Abstract:
:Cardiac failure is a major cause of death in patients with type 2 diabetes, but the molecular mechanism that links diabetes to heart failure remains unclear. Insulin resistance is a hallmark of type 2 diabetes, and insulin receptor substrates 1 and 2 (IRS1 and IRS2) are the major insulin-signaling components regulating cellular metabolism and survival. To determine the role of IRS1 and IRS2 in the heart and examine whether hyperinsulinemia causes myocardial insulin resistance and cellular dysfunction via IRS1 and IRS2, we generated heart-specific IRS1 and IRS2 gene double-knockout (H-DKO) mice and liver-specific IRS1 and IRS2 double-knockout (L-DKO) mice. H-DKO mice had reduced ventricular mass; developed cardiac apoptosis, fibrosis, and failure; and showed diminished Akt→forkhead box class O-1 signaling that was accompanied by impaired cardiac metabolic gene expression and reduced ATP content. L-DKO mice had decreased cardiac IRS1 and IRS2 proteins and exhibited features of heart failure, with impaired cardiac energy metabolism gene expression and activation of p38α mitogen-activated protein kinase (p38). Using neonatal rat ventricular cardiomyocytes, we further found that chronic insulin exposure reduced IRS1 and IRS2 proteins and prevented insulin action through activation of p38, revealing a fundamental mechanism of cardiac dysfunction during insulin resistance and type 2 diabetes.
journal_name
Diabetesjournal_title
Diabetesauthors
Qi Y,Xu Z,Zhu Q,Thomas C,Kumar R,Feng H,Dostal DE,White MF,Baker KM,Guo Sdoi
10.2337/db13-0095subject
Has Abstractpub_date
2013-11-01 00:00:00pages
3887-900issue
11eissn
0012-1797issn
1939-327Xpii
62/11/3887journal_volume
62pub_type
杂志文章相关文献
DIABETES文献大全abstract::The ATP-sensitive K(+) channel (K(ATP) channel) in pancreatic beta-cells is a critical regulator in insulin secretion. We previously reported that transgenic mice expressing a dominant-negative form (Kir6.2G132S) of Kir6.2, a subunit of the K(ATP) channel, specifically in beta-cells develop severe hyperglycemia in adu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db05-1459
更新日期:2006-07-01 00:00:00
abstract::The onset of insulin-dependent (type I) diabetes is predictable before hyperglycemia by the presence of islet cell autoantibodies (ICAs) and competitive insulin autoantibodies (CIAAs). CIAA+ICA+ first-degree relatives of individuals with type I diabetes have increased numbers of CD4 cells bearing the CD45R antigen and...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.40.5.590
更新日期:1991-05-01 00:00:00
abstract::In 112 obese compared with 42 lean children, we found that serum leptin is elevated early in the evolution of childhood-onset obesity (28.4 +/- 1.4 vs. 4.5 +/- 0.4 ng/ml in lean children, P < 0.0001) and correlates with adiposity. Obese children also had higher serum leptin normalized to fat mass. Despite high serum l...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.46.6.989
更新日期:1997-06-01 00:00:00
abstract::Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Expression of this pyr...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db11-1531
更新日期:2012-07-01 00:00:00
abstract::We studied the cross-sectional relationship between HbA1c and cardiovascular disease (CVD) in the survivors of the original cohort of the Framingham Heart Study (n = 1045). HbA1c was significantly related to prevalent CVD among women but not men. HbA1c was also related to hypertension and to the ratio of total to high...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.41.2.202
更新日期:1992-02-01 00:00:00
abstract::As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These includ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.2.398
更新日期:1999-02-01 00:00:00
abstract::PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine-to-tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0929
更新日期:2013-03-01 00:00:00
abstract::Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about it...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.1.111
更新日期:2003-01-01 00:00:00
abstract::Plasma and urine fibrinopeptide-A (FPA) levels were investigated in type I and II diabetic patients. Plasma FPA and 24-h urinary excretion of FPA were significantly elevated in diabetic patients compared with normal volunteers, indicating augmented thrombin activity in diabetes. Plasma and urine FPA did not differ bet...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.34.9.836
更新日期:1985-09-01 00:00:00
abstract:OBJECTIVE:Insulin stimulates glucose transport in skeletal muscle by GLUT4 translocation from intracellular compartments to sarcolemma and t-tubules. We studied in living animals the recruitment of GLUT4 vesicles in more detail than previously done and, for the first time, analyzed the steady-state recycling and subseq...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1578
更新日期:2008-02-01 00:00:00
abstract::Chronic hyperglycemia causes near-total disappearance of glucose-induced insulin secretion. The etiology has been suggested to be a nonsustainable stimulation of insulin release that causes beta-cells to become unresponsive to glucose through an undefined mechanism. We used an inhibitor of insulin secretion, diazoxide...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.43.2.173
更新日期:1994-02-01 00:00:00
abstract::Insulin-dependent diabetes mellitus (IDDM), cardiovascular morbidity, and vital prognosis are linked to diabetic nephropathy, which is probably determined by renal hemodynamic abnormalities and by a genetic predisposition. Angiotensin I converting enzyme (ACE) regulates systemic and renal circulations through angioten...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.43.3.384
更新日期:1994-03-01 00:00:00
abstract::We reported earlier that β-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of β-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats wit...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-0357
更新日期:2013-10-01 00:00:00
abstract:OBJECTIVE:The Diabetes Control and Complications Trial (Diabetes 44:968-983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support...
