Diabetic Disorders

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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

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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

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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

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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
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Sulfonyl Ureas
Structure Ionization
Mechanism of Action Stimulates release of
insulin from b-cells Act through ion-channels
that generate a Ca2 influx Affinity to this
receptor correlates with hypoglycemic effect In
addition, there are extra-pancreatic effects,
e.g., effects on glucose transporter
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Structures of Sulfonyl Ureas
R R
Tolbutamide
Chlorpropamide
Tolazamide
Glyburide
Glipizide
Glimepiride
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Major Pharmacokinetic Properties of Sulfonyl Ureas
Eqv. Dose (mg) Duration (h) Active metabolites
First Generation
Tolbutamide 1000-1500 12-24 No (p-COOH derivative)
Chlorpropamide 250-375 24-60 Yes (2-OH and 3OH groups)
Tolazamide 250-375 12-24 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 2) Weight Gain
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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
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Biguanides
(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
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Thiazolidinediones (glitazones)
R group
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)
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Thiazolidinediones (glitazones)
Some Metabolites
Rosiglitazone
Troglitazone
Pioglitazone
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a-Glucosidase Inhibitors - Acarbose
Inhibitor of Sugar Absorption from the GI tract
a-glucosidase
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a-Glucosidase Inhibitors - Acarbose
Transition State of hydrolysis
Acarbose transition state mimic