Antidiabetic Drugs

Until 1994, FDA-approved antidiabeticsInsulin and Sulfonylurea

Last few years, the list was expandingInsulin (different preparations and various routes)Oral Drugs:

Insulin secretagogues

sulfonylurea and non-sulfonylureaBiguanidesα-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: MetforminThiazolidinediones: Glitazones

Regardless the mechanism of action:Improve insulin sensitivityAmeliorate insulin resistance

Insulin Resistance

A less than normal biologic response to a given concentration of insulin

Causes:Abnormal β-secretory productCirculating insulin antagonistsTarget tissue defects

Insulin ResistanceCONT’D

NH2 HOOC

NH2

CO

OH

7 19

207

Insulin ResistanceCONT’D

Elevated FFAs:Increased hepatic glucose production

Decreased peripheral glucose utilizationInhibition of

glycolysis pyruvate oxidationglucose 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 ResistanceCONT’D

PI3K

Insulin Signaling Cascade

The Metabolic Syndrome

Risk factor Defining level

Abdominal obesity (waist circumference)Men >40 inWomen >35 in

Plasma triacylglycerols ≥150 mg/dl

Plasma HDL-C Men <40 mg/dlWomen <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

N C NH C NH2

H3C

H3C

NH NH

Guanidine

Biguanide

Decreased insulin resistanceAMPK-α2 activationRelease of inhibition of RTK activity

Maintenance or decrease of body weight

Food consumption (anorexia, leptin)

Energy expenditure (AMPK-α2

activation)

Insulin Sensitizers: MetforminCONT’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)

The Peroxisome Proliferator-Activated Receptors (PPARs)

CONT’DMultiple Levels of Regulation

PPAR expression

Ligand specificity and availability

RXR availability

Co-activators and Co-repressors

Phosphorylation of PPARs

Red: Direct PPAR-γ actionsGreen: 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 profilePAI-1 and Platelet aggregation

Vascular smooth musclesProliferation and M/I migrationVasodilatation

The TZDs: Other Potential Clinical Uses

Treatment of

Chronic inflammatory bowel diseasesPolycystic Ovary Syndrome

Alzheimer’s disease

Breast and stomach cancer

Insulin Sensitizers: Future and Experimental Members

Drugs targeting specific molecules in insulin signalingβ-subunit of insulin receptorIRS-1, PI-3K, and GLUT-4

Drugs targeting PPARsNon-TZD PPAR-γ agonistPPAR-γ antagonistPPAR-γ/RXR agonistDual 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