Week 1: Pharmacologic Rx for diabetes

Question 1

abnormal beta cell function in T2DM

Answer 1

• abnormal oscillatory insulin release
• increased proinsulin levels
• loss of 1st phase insulin response: 1st phase is release of preformed insulin stored in cells. Blunted in Type 2 diabetes. Bc of insulin resistance, at periphery have impaired glucose uptake. Central resistance: insulin is not getting into the liver. Need a ton of insulin to make liver stop making glucose. After fasting at night, no insulin was stored since need high insulin for liver. So come morning after breakfast, no stored insulin to release in response to eating.
• abnormal 2nd phase response: if still have glucose after first phase, immediately make and release insulin
• progressive loss of b cell function

Question 2

sulfonylureas

Answer 2

• stimulate b-cell insulin secretion
• bind to subunit of ATP inhibitable K+ channel in b cell and facilitate channel closing
• b cell depolarization and Ca entry via Ca channels
• exocytosis of insulin containing granules
• limited use of ~2 years. it increased workload, they speed up beta cell demise
• long lasting, 24 hours, can cause hypoglycemia. Also weight gain.

Question 3

Meglitinides

Answer 3

• differ in structure from sulfonylureas, but similar effect
• act at different site on channel complex
• short acting 2-4 hrs
• less postprandial hypoglycemia
• more expensive than sulfonylureas

Question 4

Metformin

Answer 4

• diminishes hepatic glucose production via unknown mechanism: fasting and postprandial
• first entry level med for DM
• can be used for pre diabetes
• side effects: nausea, diarrhea, lactic acidosis

Question 5

a-glucosidase inhibitor

Answer 5

• requires post prandial hyperglycemia
• inhibits cleavage of disaccharide to monosaccharide on brush border membrane of intestinal epithelial absorptive cell, terminal step of carb digestion in GI tract
• slows rate of absorption of carb
• side effects: flatulence, diarrhea, GI distress. Usually not prescribed

Question 6

Thiazolidinediones

Answer 6

• bind to transcription factors called peroxisome proliferation activating receptors (PPARs)
• increase/ decrease transcription of multiple genes. Don’t know exactly how this works.
• leads to increase in insulin sensitivity in classical insulin target tissues
• troglitazone: fulminant hepatic failure. DContd
• rosiglitazone: increase CHF, heart disease
• pioglitazone: lowered LDL and TGs, but bladder cancer

Question 7

GLP-1 (glucagon like peptide)

Answer 7

• secreted from L cells of distal small intestines, diminished in T2DM
• b-cells: stimulates glucose dependent insulin secretion
• a-cells: suppresses glucagon secretion in glucose dependent manner
• liver: decreased glucagon reduces hepatic glucose output
• GI: slows gastric emptying
• CNS: enhances satiety and reduces food intake
• improves insulin sensitivity

Question 8

Target values for T2DM

Answer 8

HbA1C: 6.5-7% without hypoglycemic reactions

• fasting serum glucose: 80-110
• 2 hours post prandial: 120-140
• AC??: 80-110
• HS (before bed) 100-140

Question 9

Treatment plan formula

Answer 9

with meal plan, exercise, and metformin, and HbA1C>7%

1. Can Add
   - basal insulin (most effective)
   - sulfonylureas (least expensive)
   - glitazone (if no hypoglycemia)
2. If still >7%
   - can add another drug in combo
3. intensive insulin+metformin+/-glitazone?