1. Diabetic Disorders 4th Leading cause of deaths in the US
75% of those afflicted with diabetes die from CHD
Major complications of diabetes
Fearsome 15
Elevated triglycerides and LDL; reduced HDL; High blood pressure; obesity; kidney failure; blindness; peripheral neuropathy; decline in cognitive abilities; atherosclerosis; heart attack; stroke; peripheral vascular disease; poor wound healing; frequent infections
9/20/2018
MEDC 603 Fall 2007

2. Diabetes Mellitus Type I Diabetes
aka IDDM (Insulin-dependent diabetes mellitus)
Inability of b-islet cells of pancreas to produce insulin
Type II Diabetes
aka NIDDM (Non-insulin-dependent diabetes mellitus)
Either a reduced ability of pancreas to produce or secrete insulin (some residual capacity) and/or reduced ability of target cells to respond to insulin
Gestational Diabetes
9/20/2018
MEDC 603 Fall 2007

3. Diabetes Mellitus Insulin
two chain polypeptide connected by two S-S bonds
A chain = 21 AA residues; B chain = 30 AA residues
may exist as dimer, trimer or higher oligomers in solution
produced in b-islet of Langerhans
Regulates glucose transport
stimulates GLUTs
Regulates gene transcription
~100 genes are known to be regulated by insulin
e.g., insulin inhibits gluconeogenesis …. Liver overproduces glucose in insulin-resistant state (type 2 DM)
Regulates glucose metabolism
phosphorylation of G to G-6-P …. Signal transduction
9/20/2018
MEDC 603 Fall 2007

4. Overview for Controlling Hyperglycemia
Absorption
from Diet
Biosynthesis in Liver
a-Glucosidase Inhibitors
Biguanides
Cellular Uptake
Serum Sugar
Biguanides;
thiazolidinediones
Sulfonylureas;
Benzoic Acids
Pancreas
Insulin
{Hypoglycemia}
9/20/2018
MEDC 603 Fall 2007

5. pKa ~5 Sulfonyl Ureas Structure & Ionization Mechanism of Action_
pKa ~5
Mechanism of Action
Stimulates release of insulin from b-cells
Act through ion-channels that generate a Ca+2 influx
Affinity to this receptor correlates with hypoglycemic effect
In addition, there are extra-pancreatic effects, e.g., effects on glucose transporter
9/20/2018
MEDC 603 Fall 2007

6. Structures of Sulfonyl Ureas
R R’
Tolbutamide
Chlorpropamide
Tolazamide
Glyburide
Glipizide
Glimepiride
9/20/2018
MEDC 603 Fall 2007

7. NOTE: 1) Hypoglycemia 2) Weight Gain
Major Pharmacokinetic Properties of Sulfonyl Ureas
Eqv. Dose
(mg)
Duration
(h)
Active metabolites
First Generation
Tolbutamide
12-24
No (p-COOH derivative)
Chlorpropamide
24-60
Yes (2’-OH and 3’OH groups)
Tolazamide
No (4-COOH derivative)
Second generation
Glipizide 10
10-24
No (cleavage of pyrazine ring)
Glyburide (glibenclamide)
Third generation 5
16-24
Some (trans + cis 4’-OH groups)
Glimepiride
1-2 24
Yes (-OH on CH3 of R’ group)
NOTE: 1) Hypoglycemia ) Weight Gain
9/20/2018
MEDC 603 Fall 2007

8. Substituted Benzoic Acids or ‘Glinides’
Structural similarity to Sus
pKa ~3-5 (close to SUs)
Functional similarity to SUs
More rapidly active
Shorter duration of action
Less problematic hypoglycemia
Reduced weight gain
Meglitinide
Replaglinide
Nateglinide
9/20/2018
MEDC 603 Fall 2007

9. Biguanides Phenformin Metformin Mechanism of Action (Metformin)
(not available in the US)
(introduced in the US in 1995)
Mechanism of Action (Metformin)
Unclear
Phenformin induces lactic acidosis …. Fatal in 3%
Does not depend on insulin (synthesis or secretion)
Anti-hyperglycemic (not hypoglycemic …. note !!)
Possibly two components: increased sugar usage and inhibition of gluconeogenesis
9/20/2018
MEDC 603 Fall 2007

10. Thiazolidinediones (glitazones) R group Mechanism of Action
Pioglitazone
(racemic)
Ciglitazone
(racemic)
Mechanism of Action
Enhance glucose and lipid metabolism through action on PPARg
Enhance sensitivity to insulin in target cells
Troglitazone
(racemic)
Rosiglitazone
(racemic)
9/20/2018
MEDC 603 Fall 2007

11. Thiazolidinediones (glitazones) Some Metabolites Rosiglitazone
Troglitazone
Pioglitazone
9/20/2018
MEDC 603 Fall 2007

12. a-Glucosidase Inhibitors - Acarbose
Inhibitor of Sugar Absorption from the GI tract
a-glucosidase
9/20/2018
MEDC 603 Fall 2007

13. a-Glucosidase Inhibitors - Acarbose
Transition State of hydrolysis
Acarbose – transition state mimic
9/20/2018
MEDC 603 Fall 2007