Diabetes Health Article

Diabetes insipidus

Diabetes insipidus is caused when the pituitary gland does not produce enough antidiuretic hormone (ADH), which is responsible for water reabsorption in the kidney. Without sufficient ADH, an abnormal amount of water is secreted in the urine. This results in excessive urination, thirst, weakness, and dry skin. In many cases, the cause of diabetes insipidus is unknown but may involve damage to the pituitary gland by head trauma or a tumor. In some cases, it is treatable with ADH replacement therapy.

Diabetes bronze

Diabetes bronze is a rare disease of iron metabolism that occurs in conjunction with diabetes mellitus and cardiac failure. It usually develops after 40 years. Diabetes bronze is characterized by the usual symptoms of diabetes mellitus with the addition of an enlarged liver and hyperpigmentation of the skin to a bronze color. It occurs 10 times as frequently in males than in females.

Genetic profile

Type I and type II diabetes mellitus have different causes, yet both have genetic components. A combination of inheriting a predisposition to diabetes and environmental trigger factors may make the biggest contribution to the development of the disease. A genetic predisposition contributes to, but does not automatically result, in diabetes. Studies of identical twins show that when one twin has type I diabetes mellitus, the other develops the disease about 50% of the time. When one twin has type II diabetes, the other develops the disease about 75% of the time.

Type I diabetes is an autoimmune disorder in which the immune system attacks the insulin-secreting pancreatic beta cells. The onset of type I diabetes is attributed to both inherited risk and external triggers, such as improper diet or an infection. Approximately 18 regions of the genome have been linked with risk for diabetes type I. These regions may each contain several genes that have abnormal variations in some diabetics. They are labeled IDDM1 to IDDM18.

The region, or locus, most well studied is IDDM1. IDDM1 contains genes that encode immune response proteins called the HLA genes. Variations in HLA genes are one of multiple important genetic risk factors. Normal HLA genes encode for proteins called major histocompatibility complex (MHC), which assemble on the cell surface, are viewed by the immune system as "self," and therefore are not attacked. When there are variations in the HLA genes, they encode for variable MHC proteins expressed on the cell surface. The pancreatic beta cells of some diabetics have variable MHC proteins that the immune system does not recognize as self, and attacks as it would a virus or bacteria. The IDDM1 gene locus contains these variations in HLA genes that cause the pancreatic beta cells to be attacked and destroyed by the immune system.

The inheritance of particular HLA gene variations can account for more than 50% of the genetic risk of developing type I diabetes. The genes most strongly linked with diabetes are called HLA-DR, HLA-DQ, and HLA-DP. Half of the general population inherits a copy, called an allele, of the HLA-DR gene called DR3 or DR4. Less than 3% of the general population has both alleles. However, 95% of Caucasians with type I diabetes possesses at least one allele of DR3 or DR4. Individuals with both alleles are at the highest risk of developing type I diabetes mellitus. Conversely, the HLA-DR2 allele has protective effect and lowers the risk of developing diabetes.

As seen with the DR gene, specific alleles of the DQ gene are risk factors for developing type I diabetes, and specific alleles are protective. There is a tendency for individuals who inherit DR3 or DR4 to inherit a variant of DQ that increases their genetic risk of developing type I diabetes. The protective DR and DQ alleles also tend to be inherited together. These combination tendencies are not absolute, a phenomenon known as linkage disequilibrium. The IDDM1 locus contains many diabetes susceptibility genes that exhibit linkage disequilibrium, making it difficult to research the effects of any one gene on diabetes susceptibility.

The IDDM2 locus contains the insulin gene (INS) that is located on chromosome 11. Mutations of INS cause a rare form of diabetes that is similar to MODY. Other variations of the insulin gene may contribute to susceptibility to type I and II diabetes. The IDDM2 locus contributes about 10% toward type I diabetes susceptibility incidence. The type I diabetes risk associated area of this locus is localized to a region flanking the insulin gene that contains a short sequence of DNA that is repeated many times. The repeated sequences follow one behind the other (in tandem) and the number of repeats is variable between individuals, an event called a variable number tandem repeat (VNTR). There are three classes of VNTR in the insulin gene.

