بسم الله الرحمن الرحيم

Associate Prof. of Biochemistry Ain Shams Faculty of Medicine Insulin Sensitizers By Dr. Amr S. Moustafa Associate Prof. of Biochemistry Ain Shams Faculty of Medicine

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

Antidiabetic Drugs Statistically, World-wide growing epidemic of T2DM CONT’D 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

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

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 NH2 COOH 20 7 19 7 NH2 HOOC

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

Insulin Signaling Cascade

The Metabolic Syndrome Risk factor Defining 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 H3C N C NH C NH2 H3C NH NH Guanidine Biguanide

Insulin Sensitizers: Metformin CONT’D 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) Mechanism of action: Lipid Profile Lipogenesis, TG synthesis and LDL-C AMPK-α2 activation

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

The Peroxisome Proliferator-Activated Receptors (PPARs)

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

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

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 Polycystic Ovary Syndrome Chronic inflammatory bowel diseases 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