journal_title:Diabetes
pub_type: 杂志文章,随机对照试验
doi:10.2337/db07-1618
更新日期:2008-04-01 00:00:00
abstract::Three hundred and seventy-seven children and adolescents aged 5-17 yr from the biracial (black-white) community of Bogalusa, Louisiana, were evaluated for Tanner stage of sexual development, plasma glucose, and insulin levels during an oral glucose tolerance test. Children of the two races were of similar age, weight,...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.41.3.313
更新日期:1992-03-01 00:00:00
abstract::Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemic effect of pulsatile insulin ad...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.39.4.501
更新日期:1990-04-01 00:00:00
abstract::Insulin and glucagon release and insulin sensitivity were investigated in patients with glucokinase deficiency. Five subjects with a missense mutation (Glu256Lys) were studied. They were compared with six healthy subjects with low insulin response but normal glucose tolerance. Insulin and glucagon levels were measured...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.43.12.1402
更新日期:1994-12-01 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::We examined the effects of activation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPARalpha activation by its agonist, Wy-14,643, as well as PPARgamma activat...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.12.3358
更新日期:2005-12-01 00:00:00
abstract::Recent evidence supports the strong overlap between genes implicated in monogenic diabetes and susceptibility to type 2 diabetes. Transient neonatal diabetes mellitus (TNDM) is a rare disorder associated with overexpression of genes at a paternally expressed imprinted locus on chromosome 6q24. There are two overlappin...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-0216
更新日期:2006-08-01 00:00:00
abstract::Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue phy...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.50.8.1863
更新日期:2001-08-01 00:00:00
abstract::It is often stated that type 1 diabetes results from a complex interplay between varying degrees of genetic susceptibility and environmental factors. While agreeing with this principal, our desire is that this Perspectives article will highlight another complex interplay potentially associated with this disease involv...
journal_title:Diabetes
pub_type: 杂志文章,评审
doi:10.2337/db08-0331
更新日期:2008-10-01 00:00:00
abstract:OBJECTIVE:Reactive oxygen species (ROS) is one of most important factors in impaired metabolism secretion coupling in pancreatic β-cells. We recently reported that elevated ROS production and impaired ATP production at high glucose in diabetic Goto-Kakizaki (GK) rat islets are effectively ameliorated by Src inhibition,...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db10-0021
更新日期:2011-01-01 00:00:00
abstract::The exposure of primary cultures of hepatocytes to insulin. 10(-8) M, for 16 h results in a decrease in high affinity insulin binding with no alterations in lower affinity binding. This is reflected in a decrease in the sensitivity, but normal responsiveness, of cultured hepatocytes to the acute effect of insulin on t...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.31.2.145
更新日期:1982-02-01 00:00:00
abstract::Adiponectin, one of the most abundant gene transcript proteins in human fat cells, has been shown to improve insulin action and is also suggested to exert antiatherogenic effects. We measured circulating adiponectin levels and risk factors for atherosclerosis in 45 healthy first-degree relatives of type 2 diabetic sub...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.5.1182
更新日期:2003-05-01 00:00:00
abstract:OBJECTIVE:Short sleep duration is associated with impaired glucose tolerance and an increased risk of diabetes. The effects of sleep restriction on insulin sensitivity have not been established. This study tests the hypothesis that decreasing nighttime sleep duration reduces insulin sensitivity and assesses the effects...
journal_title:Diabetes
pub_type: 杂志文章,随机对照试验
doi:10.2337/db09-0699
更新日期:2010-09-01 00:00:00
abstract::Insulin receptors on viable rat adipocytes were affinity-labeled using a biologically active and photosensitive analogue of insulin, 125I-B2(2-nitro, 4 azidophenylacetyl)-des-PheB1-insulin (125I-NAPA-DP-insulin). The radiolabeled proteins were identified by SDS polyacrylamide gel electrophoresis and autoradiography. B...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.32.11.1001
更新日期:1983-11-01 00:00:00
abstract::Insulin lispro is a human insulin analog that dissociates more rapidly than human regular insulin after subcutaneous injection, resulting in higher insulin levels at an earlier point in time and a shorter duration of action. The aim of the study was to evaluate if this pharmacokinetic difference would translate into b...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2337/diab.46.3.440
更新日期:1997-03-01 00:00:00
abstract::Toxin from the scorpion Leiurus quinquestriatus was used to release norepinephrine from sympathetic nerve endings in the perfused rat pancrease. Addition of toxin, 10 mug./ml., to perfusate containing 0.3 mg./ml. glucose caused a large increase in release of norepinephrine and glucagon. Glucagon secretion was suppress...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.25.8.645
更新日期:1976-08-01 00:00:00
abstract::The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:1995-11-01 00:00:00