Diabetes

Type 1 Diabetes

Type 1 diabetes is caused by beta cell destruction, leading to insulin deficiency. T1DM was previously called insulin-dependent diabetes mellitus (IDDM), because patients who have it require insulin for survival. It was also called juvenile-onset diabetes mellitus, because most type 1 diabetics are children or young adults. At the time of diagnosis, about 85 percent to 90 percent of people with type 1 diabetes have antibodies directed against components of their beta cells, indicating that the immune system is responsible for the progressive and irreversible beta cell destruction.

Current evidence indicates a genetic component to T1DM. HLA (histocompatibility leukocyte antigen) genes are a group of genes on chromosome 6 that encode proteins that are part of the immune system. Normally the immune system defends the body against disease by destroying foreign cells, but in the case of type 1 diabetes, the body's immune system destroys its own beta cells.

Certain types of HLA genes are strongly associated with type 1 diabetes, and other types protect against its development. However, these HLA genes are neither necessary nor sufficient to cause or protect from type 1 diabetes. T1DM is therefore a "complex" genetic disorder, in which several genes interact with the environment to result in the disease. Scientists are currently working to identify these other genes, as well as environmental factors (e.g., toxins and viruses) that provoke the development of T1DM.

Type 2 Diabetes

Type 2 diabetes is itself a group of disorders caused by some combination of insulin resistance—which occurs when cells' ability to respond to insulin is compromised—and insulin deficiency, which occurs when the beta cells' ability to make insulin is compromised. T2DM has, in the past, been called adult-onset diabetes, because most people with T2DM were adults. It was also called non-insulin-dependent diabetes mellitus (NIDDM), because people with type 2 diabetes usually do not require insulin injections. In the Unites States, T2DM is especially prevalent among certain ethnic minorities, including African Americans, Mexican Americans, Asian Americans, and Native Americans.

Obesity is a potent risk factor for T2DM. In the last thirty years, due to increased caloric intake and physical inactivity, both of which contribute to obesity, there was an explosion in the prevalence of T2DM, and it started occurring at younger ages—even in children. In addition to its association with an unhealthy lifestyle, T2DM is known to have a strong genetic component.

Scientists have been searching throughout the genome for T2DM-susceptibility genes. One such gene, calpain 10 protease, was identified on chromosome 2. A common variant of this gene may predispose certain individuals to T2DM; however, the true significance of this gene variant remains to be determined. In addition, several candidate genes have shown some evidence of being involved in T2DM. However, the effect of any single candidate gene variant on the risk of developing T2DM is modest. A candidate gene is a gene for which prior knowledge of its function leads researchers to assess whether chemical variation in it is associated with a disease.

As of 2002 there was no clinically available genetic test to predict the onset of type 2 diabetes, but it is anticipated that with a better understanding of the roles of various genes in T2DM, it will eventually be possible to use multiple genetic tests to identify individuals at risk for T2DM and to predict which treatments will be most helpful in specific patients. Although genetic susceptibility plays an important role in determining the risk of developing T2DM, studies have shown that the disease can often be prevented through diet, physical activity, and weight loss.

Other Specific Types of Diabetes

The third category of diabetes, containing other specific types, includes nongenetic forms as well as single-gene forms of diabetes. One group of single-gene diabetes disorders are genetic defects in beta cell function. The most common of the genetic beta cell defects are the disorders known as MODY, or maturity onset diabetes of the young. MODY constitutes no more than 2 percent to 5 percent of all cases of diabetes. It often occurs in children and young adults and is characterized by decreased but not absent insulin production. It is inherited in an autosomal dominant manner, which means that an affected person has a 50 percent chance of passing on the disease-version of the gene with each pregnancy. Most, but not all, people receiving a MODY gene do develop diabetes.

There are at least six different genetic forms of MODY. MODY2 is caused by a mutation in a gene on chromosome 7 that makes a protein called glucokinase, which is an enzyme in beta cells that helps to provide a chemical signal needed for insulin release. The other MODYs involve mutations in genes that encode proteins called transcription factors, which allow beta cells to develop and function properly. These are hepatocyte nuclear factor 4-alpha (HNF4-alpha, causing MODY1, on chromosome 20), HNF1-alpha (causing MODY3, on chromosome 12), insulin promoter factor 1 (IPF1, causing MODY4, on chromosome 13), HNF1-beta (causing MODY5, on chromosome 17) and NeuroD1/beta2 (causing MODY6, on chromosome 2).

