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.
Public Health Relevance Statement: Project narrative 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.
NIH Spending Category: Autoimmune Disease; Diabetes; Nutrition; Obesity
Project Terms: 2,4-Thiazolidinedione, 5-004-02-((((methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-; 2,4-thiazolidinedione; 5-((4-(2-methyl-2-(pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione-2-butenedioate; ACRP30 protein; Adipocytes; Adipose Cell; Adverse effects; Affect; Agonist; Animal Model; Animal Models and Related Studies; Animals; Anti-diabetic Agents; Antidiabetic Agents; Antidiabetic Drugs; Assay; Avandia; Behavior; Bioassay; Biologic Assays; Biological Assay; Biological Factors; Blood Plasma; Body Weight; Body Weight decreased; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Chemotherapy-Hormones/Steroids; Chronic; Clinical; Clinical Chemistry; Common Rat Strains; D-Glucose; Data; Developed Countries; Developed Nations; Developing Countries; Developing Nations; Development; Dextrose; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Diabetic mouse; Dose; Drug Kinetics; Drugs; Endocrine Gland Secretion; Evaluation; Factor, Biologic; Fat Cells; Funding; Glaxo Wellcome brand of rosiglitazone maleate; GlaxoSmithKline brand of rosiglitazone maleate; Glitazones; Glucose; Health; Heart failure; Hormones; Human; Human, General; Humulin R; IV drip; In Vitro; Industrialized Countries; Industrialized Nations; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Resistance; Insulin, Regular; Intravenous Drip; Intravenous Infusion; Investigation; Lead; Leptin; Less-Developed Countries; Less-Developed Nations; Libraries; Lipocytes; Liquid substance; MODY; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Marketing; Mature Lipocyte; Mature fat cell; Maturity-Onset Diabetes Mellitus; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Medication; Metabolic; Metabolic syndrome; Mice; Modeling; Monitor; Murine; Mus; NIDDM; Natural Products; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Novolin R; Ob Gene Product; Ob Protein; Obese Gene Product; Obese Protein; Obesity; Oral; Organ System, Cardiovascular; Outcome; PPAR; Pb element; Peroxisome Proliferator-Activated Receptors; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology; Plasma; Population; Principal Investigator; Production; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Rat; Rat model of diabetes; Rattus; Research; Reticuloendothelial System, Serum, Plasma; Route; SCHED; Schedule; Screening procedure; Serum, Plasma; SmithKline Beecham brand of rosiglitazone maleate; Societies; T2D; T2DM; Testing; Therapeutic; Therapeutic Hormone; Thiazolidinediones; Third-World Countries; Third-World Nations; Toxicology; Treatment Side Effects; Triacylglycerol; Triglycerides; Type 2 diabetes; Type II diabetes; Under-Developed Countries; Under-Developed Nations; Vascular, Heart; Weight Gain; Weight Increase; Weight Loss; Weight Reduction; adipocyte complement-related protein 30-kDa; adipocyte, C1q and collagen domain containing protein; adipogenesis; adiponectin; adiposity; adult onset diabetes; analog; anti-diabetic drugs; antidiabetic; apM-1 protein; apM1 (adipose-specific) protein; base; body weight gain; body weight increase; body weight loss; cardiac failure; circulatory system; corpulence; corpulency; corpulentia; db/db mouse; design; designing; diabetes; diabetic; diabetic patient; diabetic rat; diabetic rat model; dosage; drip infusion; drug/agent; fasting blood glucose level; fluid; glucose tolerance; heavy metal Pb; heavy metal lead; improved; in vivo; insulin resistant; insulin sensitivity; insulin sensitizer; insulin sensitizing drugs; intravenous administration; ketosis resistant diabetes; lipid biosynthesis; lipogenesis; liquid; maturity onset diabetes; model organism; mouse model; mouse model of diabetes; novel; ob/ob mouse; obese; obese people; obese person; obese population; pre-clinical; preclinical; programs; public health relevance; rosiglitazone; screening; screenings; side effect; small molecule; therapy adverse effect; thiazolidinedione; treatment adverse effect; treatment effect; vein infusion; wt gain; wt-loss
