Abstract:
:Mutations in the melanocortin-4 receptor (MC4R) gene are the most frequent monogenic causes of severe obesity. Most mutations have been described as heterozygous with loss of function, suggesting that haploinsufficiency is the most likely mechanism of dominant inheritance. We detected a heterozygous mutation, D90N, in a patient with severe early-onset obesity. Functional characterization of the mutant receptor revealed normal cell-surface expression and binding properties but loss of signal transduction activity. In coexpression studies of wild-type (WT)-MC4R and D90N, the mutant receptor had a dominant-negative effect on WT-receptor function. Further investigation of this effect with sandwich enzyme-linked immunosorbent assays and fluorescence resonance energy transfer studies showed that the WT-MC4R and the D90N mutant form homodimers and heterodimers. We hypothesize that the dominant-negative effect of the D90N mutation is caused by a functionally altered WT-MC4R/D90N receptor heterodimer. These findings necessitate the reinvestigation of other heterozygous MC4R missense mutations to discriminate between haploinsufficiency and a dominant-negative effect. The finding of receptor dimerization highlights a more complex hypothalamic signaling network governing the regulation of body weight.
journal_name
Diabetesjournal_title
Diabetesauthors
Biebermann H,Krude H,Elsner A,Chubanov V,Gudermann T,Grüters Adoi
10.2337/diabetes.52.12.2984subject
Has Abstractpub_date
2003-12-01 00:00:00pages
2984-8issue
12eissn
0012-1797issn
1939-327Xjournal_volume
52pub_type
杂志文章相关文献
DIABETES文献大全abstract::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...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.12.1744
更新日期:1996-12-01 00:00:00
abstract::A group of insulin-dependent diabetic patients was studied in order to determine the possible short-term regulatory effect of insulin and that of an antilipolytic drug on serum triglycerides. Subcutaneous crystalline insulin (one third of the usual morning dose of intermediate long-acting insulin, NPH) and an oral dos...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.26.7.615
更新日期:1977-07-01 00:00:00
abstract::The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is ubiquitously distributed in both the central and peripheral nervous systems and exerts a variety of effects. PACAP is a neuropeptide in pancreatic islets, where it has been suggested as a parasympathetic and sensory neurotransmitter. PACAP ...
journal_title:Diabetes
pub_type: 杂志文章,评审
doi:10.2337/diabetes.50.9.1959
更新日期:2001-09-01 00:00:00
abstract::We evaluated the production of antibodies against insulin in a genetically well-defined population. In the first study, 124 young patients with type I diabetes for longer than 6 mo were included. Anti-insulin antibodies were detected by polyethyleneglycol (PEG) precipitation after incubation of acidified, charcoal-str...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.35.6.634
更新日期:1986-06-01 00:00:00
abstract::Activity of the vascular large conductance Ca(2+)-activated K(+) (BK) channel is tightly regulated by its accessory β(1) subunit (BK-β(1)). Downregulation of BK-β(1) expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)-dependent F-box-only pro...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-1658
更新日期:2012-07-01 00:00:00
abstract::Vascular endothelial growth factor receptor 2 (KDR) plays a critical role in mediating a variety of vasculogenic and angiogenic processes, including diabetic retinopathy. We previously demonstrated that the promoter activity of the KDR gene in retinal capillary endothelial cells (RCECs) was regulated in part by the re...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.5.1222
更新日期:2004-05-01 00:00:00
abstract::The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6, 9, 16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 muU/ml., respectively. Since the portal v...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.24.2.225
更新日期:1975-02-01 00:00:00
abstract::We conducted a prospective study to describe the course of the pancreatic beta-cell function from the time of clinical diagnosis of insulin-dependent (type I) diabetes to determine whether DR type, presence of islet cell antibodies (ICA), presence of insulin antibodies (IA), age at onset, and sex could help in the pre...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.37.7.920
更新日期:1988-07-01 00:00:00
abstract::Diabetic microangiopathy is a slowly progressive condition that usually manifests itself years after the onset of the carbohydrate-metabolism disturbance. It is a far more striking problem in some diabetics than in others. Differences in the pattern of its effect in several body systems suggest that the local vascular...
