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
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