Type 2 Diabetes Mellitus

Matthew C. Riddle, M.D.
Oregon Health and Science University School of Medicine
Saul Genuth, M.D., F.A.C.P.
Case Western Reserve University School of Medicine

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• A metabolic disorder characterized by hyperglycemia, insulin resistance, and relative insulin insufficiency

• Polyuria
• Polydipsia
• Polyphagia
• Weight loss

• Hyperglycemia per screening tests
• Peripheral neuropathy
• Weakness
• Blurred vision
• Central obesity
• Recurrent infections (e.g., vaginitis)

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Differential Diagnosis

• Type 1: insulin deficiency, beta cell destruction
• Type 2: insulin resistance and variable insulin deficiency
• Endocrine dysfunction (e.g., Cushing syndrome, acromegaly)

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Best Tests

• Plasma glucose, randomly sampled, > 200 mg/dl with symptoms or fasting plasma glucose > 126 mg/dl with or without symptoms
• Confirm with second test

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Best Therapy

• Caloric reduction to produce weight loss (determine intake reduction on basis of degree of obesity and with dietitian's help)
• Diet < 30% total fat, < 10% saturated fat, < 10% polyunsaturated fat, 10%–15% monounsaturated fat, 10%–20% protein, 50%–55% carbohydrate
• Addition of high-fiber foods
• Awareness of carbohydrates to limit postprandial plasma glucose elevation
• Gradual increase in aerobic exercise

• American Diabetes Association goals
  • Preprandial capillary whole blood glucose levels: 90–130 mg/dl
  • Postprandial peak capillary whole blood glucose levels: < 180 mg/dl
  • Hemoglobin A_1c (HbA_1c) level 7% or lower if feasible without undue risk of hypoglycemia
• Begin with monotherapy; if response is not satisfactory by 3–6 mo, add additional drug
• Sulfonylureas (SUs): first choice for normal-weight patients; side effects are hypoglycemia, weight gain
  • Glipizide, extended release (XL)
    • Dose: lowest usual dosage, 2.5 mg q.d.; maximum effective dosage, 5 mg q.d.
    • Cost/mo: $11
  • Glimepiride
    • Dose: lowest usual dosage, 1 mg q.d.; maximum effective dosage, 4 mg q.d.
    • Cost/mo: $15
• Non-SU secretagogues; short half-life; take with meals to avoid hypoglycemia; side effects are hypoglycemia, weight gain
  • Repaglinide
    • Dose: lowest usual dosage, 0.5 mg q.d.; maximum effective dosage, 4 mg t.i.d.
    • Cost/mo: $222
  • Nateglinide
    • Dose: lowest usual dosage, 60 mg q.d.; maximum effective dosage, 120 mg t.i.d.
    • Cost/mo: $115
• α-Glucosidase inhibitors: monotherapy for postprandial hyperglycemia; must be taken at start of meals; side effects are flatulence, diarrhea
  • Acarbose
    • Dose: lowest usual dosage, 25 mg t.i.d.; maximum effective dosage, 100 mg t.i.d.
    • Cost/mo: $87
  • Miglitol
    • Dose: lowest usual dosage, 25 mg t.i.d.; maximum effective dosage, 100 mg t.i.d.
    • Cost/mo: $81
• Biguanides
  • Metformin: first choice for obese patients; contraindicated in renal insufficiency; side effects are nausea, diarrhea, lactic acidosis (rare)
    • Dose: lowest usual dosage, 500 mg q.d.; maximum effective dosage, 1,000 mg b.i.d.
    • Cost/mo: $56
  • Metformin extended release
    • Dose: lowest usual dosage, 500 mg q.d.; maximum effective dosage, 1,000 mg b.i.d.
    • Cost/mo: $48
• Thiazolidinediones: insulin sensitizers; side effects are weight gain, edema, heart failure (rare)
  • Pioglitazone
    • Dose: lowest usual dosage, 15 mg q.d.; maximum effective dosage, 45 mg q.d.
    • Cost/mo: $180
  • Rosiglitazone
    • Dose: lowest usual dosage, 2 mg q.d.; maximum effective dosage, 4 mg b.i.d.
    • Cost/mo: $211

• Use same drugs as with monotherapy, beginning with the lowest suggested dose of each
  • Sulfonylurea + metformin
  • Sulfonylurea + thiazolidinedione
  • Metformin + thiazolidinedione
  • Metformin + repaglinide
  • Repaglinide + thiazolidinedione
  • α-Glucosidase inhibitors + any other drug
  • Sulfonylurea + metformin + thiazolidinedione
  • Metformin + thiazolidinedione + repaglinide or nateglinide
  • Insulin + any other drug

• One daily injection of long-acting insulin (NPH, glargine, or detemir)
  • Dose: 10 U or 0.15 U/kg initially; increase by 2 U once or twice weekly until fasting glucose ≤ 120 mg/dl; or increase by 6–8 U weekly until fasting glucose ≤ 140 mg/dl, then increase by 2–4 U weekly until fasting glucose ≤ 120 mg/dl
• Regular or rapid-acting insulin before meals if postprandial glucose not controlled
  • Take regular insulin 30 min before meal
  • Take rapid-acting insulin just before or just after meal

• Pramlintide: if optimal glycemic control not achieved with insulin and HbA_1c < 9%
  • Dose: 30–60 µg initially, with slow titration to 120 µg if needed
  • Reduce preprandial insulin by half
• Exenatide: for patients taking a sulfonylurea, metformin, or both; hypoglycemia can occur with sulfonylurea
  • Dose: 5 µg b.i.d. initially, increase to 10 µg b.i.d. after 1 mo

• Sitagliptin: approved for use as monotherapy and as combination therapy with metformin or a thiazolidinedione
  • Blocks inactivation of GI peptide hormones
  • Dose: 100 mg/day; 50 or 25 mg/day in patients with moderate or severe renal insufficiency

• Once daily with stable control
• Once per insulin injection
• Postprandially with rapid-acting or regular insulin
• When symptoms of hypoglycemia occur

• At least every 6 mo

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Best References

DeWitt DE, et al: JAMA 289:2254, 2003 [PMID 12734137]

Gerich JE: Arch Intern Med 163:1306, 2003 [PMID 12796066]

Knowler WC, et al: N Engl J Med 346:393, 2002 [PMID 11832527]

Nathan DM, et al: Diabetologia 49:1711, 2006 [PMID 16802130]

Turner RC, et al: JAMA 281:2005, 1999 [PMID 10359389]

February 2007