A5082280074- Metabolism, Diabetes, and Cancer
- Peroxisome Proliferator-Activated Receptors
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Adipokines, Inflammation, and Metabolic Diseases
- Diabetes Treatment and Management
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Inflammatory mediators and NSAID effects
- Growth Hormone and Insulin-like Growth Factors
- Diabetes and associated disorders
- Eicosanoids and Hypertension Pharmacology
- PI3K/AKT/mTOR signaling in cancer
- Muscle Physiology and Disorders
- Fibroblast Growth Factor Research
- Diet, Metabolism, and Disease
- Diabetes Management and Research
- Cholesterol and Lipid Metabolism
- Liver Disease Diagnosis and Treatment
- Lipid metabolism and disorders
- Kruppel-like factors research
- Melanoma and MAPK Pathways
- Drug Transport and Resistance Mechanisms
- Diabetes, Cardiovascular Risks, and Lipoproteins
- CRISPR and Genetic Engineering
Sciences Po Lyon
2020-2023
Henry Ford Health System
2022
Klinik für Frauenheilkunde
2017
Eli Lilly (United States)
2007-2016
Johns Hopkins Medicine
2014
Johns Hopkins University
2014
University of Münster
2014
Merck & Co., Inc., Rahway, NJ, USA (United States)
1999-2009
Brigham and Women's Hospital
1989-2003
University of Southern California
2003
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism action. Its glucose-lowering effect results from decreased hepatic glucose production and increased utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) major regulator lipid metabolism. Here we report that metformin activates AMPK in hepatocytes; as result, acetyl-CoA carboxylase (ACC) activity reduced,...
Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic lipid control in various animal models. However, its potential to treat obesity, major health concern affecting over 30% of the population, has not been fully explored. Here we report systemic administration FGF21 for 2 wk diet-induced obese ob/ob mice lowered their mean body weight by 20% predominantly via reduction adiposity. Although no decrease total caloric intake or effect on...
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic production and increasing disposal in skeletal muscle; however, the molecular site of metformin action not well understood. AMP-activated protein kinase (AMPK) activity increases response to depletion cellular energy stores, this enzyme has been implicated stimulation uptake into muscle inhibition liver gluconeogenesis. We recently reported AMPK activated cultured rat hepatocytes,...
The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and activating the program adipocyte differentiation. potential for regulation PPAR gamma gene vivo unknown. We cloned a partial mouse cDNA developed an RNase protection assay that permits simultaneous quantitation mRNAs both l 2 isoforms encoded by gene. Probes detection P2, obese product, leptin, 18S were also employed. Both abundantly expressed...
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism action. Its glucose-lowering effect results from decreased hepatic glucose production and increased utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) major regulator lipid metabolism. Here we report that metformin activates AMPK in hepatocytes; as result, acetyl-CoA carboxylase (ACC) activity reduced,...
We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, candidate PG(s) participates these processes mechanism its action remain undefined. Using COX2-deficient mice multiple approaches, we demonstrate herein COX2-derived prostacyclin (PGI2) primary PG Several lines evidence suggest effects PGI2 are mediated by activation nuclear hormone receptor...
Adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin, or AdipoQ) is a fat-derived secreted that circulates in plasma. Adipose tissue expression Acrp30 lower insulin-resistant states and it implicated the regulation vivo insulin sensitivity. Here we have characterized ability PPARγ agonists to modulate expression. After chronic treatment obese-diabetic (db/db) mice with (11 d), mean plasma levels increased (>3×). Similar effects were noted nongenetic type 2 diabetes model...
Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator the actions incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns potential ability DPP-4 inhibition to have beneficial disease-modifying effects, specifically attenuate loss pancreatic beta-cell mass and function. Here, we investigated potent selective inhibitor, an analog sitagliptin (des-fluoro-sitagliptin), on glycemic control function mouse model with defects...
Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In screen for small molecules that activate the human insulin receptor tyrosine kinase, nonpeptidyl fungal metabolite (L-783,281) was identified acted as an mimetic in several biochemical and cellular assays. The compound selective versus insulin-like growth factor I (IGFI) other kinases. Oral administration L-783,281 two mouse models diabetes resulted significant lowering blood glucose levels. These...
The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPARα, PPARδ, and PPARγ. PPARγ has been implicated as a mediator of adipocyte differentiation the mechanism which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARδ that were identified radioligand binding assays. In transient transactivation assays these ligands to they bind. Protease protection...
OBJECTIVE Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type diabetes. RESEARCH DESIGN AND METHODS The (HbA1c glucose) (serum aminotransferase) of once-daily oral administration LY2409021 assessed two double-blind studies. Phase 2a study were randomized to 10, 30, or 60 mg placebo 12 weeks. 2b 2.5, 20 24 RESULTS...
Dipeptidyl peptidase IV (DP-IV), a member of the prolyl oligopeptidase family peptidases, is involved in metabolic inactivation glucose-dependent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), and other incretin hormones. Here, we investigated impact DP-IV deficiency on body weight control insulin sensitivity mice. Whereas WT mice displayed accelerated gain hyperinsulinemia when fed high-fat diet (HFD), lacking gene encoding (DP-IV -/- ) are refractory to development obesity...
Hyperglycemia has been implicated in the pathogenesis of both micro- and macrovascular complications diabetes. Little is known, however, about glucose transporters their regulation thevascular system. In this study, by was examined cultured BAECs BSMCs, human arterial smooth muscle cells. Both BSMCs transported via facilitated diffusion transport Glucose-transport activity vascular cells inversely reversibly regulated glucose. Exposure HSMCs to high decreased Vmax for 2DG 3-O-MG uptake,...
Studies of experimental diabetes in rodents induced by the beta-cell toxin streptozocin have shown that insulin-resistant glucose transport peripheral tissues (muscle and adipose) these animals can be ascribed part to a pretranslational reduction major insulin-sensitive transporter (GLUT4) tissues. Because central feature non-insulin-dependent mellitus (NIDDM) is an imparied ability insulin enhance disposal skeletal muscle, we examined hypothesis reduced expression GLUT4 characteristic...
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in promoters of regulated genes. Despite wealth information available on function PPARalpha PPARgamma, relatively little is known about most widely expressed PPAR subtype, PPARdelta. Here we show that treatment insulin resistant db/db mice PPARdelta agonist L-165041, at doses had no effect either glucose or...
Recent studies indicate that a peroxisome proliferator-activated receptor, PPAR gamma, functions as an important adipocyte determination factor. In contrast, tumor necrosis factor-alpha (TNF alpha) inhibits adipogenesis, causes dedifferentiation of mature adipocytes, and reduces the expression several adipocyte-specific genes. Here, we report treatment 3T3-L1 adipocytes with TNF alpha resulted in time- concentration-dependent decrease gamma mRNA to level detected preadipocytes. levels were...
Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report identification characterization a novel selective PPARgamma modulator (nTZDpa). nTZDpa bound potently with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, served selective, potent partial agonist was able antagonize activity full agonists. also displayed effects...