Abstract:
:Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.
journal_name
Diabetesjournal_title
Diabetesauthors
Allen T,Zhang F,Moodie SA,Clemens LE,Smith A,Gregoire F,Bell A,Muscat GE,Gustafson TAdoi
10.2337/db06-0618subject
Has Abstractpub_date
2006-09-01 00:00:00pages
2523-33issue
9eissn
0012-1797issn
1939-327Xpii
55/9/2523journal_volume
55pub_type
杂志文章相关文献
DIABETES文献大全abstract::To determine whether nonglucose nutrient-induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretio...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db06-1272
更新日期:2007-04-01 00:00:00
abstract::Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.10.2483
更新日期:2003-10-01 00:00:00
abstract:OBJECTIVE:Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and I...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db10-0839
更新日期:2011-01-01 00:00:00
abstract::Calcium/calmodulin-dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor (RyR) is regulated by reactive oxygen species (ROS), which is increased with high-fat feeding. We examined whether ROS-indu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db13-0816
更新日期:2014-06-01 00:00:00
abstract::In nonobese diabetic (NOD) mice, a deficiency in the number and function of invariant natural killer T-cells (iNKT cells) contributes to the onset of type 1 diabetes. The activation of CD1d-restricted iNKT cells by alpha-galactosylceramide (alpha-GalCer) corrects these deficiencies and protects against spontaneous and...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.5.1303
更新日期:2004-05-01 00:00:00
abstract::Recent studies have shown that two different voltage-dependent Ca2+ channels are expressed in pancreatic islets, the beta-cell/neuroendocrine-brain and the cardiac subtypes. The effects of chronic hyperglycemia on the levels in pancreatic islets of the mRNAs encoding the alpha 1-subunits of the beta-cell and cardiac s...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.7.948
更新日期:1993-07-01 00:00:00
abstract::Mesenchymal stem cells (MSCs) possess immunoregulatory, anti-inflammatory, and proangiogenic properties and, therefore, have the potential to improve islet engraftment and survival. We assessed the effect human bone marrow-derived MSCs have on neonatal porcine islets (NPIs) in vitro and determined islet engraftment an...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1068
更新日期:2017-05-01 00:00:00
abstract::Acute elevations of plasma free fatty acid (FFA) levels augment glucose-stimulated insulin secretion (GSIS). Prolonged elevations of FFA levels reportedly impair GSIS, but no one has previously compared GSIS after prolonged exposure to saturated or unsaturated fat. Rats received a low-fat diet (Low-Fat) or one enriche...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.51.6.1825
更新日期:2002-06-01 00:00:00
abstract::GAD is a pancreatic beta-cell autoantigen in humans and nonobese diabetic (NOD) mice. Modulation of GAD expression in pancreatic beta-cells has been suggested to be associated with the development of autoimmune diabetes. Hormonal changes through environmental stimuli are considered to influence the expression of the d...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.51.9.2764
更新日期:2002-09-01 00:00:00
abstract::Fourteen rats of the spontaneously diabetic BB line were bled from the retroorbital sinus approximately every 10 days. Sera taken from an early age up to 20 days after the onset of overt diabetes were assayed for complement-fixing antibodies against antigens of the surface of islet cells (CFA). Dispersed islet cells f...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.1.93
更新日期:1984-01-01 00:00:00
abstract::Several recent reports claim the generation of insulin-producing cells from embryonic stem cells via the differentiation of progenitors that express nestin. Here, we investigate further the properties of these insulin-containing cells. We find that although differentiated cells contain immunoreactive insulin, they do ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.10.2603
更新日期:2004-10-01 00:00:00
abstract::Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is re...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.suppl_3.s97
更新日期:2004-12-01 00:00:00
abstract::Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metab...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0876
更新日期:2013-06-01 00:00:00
abstract::Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage 1 ...
