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.