Research Project
7608527
DESCRIPTION (provided by applicant): Adiponectin is an anti-diabetic hormone exclusively secreted by adipocytes. Circulating adiponectin levels have been found to be low among obese and type II diabetic patients as compared to the normal population. Animal models and human studies suggest that elevated adiponectin levels increase insulin sensitivity. Weight loss or thiazolidinediones (TZDs) treatment increases plasma adiponectin levels. We have screened a library of drug-like compounds and natural products for novel agents that can enhance adiponectin production. We identified ITX2545 and its synthetic analogs as up-regulators of adiponectin secretion in vitro with potency levels comparable to that of rosiglitazone, a currently marketed anti-type II diabetic drug. However, unlike rosiglitazone, which acts as a PPAR agonist with weight gaining and cardiovascular side effects, ITX2545 and its analogs do not act on PPAR activity. These data suggest that ITX2545 and its analogs are potential anti-diabetic agents with novel mechanisms of action. The objective of this proposal is to investigate the pharmacology of the anti-diabetic activity of an optimal ITX2545-analog in vivo. The Specific Aims of the study are : (1) Preliminary PK-Tox evaluation - The best compounds will be selected based on in vitro potency and metabolic stability assays. Systemic exposure of the compounds will be assessed by LC-MS after oral or intravenous administration of the compounds. The delivery route that provides sufficient compound exposure in murine plasma will be used later for the efficacy study. The safe dose range will be determined by monitoring body weight, behavior, and clinical chemistry of the animals after compound administration and the results will guide the dosage for the efficacy study. (2) the in vivo efficacy study will be performed using ZDF diabetic rat model and db/db diabetic mouse model. Plasma level of adiponectin, glucose, insulin, leptin, FFA, triglyceride, and body weights will be used as the end points of anti-diabetic efficacy. A positive outcome of this in vivo efficacy study would provide the proof of principle for the anti-diabetic activity of the compound, and warrants its further development as an insulin sensitizer without the undesirable side effect associated with the current TDZs drugs on the market. PUBLIC HEALTH RELEVANCE: Animal studies revealed that elevated adiponectin levels alleviate metabolic syndrome. We identified small molecules that up-regulate adiponectin in vitro, and we hypothesize that these agents could be pharmacologically active in up-regulating adiponectin in vivo, thus potentially having therapeutic benefit against diabetes. The positive outcomes of the proposed studies may lead to the discovery of a novel class of agents for the treatment of metabolic syndrome.
