MD Conference Express ADA 2011 - (Page 24)

n SELECTED UPDATES IN NOVEL T2DM THERAPIES partners for PPAR action, the part that RXRs and their endogenous retinoid mediators exert in the vessel wall is less well understood. Biological insights into PPARRXRs may help inform interpretation of clinical trials with synthetic PPAR agonists and prospects for future PPAR therapeutics [Plutzky J. Circ Res 2011]. Novel antidiabetic drugs inhibit obesity-linked phosphorylation of PPARγ by CDK5 [Choi JH et al. Nature 2010]. Other new mechanisms of action for insulin sensitizers are under development (Figure 2). According to Dr. Plutzky, understanding of a novel non-PPAR mechanism of action presents a way forward. Figure 2. Mechanism of Action for Insulin Sensitizers. Prior Original TZDs Tro, Rosi, Pio action is inhibition of the microsomal enzyme 11βHSD, which prevents the reduction of cortisone to the active hormone cortisol (or inhibition of corticosterone production in rodents). An orally active small molecule by Incyte Corporation, INCB13739 has completed a Phase 2a clinical trial, with promising outcomes [Rosenstock J et al. Diabetes Care 2010]. G-protein-coupled receptors are a family of approximately 850 proteins that have a wide variety of ligands with diverse effects on metabolism. The focus of research to date has been on fatty acid receptors. Fatty acid-binding GPCRs have effects on inflammation and insulin release and modulate insulin action. The proposed mechanism of the drug action is activation of GPR- enhanced insulin release in a glucose-dependent manner, leading to a decrease in inflammation that may improve insulin sensitivity [Im DS. Prostaglandins Other Lipid Mediat 2009]. Another target is the GLP-1 receptor. Activation of GLP-1 receptor signaling has pleotropic effects, increasing insulin release and improving insulin action. ZY0G1 is an new, orally active, peptidomimetic molecular entity by Zydus Cadila. In vitro studies show potent activation of signaling in CJHO cells that express GLP-1R. In lean and obese mice, ZY0G1 improved glucose tolerance, decreased the area under the curve for insulin, and reduced weight gain and fasting glucose. In a Phase 1 human trial, ZY0G1 produced a dose-dependent pharmacokinetic response and a dosedependent improvement in glucose tolerance in healthy human subjects [Peters AL. Clev Clin J Med 2009]. Activation of both GIP and GLP-1 receptors is expected to have synergistic effects on insulin secretion, increasing its secretion and biosynthesis as well as improving β-cell proliferation and survival [Chia CW et al. Diabetes 2009; Baggio LL, Drucker DJ. Gastroenterology 2007]. GIP/ GLP-1 coagonists are peptide-engineered to bind and activate both the GIP and GLP-1 receptors [Tschop M, DiMarchi R et al. (in preparation)]. In animal models, the GIP/GLP-1 coagonist lowered glucose and weight in DIO mice in a dose-dependent manner, with no evidence of tachyphylaxis [Tschop M, DiMarchi R et al. (in preparation)]. The next-generation GIP/GLP-1 coagonist, an acylated coagonist with an extended half-life and high activity in vivo, has been tested in human studies since 2009. In concluding his presentation, Dr. Burant cited alternative therapies as targets: weight loss, diet, exercise, and surgery. There are many targets for pharmacological therapy for diabetes, and many groups pursuing these targets. However, there is no perfect target and no perfect drug. “To expect one is unreasonable,” he concluded. New Mito Target of TZDs (mTOT) PPARγ Cell nucleus MSDC- 0160 MSDC- 0602 (Phase 2 clinical trials) Mitochondria Modulation of nutrient signals; Wnt PPAR-Mediated Transcription Cell nucleus Nuclear Regulatory Factors Improved Insulin Action Improved Lipid Profiles Increased Brown Fat Preservation of β-cells Fat Sequestered Increased Insulin Action Fluid Retention Weight Gain Reproduced with permission Metabolic Solutions Development Company LLC. Next-Generation Metabolic Solutions Charles Burant, MD, PhD, University of Michigan, Ann Arbor, Michigan, USA, started his presentation with a slide of the myriad of metabolic drugs in the pharmaceutical industry pipeline, ranging from a bile acid receptor agonist to a nicotinic acetylcholine receptor. He followed up with the 100+ targets that the new drugs are aimed at affecting and discussed novel compounds that are under development, such as elongase of long-chain fatty acids family 6 (ELOVL6). As a rate-limiting enzyme for the elongation of saturated and monounsaturated long-chain fatty acids, ELOVL6 is abundantly expressed in lipogenic tissues, such as the liver, and its mRNA expression is upregulated in obese animal models. ELOVL6-deficient mice are protected from highfat diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes [Shimamura K et al. Eur J Pharmacol 2010]. Another target—11 β-hydroxysteroid dehydrogenase type 1 (11 Beta HSD-1)—is an NADPH-dependent enzyme that is highly expressed in the liver, adipose tissue, and central nervous system [Hollis G, Huber R. Diabetes Obes Metab 2011]. The proposed mechanism of 24 August 2011 www.mdconferencexpress.com  http://www.mdconferencexpress.com http://www.mdconferencexpress.com

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