journal_title:Diabetes
pub_type: 杂志文章,评审
doi:10.2337/diab.32.2.s64
更新日期:1983-05-01 00:00:00
abstract::Hyperglycemia upon hospital admission in patients with ST-segment elevation myocardial infarction (STEMI) occurs frequently and is associated with adverse outcomes. It is, however, unsettled as to whether an elevated blood glucose level is the cause or consequence of increased myocardial damage. In addition, whether t...
journal_title:Diabetes
pub_type: 杂志文章,随机对照试验
doi:10.2337/db13-1849
更新日期:2014-07-01 00:00:00
abstract::High glucose concentrations such as are seen in diabetes mellitus are known to have deleterious effects on cells, but the pathways by which glucose induces these effects are unknown. One hypothesis is that metabolism of glucose to glucosamine might be involved. For example, it has been shown that glucosamine is more p...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.42.9.1289
更新日期:1993-09-01 00:00:00
abstract::Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogen...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.8.936
更新日期:1995-08-01 00:00:00
abstract::Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress-sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.54.7.2179
更新日期:2005-07-01 00:00:00
abstract::Diabetic hypoglycemia produces cognitive-motor slowing, which is assumed to increase risk of automobile crashes. This study investigated driving decrements during and after hypoglycemia, and the patients' awareness of driving decrements. We used a randomized, single-blind, crossover design and conducted the study at t...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2337/diab.42.2.239
更新日期:1993-02-01 00:00:00
abstract::Glucose controls islet beta-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this st...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db05-0678
更新日期:2006-06-01 00:00:00
abstract::A new approach has been developed to examine insulin sensitivity and resistance in vivo in man. In it, tracer methods are used, which permit the assessment of nonsteady state glucose kinetics by a method that is noninvasive and does not use pharmacologic agents. Graded doses of glucagon, infused intravenously, are use...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.29.3.169
更新日期:1980-03-01 00:00:00
abstract::The presence of the enzyme aldose reductase is increasingly being linked to diabetic complications. The distribution of this enzyme in human cornea, lens, retina, and optic nerve has been studied using specific antibodies against purified human placental aldose reductase raised in both rabbit and goat. The antisera fr...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.6.562
更新日期:1984-06-01 00:00:00
abstract::The rapid conversion of glucose to sorbitol by aldose reductase and the consequent hyperosmolarity of the cytoplasm has been shown to be the primary cause of the so-called "sugar" or "osmotic" cataract in many animal lenses. It is not as clear, however, that hyperosmolarity is the principal factor in the etiology of c...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.35.4.426
更新日期:1986-04-01 00:00:00
abstract::A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving fo...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/dbi20-0017
更新日期:2020-10-01 00:00:00
abstract::Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db19-0281
更新日期:2020-03-01 00:00:00
abstract::In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either sa...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.10.1613
更新日期:1998-10-01 00:00:00
abstract:OBJECTIVE:Emerging data demonstrate that maternal diabetes has long-term health consequences for offspring, including the development of hypertension. In adults, circulating endothelial progenitor cells (EPCs) participate in vascular repair, and EPC numbers and function inversely correlate with the risk of developing v...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db07-1507
更新日期:2008-03-01 00:00:00
abstract::Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial funct...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db12-0117
更新日期:2012-12-01 00:00:00
abstract::This study examines whether the loss of metabolic control in initially normalized islet transplants can result from the inadequate composition of the donor tissue. Streptozotocin-induced diabetic rats were followed for 64 weeks after the intraportal injection of islet isografts with different composition. The implanta...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.12.1814
更新日期:1996-12-01 00:00:00
abstract::Specific allelic associations vary among ethnic groups. We studied the distribution of HLA-A,-B,-C, and -DR antigens in 34 Japanese juvenile-onset diabetic patients. The focus of our current work was HLS-DR antigens because there have been few studies of Japanese with this disease. A significant increase in the freque...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.31.2.105
更新日期:1982-02-01 00:00:00