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Changyou Zhou,
Cheng Tang,
Eric Chang,
Min Ge,
Songnian Lin,
Eric Cline,
Carina P Tan,
Yue Feng,
Yun-Ping Zhou,
George J Eiermann, [......],
Peter Meinke,
Ralph Mosley,
Taro E Akiyama,
Monica Einstein,
Sanjeev Kumar,
Joel Berger,
Andrew D Howard, Nancy Thornberry,
Sander G Mills,
Lihu Yang
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ABSTRACT: Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1298-301. · 2.65 Impact Factor
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Enpeng Zhao,
Mark P Keller,
Mary E Rabaglia,
Angie T Oler,
Donnie S Stapleton,
Kathryn L Schueler,
Elias Chaibub Neto,
Jee Young Moon,
Ping Wang,
I-Ming Wang, [......],
Robert Kleinhanz,
Jin Shang,
Yun-Ping Zhou,
Andrew D Howard,
Bei B Zhang,
Christina Kendziorski, Nancy A Thornberry,
Brian S Yandell,
Eric E Schadt,
Alan D Attie
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ABSTRACT: Type 2 diabetes results from severe insulin resistance coupled with a failure of b cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19-22-nucleotide RNA molecules that potentially regulate the expression of thousands of genes. To understand the relationship between miRNA regulation and obesity-induced diabetes, we quantitatively profiled approximately 220 miRNAs in pancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice. More than half of the miRNAs profiled were expressed in all three tissues, with many miRNAs in each tissue showing significant changes in response to genetic obesity. Furthermore, several miRNAs in each tissue were differentially responsive to obesity in B6 versus BTBR mice, suggesting that they may be involved in the pathogenesis of diabetes. In liver there were approximately 40 miRNAs that were downregulated in response to obesity in B6 but not BTBR mice, indicating that genetic differences between the mouse strains play a critical role in miRNA regulation. In order to elucidate the genetic architecture of hepatic miRNA expression, we measured the expression of miRNAs in genetically obese F2 mice. Approximately 10% of the miRNAs measured showed significant linkage (miR-eQTLs), identifying loci that control miRNA abundance. Understanding the influence that obesity and genetics exert on the regulation of miRNA expression will reveal the role miRNAs play in the context of obesity-induced type 2 diabetes.
Mammalian Genome 10/2009; 20(8):476-85. · 2.89 Impact Factor
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Alessandro Pocai,
Paul E Carrington,
Jennifer R Adams,
Michael Wright,
George Eiermann,
Lan Zhu,
Xiaobing Du,
Aleksandr Petrov,
Michael E Lassman,
Guoqiang Jiang, [......],
Xiaoping Zhang,
Michael M Sountis,
Alessia Santoprete,
Elena Capito,
Gary G Chicchi, Nancy Thornberry,
Elisabetta Bianchi,
Antonello Pessi,
Donald J Marsh,
Ranabir SinhaRoy
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ABSTRACT: Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.
We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r(-/-) and Gcgr(-/-) mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.
Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.
Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.
Diabetes 08/2009; 58(10):2258-66. · 8.29 Impact Factor
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Sarah M Ronnebaum,
Mette V Jensen,
Hans E Hohmeier,
Shawn C Burgess,
Yun-Ping Zhou,
Su Qian,
Douglas MacNeil,
Andrew Howard, Nancy Thornberry,
Olga Ilkayeva,
Danhong Lu,
A Dean Sherry,
Christopher B Newgard
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ABSTRACT: We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, it has recently been shown by other laboratories that NADP-dependent cytosolic malic enzyme (MEc), but not NAD-dependent mitochondrial malic enzyme (MEm), regulates GSIS. In the current study, we show that small interfering RNA-mediated suppression of either MEm or MEc results in decreased GSIS in both 832/13 cells and a new and more glucose- and incretin-responsive INS-1-derived cell line, 832/3. The effect of MEm to suppress GSIS in these cell lines was linked to a substantial decrease in cell growth, whereas MEc suppression resulted in decreased NADPH, shown previously to be correlated with GSIS. However, adenovirus-mediated delivery of small interfering RNAs specific to MEc and MEm to isolated rat islets, while leading to effective suppression of the targets transcripts, had no effect on GSIS. Furthermore, islets isolated from MEc-null MOD1(-/-) mice exhibit normal glucose- and potassium-stimulated insulin secretion. These results indicate that pyruvate-malate cycling does not control GSIS in primary rodent islets.
Journal of Biological Chemistry 09/2008; 283(43):28909-17. · 4.77 Impact Factor
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ABSTRACT: cAMP is a key modulator for glucose-dependent insulin secretion (GDIS). Members of the phosphodiesterase (PDEs) gene family regulate intracellular levels of cAMP by hydrolyzing cAMP to the corresponding inactive 5'AMP derivative. These studies examined the expression and function of all 18 cAMP-specific PDEs in the rat insulinoma derived INS-1 (832/13) cell and isolated rat islets using quantitative PCR and siRNA-mediated gene-specific knockdown. PDE1C, PDE3B, PDE4C, PDE8B, PDE10A, and PDE11A were significantly expressed in rat islets and INS-1 (832/13) cells at the mRNA level. PDE1C, PDE10A and PDE11A were also expressed in brain, along with PDE3B, PDE4C and PDE8B which were also highly expressed in liver, and PDE3B was present in adipose tissue and PDE4C in skeletal muscle. siRNA mediated knockdown of PDE1C, PDE3B, PDE8B and PDE4C, but not PDE10A and PDE11A, significantly enhanced GDIS in rat INS-1 (832/13) cells. Also, selective inhibitors of PDE3 (trequinsin) and PDE4 (roflumilast and L-826,141) significantly augmented GDIS in both INS-1 (832/13) cells and rat islets. The combination of PDE3 and PDE4 selective inhibitors demonstrate that these enzymes comprise a significant proportion of the cAMP metabolizing activity in INS-1 cells and rat islets.
Biochemical pharmacology 08/2008; 76(7):884-93. · 4.25 Impact Factor
