, it appears that appropriate concentrations must be present in the CNS. This places a premium on understanding the structure of the hormone in order to design more potent and selective agonists. Here we report the crystal structure at 2.4A resolution of a human mutant OB protein (leptin-E100) that has comparable biological activity to wild type but which crystallizes more readily. The structure reveals a four-helix bundle similar to that of the long-chain helical cytokine family.
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PMID:Crystal structure of the obese protein leptin-E100. 914 95

Zucker fatty (fa/fa) rats exhibit overt obesity, hypercholesterolemia, hyperlipidemia, and hyperglycemia as recessive traits. The fa mutation has been determined to be a missense mutation in the extracellular domain of the leptin receptor. We report herein the construction of CHO cells that stably express the fa-type leptin receptor and the characterization of this receptor using mRNA expression levels of the immediate early genes, c-fos, c-jun, and jun-B, which are induced by leptin as a criterion of signal transduction. The fa-type receptor not only exhibits a slightly reduced leptin-binding affinity, but also performs reduced signal transduction.
Diabetes 1997 Jun
PMID:Leptin receptor of Zucker fatty rat performs reduced signal transduction. 916 83

In the genetic mutant mouse models ob/ob or db/db, leptin deficiency or resistance, respectively, results in severe obesity and the development of a syndrome resembling NIDDM. One of the earliest manifestations in these mutant mice is hyperinsulinemia, suggesting that leptin may normally directly suppress the secretion of insulin. Here, we show that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin). The expression of leptin receptors on insulin-secreting beta-cells was also visualized utilizing antisera generated against an extracellular epitope of the receptor. A functional role for the beta-cell leptin receptor is indicated by our observation that leptin (100 ng/ml) suppressed the secretion of insulin from islets isolated from ob/ob mice. Furthermore, leptin produced a marked lowering of [Ca2+]i in ob/ob beta-cells, which was accompanied by cellular hyperpolarization and increased membrane conductance. Cell-attached patch measurements of ob/ob beta-cells demonstrated that leptin activated ATP-sensitive potassium channels (K(ATP)) by increasing the open channel probability, while exerting no effect on mean open time. These effects were reversed by the sulfonylurea tolbutamide, a specific inhibitor of K(ATP). Taken together, these observations indicate an important physiological role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion from the beta-cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.
Diabetes 1997 Jun
PMID:Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. 916 85

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

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 is the product of OB gene. This 16 kDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. It has been suggested that leptin could be the link between obesity and diabetes. Recent experiments in rodents have shown that leptin expression in adipocytes is also regulated at short-term by hormones and nutrients. Leptin expression increases after food intake and decreases during fasting and diabetes. Insulin and glucocorticoids increase leptin expression, whereas catecholamines, via beta-adrenergic receptors and cAMP, and long-chain fatty acids (and thiazolidinediones), via PPARy, inhibit leptin expression. Leptin is a cytokine that binds to transmembrane receptors similar to the receptors of cytokine family (type IL-6), and transmit their information inside the cell, after dimerisation. A short-form of leptin receptor (with a cytoplasmic domain of 34 amino residues) has been identified in the choroid plexus. This type of receptor should be used for leptin transport across the blood-brain barrier. Then leptin binds to a long-form of leptin receptor in the hypothalamus (with a cytoplasmic domain of 302 amino residues) and decreases the production of neuropeptide Y, a neuromediator of food intake. The long-form of leptin receptor, transmits its information via the Janus Kinases (JAK) who subsequently phosphorylate transcription factors of the STAT family. Intermediary forms of leptin receptor have been identified in other tissues: liver, heart, skeletal muscles, endocrine pancreas. The role of leptin receptors in these tissues remains obscure, but is of considerable interest. Recent studies have shown that leptin inhibits insulin secretion and have anti-insulin effects on liver and adipose tissue. If these effects are confirmed, leptin could play a role similar to TNF alpha and could participate in the insulin-resistance of obesity and type II diabetes.
Diabetes Metab 1997 Sep
PMID:Is leptin the link between obesity and insulin resistance? 934 38

Obesity is associated with diabetes, and leptin is known to be elevated in obesity. To investigate whether leptin has a direct effect on insulin secretion, isolated rat and human islets and cultured insulinoma cells were studied. In all cases, mouse leptin inhibited insulin secretion at concentrations within the plasma range reported in humans. Insulin mRNA expression was also suppressed in the cultured cells and rat islets. The long form of the leptin receptor (OB-Rb) mRNA was present in the islets and insulinoma cell lines. To determine the significance of these findings in vivo, normal fed mice were injected with two doses of leptin. A significant decrease in plasma insulin and associated rise in glucose concentration were observed. Fasted normal and leptin receptor-deficient db/db mice showed no response to leptin. A dose of leptin, which mimicked that found in normal mice, was administered to leptin-deficient, hyperinsulinemic ob/ob mice. This caused a marked lowering of plasma insulin concentration and a doubling of plasma glucose. Thus, leptin has a powerful acute inhibitory effect on insulin secretion. These results suggest that the action of leptin may be one mechanism by which excess adipose tissue could acutely impair carbohydrate metabolism.
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PMID:Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. 938 36


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