Antidiabetic Drugs Until 1994, FDA-approved antidiabetics Insulin and Sulfonylurea Last few years, the list was expanding Insulin (different preparations and various routes) Oral Drugs: Insulin secretagogues sulfonylurea and non-sulfonylurea Biguanides α-Glucosidase inhibitors

Antidiabetic Drugs Do we need more antidiabetic drugs? The answer is Surely Yes Why? CONT’D

Antidiabetic Drugs Statistically, World-wide growing epidemic of T2DM Clinical evidence: Tight control of hyperglycemia in T2DM prevention of micro- and macro-vascular complications Ultimate goal: Prevention of T2DM in high risk subjects CONT’D

Insulin Sensitizers FDA-approved for clinical use: Biguanides: Metformin Thiazolidinediones: Glitazones Regardless the mechanism of action: Improve insulin sensitivity Ameliorate insulin resistance

Insulin Resistance A less than normal biologic response to a given concentration of insulin Causes: Abnormal β-secretory product Circulating insulin antagonists Target tissue defects

Insulin Resistance CONT’D NH 2 HOOC NH 2 COOH

Insulin Resistance CONT’D Elevated FFAs: Increased hepatic glucose production Decreased peripheral glucose utilization Inhibition of glycolysis pyruvate oxidation glucose transport Accumulation of TG in skeletal muscle

Insulin Receptor CAP-Cbl IRS Shc PIP3-Ser/Thr Kinases PDK Akt PKC Grb-2/Sos Ras/Raf/MAPK Insulin Resistance CONT’D PI3K

Insulin Signaling Cascade

The Metabolic Syndrome Risk factorDefining level Abdominal obesity (waist circumference) Men>40 in Women>35 in Plasma triacylglycerols≥150 mg/dl Plasma HDL-C Men<40 mg/dl Women<50 mg/dl Blood pressure≥130/85 mmHg Fasting plasma glucose≥110 mg/dl

The Role of Adipokines in Atherosclerosis

The Link between Obesity, Insulin Resistance and Atherosclerosis

Insulin Sensitizers: Metformin NCNHNHCNH2NH2 H3CH3C H3CH3C NH Guanidine Biguanide

Decreased insulin resistance AMPK-α2 activation Release of inhibition of RTK activity Maintenance or decrease of body weight Food consumption (anorexia, leptin) Energy expenditure ( AMPK-α2 activation ) Insulin Sensitizers: Metformin CONT’D Lipid Profile Lipogenesis, TG synthesis and LDL-C AMPK-α2 activation Mechanism of action:

Thiazolidinediones b) Avandia (rosiglitazone, SmithKline Beecham ) c) Actos (pioglitazone, Takeda & Lilly ) a) Rezulin (troglitazone, Warner-Lambert )

The Peroxisome Proliferator- Activated Receptors (PPARs)

CONT’D Multiple Levels of Regulation PPAR expression Ligand specificity and availability RXR availability Co-activators and Co-repressors Phosphorylation of PPARs

Red: Direct PPAR-γ actions Green: Adipokine effects The effects of TZDs on primary insulin-responsive tissues

The TZDs and Atherosclerosis Adipokine production Leptin, TNF-a and PAI-1 Adiponectin Lipid profile TG HDL-C, LDL-C, Cholesterol efflux Coagulation profile PAI-1 and Platelet aggregation Vascular smooth muscles Proliferation and M/I migration Vasodilatation

The TZDs: Other Potential Clinical Uses Treatment of Chronic inflammatory bowel diseases Polycystic Ovary Syndrome Alzheimer’s disease Breast and stomach cancer

Insulin Sensitizers: Future and Experimental Members Drugs targeting specific molecules in insulin signaling β-subunit of insulin receptor IRS-1, PI-3K, and GLUT-4 Drugs targeting PPARs Non-TZD PPAR-γ agonist PPAR-γ antagonist PPAR-γ/RXR agonist Dual PPAR-α/PPAR-γ agonist Others, inhibitors of gluconeogenesis, activator of glycogen Synthesis, resistin antagonist, IGF-1, ….

Invitation There is a justified open invitation for the development of new generations of insulin sensitizers and newer members of antidiabetics for better control of insulin resistance syndrome and for the prevention of T2DM