Originally Published Sept  2007

 

WHAT CAUSES TYPE ll DIABETES?

Type ll diabetes is caused by a complicated interplay of genes, environment, insulin abnormalities (reduced insulin secretion in the beta cells and insulin resistance in muscle cells), increased glucose production in the liver, increased fat breakdown, and possibly defective hormonal secretions in the intestine. The recent dramatic increase indicates that lifestyle factors (obesity and sedentary lifestyle) may be particularly strong in releasing the genetic elements that cause this type of diabetes.

CAUSES OF INSULIN RESISTANCE

The characteristic feature of diabetes type ll is the body's resistance to the actions of insulin. In many people, before diabetes develops, normal or even excessive levels of insulin compensate for this resistance. Over time however, insulin production often drops and resistance worsens. Researchers are trying to determine why these events occur.

Elevated levels of free fatty acids and the hormones resistin and leptin have been associated with insulin resistance at different phases. Such factors are also present in obesity. It is not known yet if elevated levels are simply a product of obesity or play some causal role in diabetes.

Some researchers suggest that proteins called calpains may play an important role in both insulin secretion and insulin action.

Elevated growth hormone during puberty appears to increase the risk for insulin resistance in overweight adolescents.

Some experts theorize that abnormal regulation of certain important peptides (amylin and CGRP) may occur, thus affecting both the nervous and circulatory systems. One effect is to alter blood flow, which may contribute to insulin resistance. How each of these factors contributes to type ll diabetes is under investigation.

One 2001 study found high levels of interleukin 6 (IL-6) and C-reactive protein (CRP) in people with diabetes. Both of these substances are markers for inflammation and damage caused by an over-active immune response. Some researchers believe such inflammation may contribute to the disease process leading to diabetes.
GENETIC FACTORS

Genetic factors play an important role in type ll diabetes, but the pattern is complicated, since both impairment of beta-cell function and an abnormal response to insulin are involved. Researchers have identified a number of genetic suspects:

Researchers have identified genes responsible for maturity-onset diabetes in youth (MODY), a rare genetic form of type ll diabetes that develops only in Caucasian teenagers. (It should be noted that this is not the diabetes associated with obesity that is now being seen increasingly in young people.)

Some research is now investigating genes that may be responsible for inherited cases of type 2 diabetes in middle-aged Caucasians.

A defective fatty-acid binding protein 2 (FABP2) gene may result in higher levels of unhealthy fat molecules (particularly triglycerides), which may be critical in the link between obesity and insulin resistance in some people with diabetes type ll.

A defective lipoprotein lipase (LpL) gene may pose a risk for coronary artery disease and type ll diabetes in people who have it.

Variations in a gene that regulates a protein called calpain-10 is proving to affect insulin secretion and action and may play a role in diabetes type ll. There is some disagreement, however, about its significance.

Defective genes that regulate a molecule called peroxisome proliferator-activated receptor (PPAR) gamma may contribute to both type ll diabetes and high blood pressure in some patients.

A defective gene has been detected that reduces activity of a protective substance called beta 3-adrenergic receptor, which is found in visceral fat cells (those occurring around the abdominal region). The result is a slow-down in metabolism and an increase in obesity. The defective gene has been found in Pima Indians and other populations with a very high incidence of type ll diabetes and obesity.

The Thrifty Gene. One theory suggests that some cases of type ll diabetes and obesity are derived from normal genetic actions that were once important for survival. Some experts postulate the existence of a so-called "thrifty" gene, which regulates hormonal fluctuations to accommodate seasonal changes. In certain nomadic populations, hormones are released during seasons when food supplies have traditionally been low, which results in resistance to insulin and efficient fat storage. The process is reversed in seasons when food is readily available. Because modern industrialization has made high-carbohydrate and fatty foods available all year long, the gene no longer serves a useful function and is now harmful because fat, originally stored for famine situations, is not used up. Such a theory could help explain the high incidence of type ll diabetes and obesity found in Pima tribes and other Native American tribes with nomadic histories and Western dietary habits. It is also used to explain the relationship between low birth weight and future diabetes in Pima tribes: poor nutrition in fetuses or infants cause changes that reduce insulin sensitivity so that fat storage increases, leading to later obesity and diabetes.