Lynn Decarr

Publications (2)7.01 Total impact

• Article: Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss.

  William P Esler, Joachim Rudolph, Thomas H Claus, Weifeng Tang, Nicole Barucci, Su-Ellen Brown, William Bullock, Michelle Daly, Lynn Decarr, Yaxin Li, Lucinda Milardo, David Molstad, Jian Zhu, Stephen J Gardell, James N Livingston, Laurel J Sweet
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  ABSTRACT: Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.
  Endocrinology 12/2007; 148(11):5175-85. · 4.46 Impact Factor
• Article: PDE-10A inhibitors as insulin secretagogues.

  Louis-David Cantin, Steven Magnuson, David Gunn, Nicole Barucci, Marina Breuhaus, William H Bullock, Jennifer Burke, Thomas H Claus, Michelle Daly, Lynn Decarr, [......], Herbert O Ogutu, Alan Olague, Ronda Ott-Morgan, Robert W Schoenleber, Adrian Tersteegen, Philip Wickens, Zhonghua Zhang, Jian Zhu, Lei Zhu, Laurel J Sweet
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  ABSTRACT: Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
  Bioorganic & Medicinal Chemistry Letters 05/2007; 17(10):2869-73. · 2.55 Impact Factor