Genetics of Type II Diabetes - Genetics and Diabetes

Genetics of Type II Diabetes

Genetics of Type II Diabetes

Definition
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.

Major Susceptibility Locus for Type II Diabetes
There have been several different regions of the human genome associated with susceptibility to Type II diabetes. One locus on the distal part of the long arm of chromosome 2 in the human genome has been well characterized to be linked with type II diabetes in humans. Information about this locus can be obtained at:

OMIMNIDDM 1

"Hanis et al. (1996) performed a genome-wide search that revealed a major susceptibility locus for noninsulin dependent diabetes mellitus (125853) on chromosome 2. The study was performed on 330 affected sibpairs from Mexican American families living close to the Rio Grande River in Texas. Marker D2S125, which is located in the distal part of the long arm of chromosome 2, showed significant evidence of linkage to NIDDM and appeared to be a major factor affecting the development of diabetes mellitus in Mexican Americans. Hanis et al. (1996) proposed that the locus be designated NIDDM1."

Hanis, C. L.; Boerwinkle, E.; Chakraborty, R.; Ellsworth, D. L.; Concannon, P.; Stirling, B.; Morrison, V. A.; Wapelhorst, B.; Spielman, R. S.; Gogolin-Ewens, K. J.; Shephard, J. M.; Williams, S. R.; Risch, N.; Hinds, D.; Iwasaki, N.; Ogata, M.; Omori, Y.; Petzold, C.; Rietzsch, H.; Schroder, H.-E.; Schulze, J.; Cox, N. J.; Menzel, S.; Boriraj, V. V.; Chen, X.; Lim, L. R.; Lindner, T.; Mereu, L. E.; Wang, Y.-Q.; Xiang, K.; Yamagata, K.; Yang, Y.; Bell, G. I.: A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet. 13: 161-166, 1996.

GeneCard for Diabetes mellilitus type 2

Rebhan, M., Chalifa-Caspi, V., Prilusky, J., Lancet, D.: GeneCards: encyclopedia for genes, proteins and diseases. Weizmann Institute of Science, Bioinformatics Unit and Genome Center (Rehovot, Israel), 1997. GeneCard for Diabetes mellilitus type 2 (NIDDM 1)

Information about animal models for diabetes can be obtained at:

OMIMNIDDM "Discussion of the polygenic or at least digenic inheritance of diabetes in mouse and rat models with pointers to related genetic studies in humans."

Type II Diabetes -- Genotype by Environment Interaction
Some ethnic groups, such as most Native Americans and Hispanics, have a definite genetic susceptibility to diabetes, while some groups, including Caucasians, Melanesians, and Eskimos, are at low risk. Since Type II diabetes essentially did not exist 100 years ago, it's obvious that a change in the environment has created the disease, but there is genetic susceptibility on top of that.Very little is known about the genetics of diabetes other than that there is a gene-environment interaction with multiple genes involved. It's reasonable to think that when linkage analyses are done, researchers will find diabetes-related genes; they may be primary-related diabetes genes or modifying genes, such as obesity-related genes.

The Pima Indians of Arizona have been the focus of a major study on diabetes.Pima Indians do not have a higher incidence of diabetes than other tribes,but they are a culturally cohesive group. In the early 1980's, studies were done on every child over the age of five, and the subjects were subsequently followed for 15 years. The studies showed that many teenagers and young adults have IGT. Although not a disease, IGT is a predictor of diabetes.

Genetic factors combine with environmental factors to cause diabetes; diet and exercise can control diabetes. A group of Pima Indians in Mexico are believed to be genetically the same as the Pimas in Arizona, but live in area with no refrigeration, no trucks, no roads, no electricity, and no remote controlled tv's. The Mexican Pimas have no incidences of diabetes.

The high incidence of diabetes is not confined to the Pima tribe. Southwestern native Americans, including Navajo and Pueblo, have the highest rates of diabetes in the world. Years ago, there was no diabetes on Indian reservations.Over the past five years, there has been a four-fold increase in Type II diabetes in kids. A high incidence of diabetes is seen in Hispanics because of admixture of Native American genes.

Economic Impact of Type II Diabetes
Diabetics use medical resources at a higher rate than average nationwide. Diagnosed diabetics constitute about six percent of the total population (although, in New Mexico, that figure is much higher), but diabetes costs account for about 13-14% of all health care expenditures. Diabetes treatment costs about $113 billion a year - more than three and a half times as much as the care for non-diabetic patients.

Most Americans are alarmed at the rising cost of medicine, and one solution being discussed is a managed care system. Money will be distributed to the individual states by multiplying the population of each state times the average per person cost of health care across the United States. The potential problem with such a system is that states with very high rates of diabetes, such as New Mexico, have health care costs much higher than average. Native Americans and Hispanics use medical resources more intensively because of their high rate of diabetes. Should managed care become the norm, New Mexico will be in a very precarious financial situation and will have a medically under-served population.

Another important area is the genetics of the complications (since this is where the problems lie). It is very clear that there's a genetic susceptibility to developing complications; a Caucasian with a blood sugarcount of 200 will have about 20% chance of developing diabetes after 20 years;a Native American with a 200 count will have an 80% chance. It's clear that these percentages are not influenced by environment as much as by genetics.

Anthropologist Robert Ferrell hypothesized that Type II diabetes is a New World syndrome. He has postulated the concept of a "Thrifty Genotype"; since native Americans went through cycles of feast and famine, they needed a gene that conserves blood sugar (perhaps so that mothers could conserve bloodsugar for their babies), and this genotype was selected as a survival mechanism(Yearbook of Physical Anthropology 27:153-178 (1984)).

What are the factors that will predict the incidence of diabetes in a cohort of children? Family history, obesity, and high plasma insulin are the main indicators; insulin resistance is a predictor of type II diabetes, even if a child feels fine at the time he or she is tested. Also, when a child is exposed to high sugars in utero (when the mother has gestational diabetes) the child has an eight-fold greater risk of getting diabetes as a teenager.