Pharmacotherapy of Diabetes Mellitis

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Pharmacotherapy of Diabetes Mellitis

• Keith W. Crawford, R.Ph.,Ph.D.
• Department of Pharmacology
• Howard University College of Medicine

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Pathogenesis of Insulin Resistance

• In obesity, adipose tissue liberates a diverse
  array of compounds that impair phosphorylation
  and activation of insulin receptors. These
  compounds include
• - Tumor necrosis factor
• - Free fatty acids

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Insulin Products

• - Purified Animal Insulins (porcine, bovine)
• purified by gel flitration, single peak
  purity, few
  contaminants
• - Recombinant human insulins (Humulin)
• Extremely low-risk of insulin allergy
• - Designer Insulins biochemical
  modifications of human insulins altering their
  absorption profile, duration of action

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Bolus-Basal Insulin Dosing (Type 1 Diabetes)

• The goal of this strategy is to mimic the normal
  physiologic pattern of insulin secretion.
• Rapid-acting insulins (Lispro, Aspart) or Regular
  insulin are given prior to meals to manage
  post-prandial glucose levels
• Isophane insulin (NPH) or long-acting insulins
  (insulin glargine, insulin detemir) provide basal
  insulin coverage

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Insulin Pumps

• A continuous subcutaneous delivery device that
  most closely mimics physiologic secretory
  patterns
• The programmable pump delivers bolus and basal
  insulin doses based on blood glucose monitoring.
  Basal levels are usually relatively constant
  bolus doses vary based on food consumption.
• Pumps use rapid acting insulins (lispro or
  aspart)
• or regular insulins.

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Primary failure

• Poor Initial patient selection (age, BMI, disease
  severity)
• Failure to comply with diet or exercise
• Co-morbidities
• Poor dietary compliance

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Secondary Failure

• Occurs at a rate of 5-10/year of patients who
  initially achieve control
• - Beta Cell Exhaustion
• - Disease Progression
• - Co-morbidities

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Non-sulfonyurea insulin secretagogues

• Rapid acting oral agents with short half-lives
• Share binding sites and mechanism of action with
  the sulfonylureas
• Administer prior to meals to manage postprandial
  hyperglycemia
• Meglinides Repaglinide
• D-phenylalanine derivative Nateglinide
  partially restores the initial phase of insulin
  secretion, requires elevated blood glucose for
  maximal effect

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Biguanides in the Treatment of Diabetes Mellitis

• In medieval Europe, a plant locally known as
  Goats Rue (Galega officinalis) was used to treat
  symptoms of diabetes. The plant contained the
  compound guanidine.
• In the 1950s, the biguanide Phenformin was
  introduced for treating type II diabetes in the
  U.S.. It was withdrawn from the market due to
  cases of fatal lactic acidosis.

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Benefits of Thiazolidionediones

• May improve lipid profile
• Can be combined with other agents
• Over time, these drugs appear to restore
  beta-cell function