• (1) Diet – calorie diversity (50-60% CHO, 30% fat, 20% protein); regularly spaced meals; increased fiber consumption
• (2) Education
• (3) Exercise – upregulates insulin receptors and insulin production, improves blood lipid profile and BP, weight loss
• (4) Pharmacologic agents – include insulin and oral anti-hyperglycemic agents
• insulin is used only if glucose > 300 mg/dL and ketones are present; used in combination with oral agents
• insulin can reverse b cell glucose toxicity and cause b cells to become responsive to glucose again

Oral Hypoglycemic Agents – five drugs in three catagories

• (1) Insulin Secretagogs – increase secretion of insulin
• Sulfonylureas – include Glyburide, Glipizide, Glimepiride; least expensive of the oral antidiabetic agents
• Mechanism – binds receptor on b -cells, close ATP-dependent K⁺ channelsÞ depol.Þ Ca⁺⁺ influxÞ insulin release
• insulin ß fasting plasma glucose (FPG) due to inhibition of hepatic glycogen phosphorylase (HGP).
• Efficacy – ß FPG by 60-70 mg/dL (25% of patients achieve FPG<140 mg/dL), ß HbA1c by 1.5-2.0%.
• 75% of hypoglycemic action occurs at half maximal dose, so start with lowest dosage and titrate upwards
• First generation sulfonylureas have lower binding affinity than second generation
• Secondary Failure – 5-7% per year
• patient-related factors – weight gain, ß exercise, noncompliance
• therapy-related factors –concomitant antagonists, b -cell desensitization, inadequate dosage, impaired absorption
• disease-related factors – Ý insulin deficiency and resistance
• Cardiovascular effects – no effect on HDL, LDL, fibrinolytic system; improvement in triglycerides; weight gain
• Safety – hypoglycemia (2-4%) in elderly, renal failure – contraindicated in patients with renal or hepatic insufficiency
• Repaglinide – similar to sulfonylurea (same mechanism, efficacy, cardiovascular effects) – more expensive but safer
• Dosing – Administer 15 min. before meals because rapid absorption/elimination; 1 mg tid produces 90% of max effect
• Safety – hypoglycemia occurs less often than sulfonylureas; not contraindicated in renal failure
• (2) Insulin Sensitizers – Increase Response to Insulin – no effect on b -cell function!
• Biguanides – includes metformin (also buformin and phenformin, but these are no longer available)
• Mechanism – inhibits hepatic gluconeogenesis and glycogenolysis, enhances muscle insulin sensitivity
• Ý insulin receptor, Ý GLUT-4 transporter number and activity, Ý inositol 1,4,5-triphosphate, Ý glycogen synthesis
• Efficacy – same as sulfonylurea – but not as potent: starting dose 500 mg x2 / day
• Cardiovascular effects – only agent shown to reduce macrovascular complications (including MI and stroke)
• effects on lipid profile – 10-15% ß in triglycerides and LDL, no change or slight increase in HDL
• postprandial hyperlipidemia, ß free fatty acids and fatty acid oxidation, ß PAI-1; weight loss (2-3 kg in first 6 mo.)
• Safety – GI side effects (20-30%), interferes with Vit B₁₂ absorption, very rarely hypoglycemia or lactic acidosis
• do not use in organ failure – renal, respiratory, liver, heart
• Thiazilidiones – includes troglitazone (Rezulin), rosiglitazone (Avandia – most potent), pioglitazone (Actos)
• Mechanism – binds novel intracellular Peroxisome Proliferator Activated Receptor (PPAR) – affects gene transcription
• leads to Ý peripheral (muscle and adipose) insulin sensitivity due to Ý glucose transporter
• Efficacy: ß FPG 34 mg/dL (more effective with other drugs) – trog. 200-600 mg, ros. 4-8 mg, piog. 15-45 mg
• Cardiovascular effects: ß TG (10-20% patients), Ý HDL (5-10%), Ý LDL (10-15%), weight gain, small reduction in BP
• Safety – may be toxic to liver (troglitazone no longer FDA approved because of this); ß hematocrit in 3-4%; edema in 5% of patients – therefore not to be used in CHF
• (3) Glucose Absorption Inhibitors
• Alpha-glucosidase Inhibitors – includes acarbose (decrease glucose Ab’s)
• Mechanism – competitively inhibits intestinal brush border enzymes that break down carbohydrates to monosacc.
• Efficacy – ß post-prandial glucose by 40-50 mg/dL (effects on fasting glucose not as great), ß HbAc1 by 0.7-1.0%
• Cardiovascular effects – ß TG, but no effect on HDL, LDL, or body weight
• Dosing – must take with first bite of meal, start slow at 25 mg qd or bid. Max dose is 75 mg tid.
• Safety – 30% experience GI side effects, possibly causes liver damage, rarely hypoglycemia
• contraindicated in inflammatory bowel disease