Class I has alleles that range 26–63 repeat units, class II has alleles with approximately 80 repeat units, and class III has alleles ranging 141–209 repeat units. In Caucasians, who have the highest rate of type I diabetes, the class-I VNTRs are most common. Class I alleles are responsible for 70% of the VNTR alleles, with nearly all the other alleles being class III. The short class I alleles are associated with a higher risk of developing type I diabetes, whereas the longer class III alleles are protective. The presence of at least one class III allele is associated with a threefold reduction in the risk of type I diabetes. Class III VNTR alleles are associated with higher levels of insulin in the thymus. The thymus gland has an important role in training the immune system to not attack the body's own cells. Immature immune cells called T cells are presented with chains of amino acids, such as insulin, to recognize as self. Any T cells that form a response to them, to attack them, are deleted to prevent autoimmunity. Because the longer VNTRs cause more insulin to be produced in the thymus, the detection and deletion of autoreactive T cells that would attack the body's cells may be more efficient. The resulting improved immune tolerance to insulin would lessen the risk of a future onset of type I diabetes caused by anti-insulin immune responses.

There is conflicting evidence for the role of INS in predisposition to type II diabetes. Certain mutations in INS can result in mutant insulin that results in rare forms of diabetes. One type of mutant insulin, called Chicago insulin, has been found in individuals who have a rare form of diabetes that resembles MODY. This form of diabetes is caused by a single gene mutation and is inherited in an autosomal dominant fashion. The INSR gene encodes the receptor for insulin. Mutations of the insulin receptor can also cause rare forms of diabetes and may play a role in susceptibility to type II diabetes. However, most diabetics have a normal sequence of the insulin receptor, indicating that if insulin receptor mutations contribute to the development of type II diabetes, they will be present only in a minor fraction of the diabetic population.

In determining the risk of developing type II diabetes mellitus, environmental factors such as diet and exercise play an important role. The majority of individuals with type II diabetes are either overweight or obese. Inherited factors are also keys to the development of type II diabetes. However, as of 2004 the multiple genes involved remained poorly defined. Genes that have been implicated may have only subtle variations that are extremely common, known as single nucleotide polymorphisms (SNPs). It is very difficult to link common gene variations with an increased risk of developing diabetes. Many of the links that have been found seem to be important in only select ethnic or geographical populations.

Calpain 10 (CAPN10) is one such gene that maps to chromosome 2. CAPN10 is a calcium-activated enzyme that breaks down proteins. SNPs in part of the CAPN10 gene are associated with a threefold increased risk of type II diabetes in Mexican Americans. It is thought that these genetic variants of CAPN10 may alter pancreatic beta cell survival, insulin production, insulin action, and liver glucose production. CAPN10 may also be involved in development of type II diabetes in Chinese populations. However, in European, Japanese, and Samoan populations, CAPN10 does not appear to play an important role.

The HFN4A gene encodes a transcription factor that is found in the liver and pancreas. HNF4A maps to a region of chromosome 20 that is linked with type II diabetes. HNF4A mutations cause a rare form of autosomal dominant diabetes. The HNF4A gene is now also being researched for involvement in predisposition to type II diabetes. It is thought that pancreatic beta cells are responsive to the amount of HNF4A present to regulate insulin production. SNPs in HNF4A have an impact on pancreatic beta cell function, increasing or decreasing insulin secretion. In the British population, individuals with SNPs that cause increased insulin secretion capacity have a reduced risk for diabetes. In the Ashkenazi Jewish population and Finnish population, four SNPs near the HNF4A gene have been identified as associated with type II diabetes via an unknown mechanism that may cause pancreatic beta cell malfunction.

