Pathophysiology and Pathogenesis of Type 2 Diabetes Type 2 diabetes is the most common form of diabetes, with more than

90% of diabetics being Type 2, and 5%-10% being Type 1. Type 2 diabetes mellitus is a heterogeneous disorder with varying prevalence among different ethnic groups. In the United States the populations most affected are Native Americans, particularly in the desert Southwest, Hispanic-Americans, African-Americans, and AsianAmericans. However, Caucasian-Americans are also affected, but not at the same disproportionate percentage levels. The pathophysiology of Type 2 diabetes mellitus is characterized by peripheral insulin resistance (insulin insensitivity), cell damage, impaired regulation of hepatic glucose production, and later on: declining beta () cell function, eventually leading to possible -cell failure. The primary events are believed to be an initial insensitivity of insulin resulting in peripheral insulin resistance; and, later on, relative insulin deficiency. The key message here is that the key cellular dysfunction that occurs in Type 2 diabetes is not due to the cells (as in Type 1 diabetes) -- it's the muscle, liver, and fat cells, and also the damage to the red blood cells (due to glycation)! Author's Note: During my medical workshops with doctors, nurses, and other healthcare professionals, they were shocked to discover that cell dysfunction is NOT the primary issue with Type 2 diabetics -- especially when I show them the data from thousands of Type 2 diabetics. In fact, I was one of those Type 2 diabetics who was put on a drug protocol of 4 insulin shots a day because the doctors believed I was either a Type 1 diabetic, or a Type 2 diabetic with cell dysfunction. But, because of my biochemistry background I knew enough to ask for specific blood/urine/hormone tests that verified that I wasn't Type 1 and didn't have beta cell dysfunction, i.e. insulin serum test, c-peptide, urine ketone test, hemoglobin A1C, glutamic acid decarboxylase (GAD) antibody tests, islet cell antibody (ICA) tests, insulin antibody tests, GTT. Unfortunately, most Type 2 diabetics don't know this, and are led to take diabetic drugs that don't really help in the long run. If I had not recognized this discrepancy I would still be diabetic today and I would be taking even more insulin.

Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus. Humans are capable of digesting some carbohydrates, in particular those most common in food; starch, and some disaccharides such as sucrose, are converted within a few hours to simpler

forms, most notably the monosaccharide glucose, the principal carbohydrate energy source used by the body. The rest are passed on for processing by gut flora largely in the colon. Insulin is released into the blood by beta cells (-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about twothirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the -cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin. Glucose thus forcibly produced from internal liver cell stores (as glycogen) re-enters the bloodstream; muscle cells lack the necessary export mechanism. Normally, liver cells do this when the level of insulin is low (which normally correlates with low levels of blood glucose). Higher insulin levels increase some anabolic ("building up") processes, such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat-burning metabolic phase). If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not have its usual effect, so it will not be absorbed properly by those body cells that require it, nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis. When the glucose concentration in the blood is raised beyond its renal threshold (about 10 mmol/L, although this may be altered in certain conditions, such as pregnancy), reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst.