GENETIC FACTOR

Diabetes means just one thing - a high blood sugar level. While there are many conditions and problems associated with diabetes, such as obesity and heart problems, the disease itself is defined only by plasma glucose levels. Diabetes is a disease of glucose metabolism. Many people with diabetes have no clinical symptoms. The diagnosis of diabetes is based on one of two tests:the fasting plasma glucose test or an oral glucose tolerance test. It is important to remember that diabetes is not defined by obesity or its complications; nor is it defined by a urine test.

Diabetes is defined by the blood glucose level after undergoing a fasting plasma glucose test or an oral glucose tolerance test. Medical professionals recognize three strata associated with diabetes: people who are not diabetic; those with Impaired Glucose Tolerance (IGT); and those with diabetes.

There are three types of diabetes:

• Type I is insulin dependent and often called juvenile onset diabetes.
• Type II is non-insulin dependent, and often called adult onset.
• Gestational diabetes.

In Type I, the pancreas does not make enough insulin. Without taking insulin, the affected person will die; when given insulin, the affected person will live. People afflicted with Type I diabetes develop antibodies and auto-immunity to pancreatic insulin-producing b-cells. Studies have shown that concordance in twins for Type I is minimal, therefore the inheritance factor of Type I is small. Researchers believe that a combination of environmental factors and, probably, viral antigens are responsible for Type I diabetes. This type is intensively managed by controlling the blood sugar. Type I diabetes has a much smaller economic impact as compared to Type II.

Type II diabetes is 10 times more prevalent in America than Type I and it's economic impact is much greater. It is one of the most common chronic conditions in the United States. Since, at the beginning, there are no obvious symptoms,many Type II cases are not diagnosed. Those with the disease don't have an absolute deficiency of insulin since their pancreas does make some.

Type II diabetes is associated with obesity and with aging. It is a lifestyle-dependent disease, and has a strong genetic component (concordance in twins is 80-90%). The problem seems not so much in insulin production,but that when the insulin reaches its target cells, it doesn't work correctly.Most Type II diabetes patients initially have high insulin levels along with high blood sugar. However, since sugar signals the pancreas to release insulin,Type II diabetics eventually become resistant to that signal and the endocrine-pancreas soon will not make enough insulin. These people end up managing the disease with insulin and they need much higher doses because they are resistant to it.

When a person takes in a high load of sugar, the sugar stimulates the pancreas to release insulin. The targets for insulin are muscle, fat, and liver cells.These cells have insulin receptor sites on the outside of the cell membrane.For most people, when insulin has bound to the receptors, a cascade of events begins, which leads to sugar being transported from the blood into the interior of the cell. In Type II diabetics, even when insulin is present on the cell membrane, the process doesn't work. The glucose is never taken up into the cell and remains in the bloodstream.

The liver is responsible for glucose production and insulin is the regulatory agent of production. A high blood sugar content causes the pancreas to release insulin, and the insulin should signal the liver to stop making sugars. But, in diabetics, there's resistance to that signal and the liver keeps producing glucose. Hyperglycemia leads to glucose toxicity.

It is not high blood sugar that is the disease process of diabetes, but complications from the high blood sugar. Standard complications for many diabetics are: retinopathy (blindness); neuropathy (nerve damage) which leads to foot ulcers, gangrene, and amputations; kidney damage, which leads to dialysis; and cardiovascular disease. A major problem faced by doctors is that some people with high blood sugar feel fine; it's hard to treat diseases that are asymptomatic since most people don't want to take a pill for something that they don't feel bad about.

Type II Diabetes -- Genetic Factors

Normally, genetic studies are conducted by a classical linkage analysis using an LOD (Logarithm of Odds) score. This type of pedigreed, generational study works well if the disease is an autosomal dominant, recessive disorder. A study of this kind focuses on a particular gene locus to see if it tracks or co-segregates with the disease.

The problem with diabetes is that, even if the exact same mutation caused it in everyone, it would look different from person to person and family to family, depending on environmental influences, the genetic background it's laid upon, and modifier genes. Its expression would be variable.Furthermore, studies have shown that diabetes is not simple; it's genetically complex, involving multiple genes, and multiple gene-environment interactions.

Since classical linkage analysis doesn't work very well when studying genes in a mixed population, geneticists are moving to sib-pair analysis, called IBD - Identity by Descent. Siblings share 50% of their genes. If a gene locus has no association with a disease, it would be predicted that the siblings would share the locus 50% of the time.

One new, and somewhat controversial, method of studying the genetic component of diabetes is an Admixture Linkage Analysis. In this method, researchers view the admixed population as an F1 cross. If a disease is linked to a chromosomal locus in a genetically distinct population, it will stay in linkage association for multiple generations, until it finally sorts out through recombination. Since it's been 15 generations or so since the Europeans came over and admixed with the Native American population, now is the perfect time to do this kind of linkage analysis. The idea is that since DNA is inherited as a block, a gene locus and a marker will stay in association longer, the closer they are on the chromosome - if they are far away, the marker will fall out and they will no longer be linked.