• It is not a single disease 
• It is a group of metabolic disorders sharing the common underlying feature of hyperglycemia
• Chronic hyperglycemia may be associated with secondary damage in multiple organ systems

• Sixteen million in the US with diagnosed disease 
• Another 6 to 7 million have diabetes but do not know it 
• Every year in the US, 800,000 people will develop diabetes 
• About 54,000 will die per year from diabetes 
• The risk is 2 to 5 times higher in the African-American, Hispanic, and Native American communities 
• By 2025, the number of people with diabetes is expected to double world-wide 
• There is an epidemic of Type 2 diabetes in the US among adolescents and young adults related to obesity

• Blood glucose normally maintained in the narrow range of 70 to 109 mg/dL 
• Impaired fasting glucose, or “Pre-diabetes”, 110—125 mg/dL (a precursor to type 2 diabetes) 
• Two different Glycosylated Hemoglobin (HBA1c) tests showing an HBA1c greater than 6.5%. 
•  A fasting glucose > 126 mg/dL on more than one occasion
• A random glucose > 200 mg/dL
  • with classical signs and symptoms, i.e., polyphagia, polydipsia, polyuria, weight loss, fatigue 
• An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200 mg/dL, two hours after a standard carbohydrate load

• Type 1
•  Type 2 
• Gestational diabetes

• (primary diabetes) 
• is characterized by an absolute deficiency of insulin caused by pancreatic Beta-cell destruction
• It accounts for approximately 3% to 5% of cases.

• (primary diabetes) 
• is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic Beta-cells 
• Approximately 95% of patients have type 2 diabetes

• occurs in approximately 4 % of women during pregnancy 
• insulin resistance caused by placental hormones

• Type 1 and Type 2 DM have different pathogenic mechanisms 
• The long-term complications in kidneys, eyes, nerves, and blood vessels are the same, as are the principal causes of morbidity (disability) and death.

• autoimmune (Type IV immune response) disease in which islet destruction is caused primarily by T lymphocytes, reacting against as yet poorly defined Beta-cell antigens, or fragments of endogenous insulin
• Genetic susceptibility—class II MHC (HLA) locus on chromosome 6p21 (HLA-D) 
• Environmental factors—CMV, Coxsackie virus B

• T lymphocytes react against Beta-cell antigens (Glutamic acid decarboxylase, GAD) and cause cell damage
• These T cells include:
  • (1) CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages 
  • (2) CD+8 cytotoxic T lymphocytes which directly kill Beta-cells and also secrete cytokines that activate macrophages 
  • (3) Early lesion of insulitis (inflammation of the Beta-cell islet) 
  • (4) Overt immunologic abnormalities may occur in early childhood (before the age of 10) but overt clinical diabetes may not occur until young adulthood (20 to 25 years of age).

• The two metabolic defects that characterize type 2 diabetes are: 
  • (1) a decreased ability of peripheral tissues, e. g., skeletal muscle and fat, to respond to insulin (insulin resistance) 
  • (2) Beta-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. 
• Insulin resistance may be associated with loss of function of the insulin receptor, e.g., decreased affinity of insulin, or loss of intracellular signals, e.g., MAP kinase, in insulin dependent cells

• Profound hyperglycemia – diabetic coma 
• Ketoacidosis (KDA)—life threatening 
• Insulin shock—too much insulin, not enough food, increase in exercise, or a combination thereof—life threatening

• Women who have never had diabetes before but who have hyperglycemia during pregnancy are said to have gestational diabetes 
• Placenta produces hormones to sustain pregnancy; these hormones (cortisol, progesterone, prolactin) make cells resistant to insulin
• the maternal pancreas secretes extra insulin; 
• and as the placenta grows larger during the second and third trimesters, it is even harder for the maternal insulin to work effectively—insulin resistance 
• Hyperglycemia results because the mother’s insulin cannot match rising blood sugar levels and the mother may need three times as much insulin to control her blood sugar 
• Untreated or poorly controlled gestational diabetes can harm the developing fetus 
• Maternal hyperglycemia causes the fetal pancreas to make extra insulin; the maternal insulin does not cross the placenta; however, the maternal glucose does 
• Since the future baby is getting more energy (from maternal blood glucose) than it needs to grow and develop, the extra energy is stored as fat—macrosomia or a “fat” baby 
• These babies become children who are at risk for obesity and adults who are at risk for type 2 diabetes 
• Usually develops during the second trimester—sometimes as early as the 20th week 
• Gestational diabetes (GD) is short-lived—blood sugar levels typically return to normal soon after delivery 
• Chances are 2 in 3 of getting GD in future pregnancies if a woman has had GD previously 
• Many women who have GD go on to develop type 2 diabetes years later (almost 40 %)—GD and type 2 diabetes both involve insulin resistance

• Affects about 4 % of pregnant women—about 135,000 cases per year in the US 
• Women older than age 25 are more likely to develop GD 
• Increased risk if the woman has “pre-diabetes”; or a parent or sibling (her first degree relative) has type 2 diabetes 
• If GD occurred during a previous pregnancy; or if a baby was delivered that weighed more than 9 pounds 
• Overweight before pregnancy 
• Race—Black, Hispanic, American Indian, or Asian are more likely to develop GD than other women

• Macrovascular disease—large and medium-sized muscular arteries 
• Microvascular disease—capillary dysfunction in target organs 
• Macrovascular disease causes accelerated atherosclerosis with an increased risk of MI, stroke, and lower extremity gangrene 
• Microvascular disease causes retinopathy, nephropathy, and neuropathy

• Control of blood sugar appears critical in delaying progression of microvascular disease
• Chronic hyperglycemia leads to microvascular complications (eye, kidney, nerve) 
• Control of blood pressure and cholesterol, however, may be far more critical than control of blood glucose in averting the complications associated with macrovascular disease, namely, MI and stroke.

• form as a result of nonenzymatic reactions between intracellular glucose and cross-linking with extracellular matrix proteins
  • i.e., collagen and laminin
• are resistant to proteolytic digestion. Thus, cross-linking decreases protein removal while enhancing protein (collagen) deposition, e.g., thickening of basement membrane, as in diabetic nephropathy
• AGE-modified matrix components also trap, e.g., LDL. In large vessels (the aorta), trapping of LDL retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima, thus accelerating atherosclerosis.

• The kidneys are prime targets in diabetes
• Renal failure is second only to MI as a cause of death 

Three lesions are encountered in the kidney:

• (1) glomerular lesions
  • nodular glomerulosclerosis
  • Kimmelstiel-Wilson lesion
  • capillary basement membrane thickening; 
• (2) renal vascular lesions, principally arteriolosclerosis
• (3) pyleonephritis, including necrotizing papillitis. 

This results in Nephrotic syndrome—

• proteinuria, hypoalbuminemia, and edema

The American Diabetes Association (ADA) estimates that two out of three patients with diabetes achieve, at best, marginal control 

• Fasting Blood Sugar 
• Glycosylated Hemoglobin (HbA1c)
  • 4 month assessment
  • target to HbA1c of 7 %
• Postprandial (post-meal) blood sugar
  • one to two hours
  • hyperglycemic spikes
  • may be associated in the long term with chronic renal failure