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)

We recently reported that intraperitoneal administration of leptin-related synthetic peptide 116-130 [LEP-(116-130)] resulted in reduced food intake and significant weight loss in homozygous female C57BL/6J ob/ob mice. In this study, we used two in vitro bioassays to show that the interaction of LEP-(116-130) with the long form of the leptin receptor (OB-Rb), the receptor isoform that is predominantly expressed in the hypothalamus, is not required for the observed in vivo effects of the peptide on energy balance. LEP-(116-130) was unable to compete the binding of alkaline phosphatase-leptin fusion protein to OB-R. Moreover, LEP-(116-130) was unable to activate signal transduction by OB-Rb in vitro. In homozygous female C57BLKS/J-m db/db mice that do not express OB-Rb, intraperitoneal administration of LEP-(116-130) reduced body weight gain and blood glucose levels but not food intake, which further supports a mechanism of action that does not require peptide interaction with OB-Rb.
Diabetes 1999 Nov
PMID:Inhibitory effects of leptin-related synthetic peptide 116-130 on food intake and body weight gain in female C57BL/6J ob/ob mice may not be mediated by peptide activation of the long isoform of the leptin receptor. 1053 55

Five allelic mutants of the diabetes (db) gene have been previously described in mice and rats causing obesity, infertility, and varying degrees of diabetes. We have identified a new, spontaneous mutation resulting in obesity and diabetes in a colony of CD-1 outbred mice, Mus musculus domesticus. Genetic complementation studies indicated that the new mutation was an allele of the diabetes locus. Sequence analysis of cDNA fragments showed a deletion of one G residue located in exon 12 of the leptin receptor gene. The mutation, Lepr(db-NCSU), results in a frameshift and reduces Lepr transcript levels 10-fold. Mutant mice drank up to four times more water and were up to two times heavier than wild-type mice. Blood glucose and plasma insulin and leptin concentrations were sexually dimorphic among affected mice, suggesting an effect of sex steroids. Mortality of affected males was 100% by 5 mo, whereas affected females survived up to 10 mo of age.
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PMID:Spontaneous mutation in the db gene results in obesity and diabetes in CD-1 outbred mice. 1066 31

Non-insulin-dependent diabetes mellitus (type 2 diabetes) is known to be a polygenic and polyfactorial disorder. Here we describe the long-term examination of a transgenic mouse line showing the disruption of the leptin receptor (Lepr, Ob-R) gene caused by transgene insertion. The absence of the expression of the long isoform Ob-Rb uncovered a strong variation of the obesity and diabetes phenotype in the homozygous mutant mice of the outbred strain used. One part of the homozygous mice developed severe persistent early-onset obesity, whereas the other part developed cachexia after having shown initial obesity in the examination period up to 26 weeks p.p. The leptin-receptor-defective mice of this line might serve as a model for the investigation of genes modulating the development and mode of expression of diabetes.
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PMID:Contrasting obesity phenotypes uncovered by partial leptin receptor gene deletion in transgenic mice. 1070 83

The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxonidine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
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PMID:Molecular pathology in the obese spontaneous hypertensive Koletsky rat: a model of syndrome X. 1084 68

Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.
Diabetes 2000 Feb
PMID:Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. 1086 41

Leptin is mainly produced in white adipose tissue and acts both at distant sites and locally at the tissue from which it originates. The cellular and subcellular localization of leptin and its receptor (Ob-receptor [Ob-R]) and their relationship to various stages of fat cell maturation have not been characterized as yet. Therefore, we analyzed leptin and Ob-R by using reverse transcriptase-polymerase chain reaction, immunohistochemistry, and ultrastructural immunogold labeling in human white adipose tissue and in human adipocyte cell cultures at early and late stages of differentiation. Both leptin and its receptor were present in mature unilocular fat cells. The thin cytoplasmic rim of the adipocytes exhibited the strongest expression of both leptin and Ob-R. At early stages of differentiating human adipocytes, leptin was mainly expressed in multilocular preadipocytes, whereas the Ob-R was found predominantly on fibroblast-like cells. Other cellular components of human white adipose tissue were characterized by anti-CD31 for endothelial cells, anti-CD68 for macrophages, and antibodies specifically labeling B-cells and T-cells. In addition to fat cells, endothelial cells were immunopositive for the full-length leptin receptor. On the ultrastructural level, leptin was mainly found attached to cellular membranes and in small alveolate vesicle-like structures in the cytoplasm of adipocytes. Leptin was also present on the cell membranes of endothelial cells and macrophages. We conclude that the expression of the Ob-R in human white adipose tissue is not restricted to adipocytes but is present in resident endothelial and immune cells. Ultrastructural localization studies revealed an association of leptin with cell membranes and small vesicles. The cellular and subcellular distribution of leptin and its receptor suggests an important autocrine and paracrine role for leptin in human adipose tissue.
Diabetes 2000 Apr
PMID:Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. 1087 Nov 89

Leptin expression in third trimester placenta (p) and leptin concentrations in umbilical cord blood (cb) were investigated in normal pregnancies [n = 10 (p), 31 (cb)] and abnormal pregnancies complicated with (i) maternal insulin-dependent diabetes [IDDM: n = 3 (p), 13 (cb)], (ii) gestational diabetes [GD: n = 2 (p), 10 (cb)] and (iii) fetal growth retardation [FGR: n = 5 (p), 5 (cb)]. By in-situ hybridization and immunohistochemistry, placental leptin mRNA and protein were co-localized to the syncytiotrophoblast and villous vascular endothelial cells. Leptin receptor was immunolocalized to the syncytiotrophoblast. Relative to controls, the FGR group was characterized by low concentrations of placental and cord blood leptin. In a twin pregnancy, the normal-sized infant exhibited more placental and cord blood leptin than its growth-retarded twin. In contrast, both diabetic groups exhibited high concentrations of placental leptin mRNA and protein. The IDDM group exhibited the highest concentrations of leptin in cord blood. No change was observed in the expression of the leptin receptor in either the growth-retarded or diabetic pregnancies. In conclusion, the localization of placental leptin suggests that it may be released into both maternal and fetal blood. Furthermore, in fetal growth-retarded and diabetic pregnancies, the changes in leptin expression in the placenta and in leptin concentrations in umbilical cord blood appear to be related.
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PMID:Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. 1090 88

Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a highfat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (Vp) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (125I and 131I) to separately determine the PS and Vp values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml x g(-1) x ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The Vp values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study.
Diabetes 2000 Jul
PMID:Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. 1090 81

Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.
Diabetes 2000 Aug
PMID:Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass. 1092 36

Long-form leptin receptor (OB-R(L)) is a signal-transducing member of the cytokine receptor superfamily that is essential for mediating the effects of leptin on mammalian body weight homeostasis. At present, the range of transcriptional targets responsive to OB-R(L) activation, and consequently, the likely mediators of leptin action, remain undefined. In this report, we have used cDNA subtractive hybridization to identify transcripts induced by leptin in immortalized hypothalamic neurons expressing OB-R(L). Differential expression of the identified transcripts in these cells was confirmed by both array technology and Northern blotting. In situ hybridization studies indicate that these transcripts are expressed in the mouse central nervous system, including nuclei of the hypothalamus that coexpress OB-R(L). Comparative in situ analysis of slices of hypothalami generated from control and leptin-injected ob/ob mice demonstrates that a subset of the identified transcripts is induced in vivo after leptin injection. The potential role of the proteins encoded by these transcripts in mediating the effects of leptin on body weight and energy homeostasis are discussed.
Diabetes 2000 Sep
PMID:Identification of leptin-induced transcripts in the mouse hypothalamus. 1096 27


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