1. بسم الله الرحمن الرحيم

2. 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

3. 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

4. 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?

5. 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

6. 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

7. 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

8. Insulin Resistance
CONT’D
NH2
COOH 20 7 19 7
NH2
HOOC

9. 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

10. 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

11. Insulin Signaling Cascade

12. 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

13. The Role of Adipokines in Atherosclerosis

14. The Link between Obesity, Insulin Resistance and Atherosclerosis

15. Insulin Sensitizers: Metformin
H3C N C NH C
NH2
H3C
NH NH
Guanidine
Biguanide

16. 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

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

18. The Peroxisome Proliferator-Activated Receptors (PPARs)

19. 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

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

21. 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

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

23. 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, ….

24. 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