In 2004, research began on various other genes that are candidates for type II diabetes predisposition in specific populations, many of which reside on various IDDM loci. The ABCC8 gene encodes the receptor for sulfonylurea. Sulfonylureas are a class of drug used to lower blood glucose levels in type II diabetics by inter-acting with the sulfonylurea receptor of pancreatic beta cells and stimulating insulin release. Genetic variations of ABCC8 may impair the release of insulin in some diabetics. The GCGR gene encodes the hormone glucagon, which regulates glucose levels. A mutation in GCGR has been associated with type II diabetes in the French and Sardinian population. The GCK gene encodes for the enzyme glucokinase, which speeds up glucose metabolism and acts as a glucose detector in pancreatic beta cells. Mutant glucokinase causes a rare form of diabetes and may also play a role in type II diabetes in some populations. Mutations known to activate glucokinase are all clustered in one area of the glucokinase structure that is called the allosteric activator site. These mutations cause an increase in insulin release. Research is being performed to discover pharmacological agents that act as allosteric activators to increase glucokinase activity, increase the release of insulin, and can be used in the treatment of diabetes. Because glucokinase activators also stimulate liver glucose metabolism, they would be doubly effective in reducing the blood sugar of diabetics. The GLUT2 gene encodes a glucose transporter which controls the entry of glucose into pancreatic beta cells and detects blood glucose. Mutations of GLUT2 cause a rare genetic syndrome that disturbs blood glucose control. Common variants of GLUT2 may also be linked with type II diabetes. The KCNJ11 gene encodes a potassium ion channel on the surface of pancreatic beta cells. Closure of potassium channels in these cells triggers insulin release. Pharmacological agents that close the channels are used in the treatment of diabetes.

Variations in KCNJ11 have been linked to both increased and decreased insulin release. A controlled study done in non-diabetic adults with a SNP in KCNJ11 demonstrated that the variation was associated with impaired insulin release in response to glucose and increased body mass index (BMI). Lipoprotein lipase (LPL) is an enzyme that breaks down triglycerides. LPL is functionally impaired or present at low levels in many type II diabetics. Evidence suggests that insulin may help regulate LPL synthesis. A common complication of type II diabetes is protein excreted in the urine because of chronic inflammation and kidney damage. There is a correlation between the severity of this condition and genetic variation in LPL. SNPs in the LPL gene are associated with insulin resistance in Mexican Americans. The same variation is associated with coronary artery disease, and may provide some of the link between diabetes and atherosclerosis.

An important diabetes risk factor and drug target is peroxisome proliferator activated receptor gamma (PPARc). This protein is a transcription factor that regulates fat cell development. Diabetics are prescribed drugs that activate PPARc to increase insulin sensitivity and lower blood sugar. Variations in PPARc influence the risk of developing obesity and type II diabetes. A common variation at position 12 confers a small risk of developing obesity of about 1.3% increase. For the individual, this 1.3% is a small increase of risk, but 75% of the population has this variation, which translates into a large impact on the prevalence of diabetes. The Pima Indians of Arizona, a population known for type II diabetes incidence, contain several SNPs in the gene for PPARc. There are other SNPs in the gene for PPARc that confer a degree of protection against insulin resistance and obesity. Mutations in some of these genes may also lead to a rare form of diabetes known as MODY (maturity-onset diabetes of the young). MODY is inherited in an autosomal dominant fashion. It is similar to non-insulin dependent diabetes, but develops in individuals before the age of 25.

Environmental triggers for type I diabetes are varied. Type I diabetes develops more often in cold climates than warm climates. Type I diabetes is less common in individuals who were breastfed and those whose first solid foods were at later ages. A family history of type II diabetes is only a strong risk factor for individuals living a western lifestyle of high fat diets with little exercise. Individuals who live in areas that do not have westernized lifestyles tend not to develop type II diabetes no matter how high their genetic risk. Obesity is a strong risk factor for type II diabetes; the highest environmental risk is correlated with obesity at early age or for extended periods of time. Women who develop gestational diabetes are likely to have a maternal family history of type II diabetes. The environmental factors that predispose to gestational diabetes are older age and higher weight. The ethnic group in the United States with the highest risk for type I diabetes is Caucasian. The ethnic groups in the United States with the highest risk for type II diabetes are African Americans, Mexican Americans, and Pima Indians.