journal_title:Diabetes
pub_type: 杂志文章
doi:
更新日期:1976-01-01 00:00:00
abstract::Previous studies have indicated that individuals with type 2 diabetes have an increased resting metabolic rate (RMR) but decreased insulin-induced thermogenesis (IIT) compared with those with normal glucose tolerance (NGT). When and by which mechanisms these abnormalities occur during the development of diabetes remai...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.8.1607
更新日期:1999-08-01 00:00:00
abstract::Cultured skin fibroblasts from clinically normal offspring of two parents with non-insulin-dependent diabetes have demonstrated premature senescence as a decreased ability of cells to establish colonies when inoculated at low density (plating efficiency). The present study tested the hypothesis that there is an inhere...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.27.3.338
更新日期:1978-03-01 00:00:00
abstract::The inhibitory action of insulin and proinsulin on basal and glucagon-activated glycogenolysis was studied in cultured rat hepatocytes containing [14C]glycogen. Insulin or proinsulin given as sole hormones in the presence of 5 mM glucose decreased basal release of [14C]glucose from [14C]glycogen to 20%. Half-maximal e...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.36.5.551
更新日期:1987-05-01 00:00:00
abstract::We identified a heterozygous missense mutation that substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient who displayed typical symptoms of Type A syndrome of insulin resistance. The proband's mother and younger brother were also found to be heterozygous for the muta...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.12.1837
更新日期:1993-12-01 00:00:00
abstract:OBJECTIVE:Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat type 2 diabetes mellitus. The A Diabetes Outcome Progression Trial (ADOPT) shows that women taking RSG experienced more fractures than patients taking other type 2 diabetes drugs. These were not osteoporotic vertebral fractures but, rather, occu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db10-1672
更新日期:2011-12-01 00:00:00
abstract::We demonstrate the presence of specific insulinlike growth factor I (IGF-I) receptors in human adipocytes. Competition studies with 125I-labeled IGF-I and unlabeled IGF-I, IGF-II, and insulin showed the specificity of 125I-IGF-I binding to the IGF-I receptors in adipocytes, membranes, and partially purified detergent-...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.10.1217
更新日期:1989-10-01 00:00:00
abstract::The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.10.2554
更新日期:2003-10-01 00:00:00
abstract::To test whether treatment with aminoguanidine, a drug known to prevent cross-linking between glycated proteins, is effective in improving reduced erythrocyte deformability in diabetes, we studied a group (n = 6) of ALX-induced long-term (12.7 +/- 2.2 mo of hyperglycemia) diabetic New Zealand white rabbits before and a...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.4.590
更新日期:1993-04-01 00:00:00
abstract::It is accepted for insulin-secreting cells in culture that the closure of ATP-sensitive K+ channels causes the glucose-dependent depolarization of pancreatic beta-cells seen at subthreshold levels (less than 100 mg/dl) of glucose. The question remains for the more thoroughly studied beta-cells in freshly dissected int...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.4.416
更新日期:1989-04-01 00:00:00
abstract::The pancreases of 14 children who died of type I diabetes were studied immunohistochemically for aberrant expression of HLA-DR antigens on islet endocrine cells. Two cases in which no residual insulin-secreting beta-cells were present had no evidence of HLA-DR expression on endocrine cells. Insulin-containing islets w...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.35.11.1215
更新日期:1986-11-01 00:00:00
abstract::We evaluated the effectiveness of a more potent and longer-acting somatostatin analogue (SMS 201-995) as an adjunct to insulin therapy, in a double-blind placebo-controlled randomized study of 26 C-peptide-negative type I (insulin-dependent) diabetic patients (20 women, 6 men, aged 22-40 yr) on their conventional drug...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2337/diab.38.6.704
更新日期:1989-06-01 00:00:00
abstract::The relationship of plasma glucose levels to risk of death over a five-year follow-up period was studied in 2,770 male survivors of myocardial infarction in the placebo group of the Coronary Drug Project (CDP). In univariate analyses, a positive association was observed between mortality rates and both fasting and one...
journal_title:Diabetes
pub_type: 临床试验,杂志文章
doi:
更新日期:1977-05-01 00:00:00
abstract::Mammalian erythrocytes have been shown to bind, but not to respond to, physiologic doses of insulin. Insulin binding was studied in normal rat erythrocytes and erythroblastic leukemic (EBL) cells by standard 125I-insulin competitive binding assays. EBL cells exhibited marked insulin degradation, which was time, temper...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.29.7.571
更新日期:1980-07-01 00:00:00
abstract::To identify mitochondrial haplogroups that confer resistance against or susceptibility to metabolic syndrome, we performed a large-scale association study on 1,337 unrelated Japanese individuals, including 871 subjects with metabolic syndrome and 466 control subjects. Metabolic syndrome was diagnosed according to modi...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1105
更新日期:2007-02-01 00:00:00
abstract::Platelet aggregation and related plasma factors have been studied in experimentally diabetic dogs, experimentally galactosemic dogs, and in normal dogs. Platelet aggregation, when induced in vitro by ADP (up to 22 microM) or collagen (up to 4 micrograms/ml), was not significantly different from normal in the diabetic ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.9.846
更新日期:1984-09-01 00:00:00
abstract::Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenerg...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.8.1115
更新日期:1996-08-01 00:00:00
abstract::This study investigated changes in levels of mRNAs encoding the three neurofilament (NF) proteins NF-L (low), NF-M (medium), and NF-H (high) and two growth-associated proteins, GAP-43 and T alpha 1 alpha-tubulin, in lumbar dorsal root ganglia of control and streptozocin-induced diabetic rats. After 8 weeks of diabetes...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.1.25
更新日期:1995-01-01 00:00:00
abstract::We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (db/db). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The db/db mice developed hyperglycemia, oxidative stress,...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1588
更新日期:2017-07-01 00:00:00
abstract::The Diabetes Control and Complications Trial (DCCT) is a multicenter randomized clinical trial studying the effect of intensive insulin therapy on the early vascular and neurological complications of insulin-dependent diabetes mellitus (IDDM). During the feasibility phase of the DCCT, baseline neurological histories, ...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1988-04-01 00:00:00
abstract:OBJECTIVE:Monocytes in childhood-onset type 1 diabetes show distinct gene expression. We hypothesize that monocyte activation in monozygotic (MZ) twin pairs discordant for childhood-onset type 1 diabetes could reflect distinct stages of the disease process including diabetes susceptibility (differences between twins, b...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-1433
更新日期:2010-07-01 00:00:00
abstract::Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focuse...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-1541
更新日期:2012-06-01 00:00:00