A very rare genetic insulin secretion disorder is maternally inherited diabetes and deafness (MIDD), caused by changes in the DNA of the mitochondria. The mitochondria are the energy powerhouses of the cell and the only part of the cell to contain DNA other than the nucleus, where most DNA is contained. MIDD and other mitochondrial disorders are maternally inherited because the fertilized egg has only mitochondria derived from the mother. The clinical features of MIDD can be similar to type 2 diabetes, and the hearing loss can be mild or even undetectable, except by special tests.

Another group of rare genetic diabetes types is characterized by extreme insulin resistance, which is defined as occurring when the ability of the body's cells to respond to insulin is severely compromised. Disorders of extreme insulin resistance include type A syndrome, leprechaunism, and Rabson-Mendenhall syndrome, and they are caused by inherited defects in the gene on chromosome 19 that makes the insulin receptor, a protein that allows cells to respond to insulin. Without properly functioning insulin receptors, insulin cannot work effectively. In addition to diabetes, individuals with insulin receptor defects may also have dental, genital, skin, and growth abnormalities. Most insulin receptor gene defects manifest in an autosomal recessive manner. That is, two defective copies of the gene are required for disease expression, and couples in which each partner has one defective copy (and in which neither is therefore affected) have a 25 percent chance of having an affected child, with each pregnancy.

Familial partial lipodystrophic diabetes (FPLD) is a rare condition in which children develop an unusual fat distribution at puberty, with little or no fat on their arms, legs, and trunk. They also develop insulin-resistant diabetes. FPLD is an autosomal dominant condition caused by mutations in the lamin A/C gene on chromosome 1. Another rare form of lipodystrophic diabetes is congenital (i.e., present at birth) generalized lipodystrophic (CGL) diabetes, which is autosomal recessive, and in about half of cases is due to mutations in the gamma-3-like gene (GNG3; also called the seipin gene), on chromosome 11.

Wolfram syndrome is a rare autosomal recessive condition presenting in childhood that includes diabetes mellitus as well as other problems, including deafness and deficiency of antidiuretic hormone. Mutations in the wolframin gene on chromosome 4 are responsible for some cases, but other cases appear to be caused by a gene in a different area of chromosome 4.

Another rare autosomal recessive childhood condition, thiamine-responsive megaloblastic anemia syndrome (TRMA), consists of several features, including blood abnormalities, deafness, and diabetes. TRMA, which responds to treatment with thiamine (a form of vitamin B), is a disorder caused by mutations in the thiamine transporter gene SLC19A2, on chromosome 1.

Transient neonatal diabetes (TNDM) is a condition in which infants are born requiring injected insulin but are able to make sufficient insulin later in infancy. Later in childhood or in adulthood, they may again develop diabetes, which may or may not require insulin treatment. Most cases of transient neonatal diabetes appear to be caused by the inheritance of an extra copy of a region of chromosome 6 from the father.

Many known genetic disorders other than those mentioned previously are associated with an increased risk of diabetes. Among those most strongly associated are Friedreich's ataxia, cystic fibrosis, and hemochromatosis.

Gestational Diabetes Mellitus

Hormones associated with pregnancy may cause diabetes in susceptible individuals. Although the diabetes goes away after the pregnancy, individuals who have had GDM are at increased risk of developing T2DM. Currently very little is known about the genetic basis of GDM. It is possible that some of the same genes responsible for T2DM are also involved in GDM.

Genetic Susceptibility to Complications

As mentioned above, diabetes is associated with complications involving the eyes, kidneys, blood vessels, and heart. However, not all individuals with diabetes develop these complications. There is increasing evidence that there are genes other than those that increase susceptibility to developing the disease that may influence susceptibility to developing its complications. These genes are not yet identified, but they are likely to interact with other known risk factors for complications, including poor blood-sugar control and increased blood-pressure and blood-cholesterol levels.

SEE ALSO COMPLEX TRAITS; DISEASE, GENETICS OF; GENE AND ENVIRONMENT; GENE DISCOVERY; IMMUNE SYSTEM GENETICS; MITOCHONDRIAL DISEASES.

Toni I. Pollin

and Alan R. Shuldiner

Bibliography

Internet Resources

American Diabetes Association. <http://www.diabetes.org>.

Joslin Diabetes Center. <http://www.joslin.org>.

Juvenile Diabetes Research Foundation International. <http://www.jdrf.org>.

National Institute of Diabetes and Digestive and Kidney Diseases. <http://www.niddk.nih.gov>.

Online Mendelian Inheritance in Man. Johns Hopkins University, and National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Omim>.