DIABETES--DEFINITIONS, CLASSIFICATION, PATHOPHYSIOLOGY


I. Definitions & Diagnostic Criteria

  1. "A group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both"
  2. Diagnostic Criteria--Must meet one of the criteria below on two separate days (doesn't have to be the same criterion both times)
    1. Sx of DM (polyuria, polydipsia, unexplained weight loss) plus random blood glucose > 200
    2. Fasting (>8h) glucose > 125mg/dl (probably as accurate as, and more reproducible than, the 2h post-glucose reading in the oral glucose tolerance test)
    3. 2h glucose > 200 mg/dl at any of the draws done during an oral glucose tolerance test (75g glucose after an overnight fast, check glucose at 1,2, and 3h)
  3. Note that plasma glucose values are us. 10-15% higher than whole blood glucose values
  4. HbA1c can be used to diagnose DM (if 6.5% or greater and confirmed with a repeat), per an "International Expert Committee" including representatives of the ADA (Diab. Care 32:1327, 2009-JW)

II. Classification and Pathophysiology--"For the clinician and patient it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively"

  1. Type 1 diabetes--due to absolute deficiency in insulin secretion prine to DKA. Usually starts in childhood or adolescence but can occur at any age
    1. Immune-Mediated (autoimmune destruction of pancreatic beta-cells)
      1. Serologic evidence present in 85-90% of pts with type 1 DM (anti-ICA, IAA, GAD, IA-2, etc.)
      2. Serologic evidence suggests an association between infection with enterovirus and onset of type 1 diabetes. (BMJ 342:d35, 2011-JW)
    2. Idiopathic (no evidence for immune-mediated beta-cell destruction)
      1. Mostly of African or Asian descent
  1. Type 2 diabetes--due to insulin resistance and relative deficiency in insulin secretion; less prone to DKA than type 1; more likely to remain asymptomatic than type 1; more prevalent
    1. Pathophysiology
      1. Peripheral insulin resistance (either due entirely to excess fat tissue and hyperglycemia or to intrinsic insulin resistance in muscle and liver)
      2. Relative insulinopenia, though may have actually high insulin levels at some point; in late disease, can get absolute insulinopenia ("burnt-out" pancreas)
    1. In children, may be associated with ketonuria and ketoacidosis
    2. Risk factors for Type 2 Diabetes
  1. Family history (more so than with Type 1)
  1. RR 2.0 with one first-degree relative, 4.0 with two
  2. More common in African-Americans and Native Americans
  1. Obesity, esp. upper-body, and sedentary lifestyle
  2. Age--steep rise after 45yo
  3. High progesterone states, e.g. pregnancy
  4. Diet: low fiber and high "dietary glycemic index" (higher with simpler carbohydrates and refined starches) associated with RR 1.47 of developing NIDDM after adjustment for age, MDI, smoking, exercise, family hx, alcohol and total caloric intake in 65,000 prospectively studied female RN's age 40-65 over 6y of f/u (branch of Nurses' Health Study, JAMA 277:472, 1997; comparing lowest to highest quintiles)
  5. Caffeine may be protective
    1. Data from the prospective Nurses' Health Study and Health Professionals' Follow-up Study showed a sig. reduced risk for new dx of DM with increasing amounts of coffee consumption (RR 0.74 for men and 0.85 for women with 4 cups or more a day vs. no coffee, after adjustment for age, BMI, and other risk factors). (Ann. Int. Med. 140:1, 2004--abst)
  1. Gestational diabetes
  1. Other specific types
    1. Genetic defects of beta-cell function
      1. Maturity-Onset Diabetes of the Young ("MODY")--us < 25yo; insulin-deficient; autosomal dominant inheritance
    2. Genetic defects in insulin action
    3. Pancreatic damage from any cause
      1. Pancreatitis
      2. Trauma
      3. Infection (mumps, CMV, etc.)
      4. Cancer
      5. Surgical excision
      6. Cystic fibrosis
      7. Hemochromatosis
      8. Fibrocalculous pancreatopathy
    4. Endocrinopathies
      1. Acromegaly
      2. Cushing's syndrome
      3. Glucagonoma
      4. Pheochromocytoma
      5. Hyperthyroidism
      6. Somatostatinoma
      7. Aldosteronoma
      8. etc.
    5. Drug- or chemical-induced (note--us. not the only cause but may exacerbate DM from other causes; see Pathophysiology section for details)
  1. B-blockers (decrease insulin secretion)
  2. Thiazides (decrease insulin secretion)
  3. H2-blockers
  4. Glucocorticoids
  5. Niacin
  6. OCPs
  7. Ca-blockers
  8. Systemic beta-agonists
  9. Pentamidine
  10. Phenytoin
  11. Thyroxine
  12. Phenytoin
  13. Alpha-interferon
  14. Olanzapine
  1. Many rare genetic syndromes
  1. Impaired Fasting Glucose and Impaired Glucose Tolerance
    1. Defined by the American Diabetes Association as fasting glucose 100-125 or 2h glucose 140-199 in fasting oral glucose tolerance test with 75g glucose (the latter more sensitive) (Diab. Care 26:3160, 2003)
      1. Historical note--From 1997 (when the ADA established the IFG/IGT categories) until 2002, the range for IFT was defined as 110-125.  Clinical studies dating from this period referring to "Impaired Fasting Glucose" may be referring to this older reference range.
    2. "Many individuals with IGT are euglycemic in their daily lives)
    3. Ass'd with fasting hyperinsulinemia, obesity, dyslipidemias, and risk of developing DM
    4. In a randomized trial of 1,429 pts 40-70yo with IGT (mean age 54y, mean BMI 30.9)  randomized to Acarbose 100mg TID vs. placebo; all had nutritional counseling and advice re: exercise.  Over minimum 3y f/u, incidence of DM (defined by 2h GTT) was sig. lower in acarbose group (32% vs. 42%) ("STOP-NIDDM" trial; Lancet 359:2072, 2002--JW)
      1. Another publication from the same trial reported a HR of 0.51 for combine outcome of (CAD incidence, CV death, CHF, cerebrovascular event, or PVD diagnosis), HR 0.09 for MI, and HR 0.66 for new dx of HTN (all sig.) over mean 3.3y f/u ("STOP-NIDDM" trial, JAMA 290:486, 2003--abst)
    5. In a study in 207  pts 30-75yo with impaired glucose tolerance randomized to (metformin 500mg + rosiglitazone 2mg) BID vs. placebo, incidence of progression to type 2 DM over 4y was 15.9% in the active-treatment group vs. 41.8% in the placebo group (RR 0.34; sig.) (Lancet 376:103, 2010-AFP)

III. Clinical presentation

  1. Weight loss/failure to grow normally
  2. Loss of appetite
  3. Fatigue
  4. Polydipsia & polyuria
  5. Blurred vision
  6. In kids: enuresis, behavioral disturbance
  7. In Type 1 DM, sometimes presents with diabetic ketoacidosis

(Source: American Diabetes Association "Clinical Practice Recommendations 1998," Diab. Care 21:S1, 1998. All quotes are from this document)