Diabetes

Definition

Diabetes mellitus describes a group of diseases in which there is an elevated level of the sugar glucose, the body's main source of energy for cellular functions, in the blood. The level of glucose, as well as other "fuel" molecules, is increased due to a disorder in the production or function of the hormone insulin. A range of health problems occurs primarily due to the damaging effects of elevated levels of glucose on blood vessels.

Description

To understand diabetes, it is important to understand how the hormone insulin functions in the breakdown and utilization of glucose. Insulin acts in two ways. It is necessary for the transport of glucose and other fuel molecules into the cells. It also regulates several pathways in metabolism that are important in the utilization of these fuel molecules. Insulin is made and released by specialized cells of the organ known as the pancreas. These beta cells of the pancreas release insulin when blood levels of glucose, amino acids, fatty acids, and ketones are high. These are all breakdown products of food, and an increase in their level in the blood signals that a person has recently eaten. The insulin acts to mobilize each of these fuel molecules so they can be used as energy to support cellular functions needed to maintain the body.

There are two main types of diabetes mellitus: type I and type II diabetes. While there are similarities, type I and type II diabetes differ in several aspects related to cause, symptoms, treatment, and associated risk factors. In addition, there are other less common forms of diabetes.

Type I diabetes

Also called insulin-dependent diabetes mellitus (IDDM), this is the most severe form of diabetes, in which shots of insulin are necessary on a daily basis. IDDM is thought to be an autoimmune condition in which one's own immune system attacks and destroys the insulin-producing cells of the pancreas. Insulin production is low or absent, and onset is generally in childhood or early adulthood. Affected individuals tend to be thin and prone to events in which ketones can become so high in the blood as to be potentially life-threatening, a complication called ketosis.

Type II diabetes

The most common type of diabetes, non-insulin dependent diabetes mellitus (NIDDM or type II), is the milder form of diabetes. Symptoms can generally be controlled with diet or oral medications that decrease blood sugar levels. True NIDDM does not develop into the insulin-dependent type of diabetes. In NIDDM, blood sugar levels become elevated because of resistance to the effects of insulin, which is usually present at normal levels. In other words, there may be plenty of insulin available, but the cells are not sensitive to insulin's effects. This results in the inability of insulin to move glucose to the inside of cells where it can be used. NIDDM typically develops after age 40, although it can occur at any age. Affected individuals tend to be obese and are not prone to ketosis.

Impaired glucose tolerance (IGT)

Impaired glucose tolerance is a symptom characterized by lab test results that indicate elevated blood glucose levels. The results are not abnormal enough to be called "diabetes." However, IGT may be an early sign of NIDDM, and is certainly a risk factor for developing NIDDM.

MODY

Clinical severity is determined in part by the specific gene associated with disease within a family. MODY3 mutations result in the most severe clinical presentation, with 97% of cases having NIDDM, as opposed to impaired glucose tolerance. Individuals with MODY1 commonly experience vascular complications and require insulin in one-third of cases. Glucokinase (GCK) gene mutations, although the most common cause of MODY, tend to result in the mildest clinical picture. Approximately 46% have NIDDM, and the remaining individuals have IGT. Individuals with GCK-related MODY rarely need insulin and usually don't experience vascular complications.

Gestational diabetes

Also called diabetes of pregnancy, this form of the disease is often limited to the time during which a woman is pregnant. Management of glucose levels in affected women during pregnancy is very important, because high glucose levels can have serious, negative effects on the developing fetus. Gestational diabetes usually disappears after delivery. However, history of gestational diabetes increases a woman's risk of developing NIDDM in the future and of having gestational diabetes again in future pregnancies. Risk factors for gestational diabetes are similar to those for NIDDM.

Genetic profile

Like many common diseases, diabetes is caused by a combination of multiple environmental and genetic risk factors. The exact set of environmental and genetic factors that causes diabetes in any one individual is usually not known.

There are several known or suspected environmental factors that increase risk of developing diabetes and/or worsening complications. Environmental risk factors for developing IDDM are less well understood than for other types of diabetes. Infection by certain viruses has been implicated as a triggering event that can lead to the autoimmune reaction that causes disease in individuals with genetic susceptibility. Risk factors that are entirely or partially environmental have been implicated in NIDDM. These include obesity, low physical activity, poor dietary habits (high fat, salt, sugar intake), and alcohol and tobacco use. Cardiovascular risk factors—increased cholesterol and blood pressure, as well as others—also increase the chance for NIDDM to develop. Impaired glucose tolerance is a risk factor and can sometimes progress to NIDDM. For women, past history of gestational diabetes or delivery of a baby who was large-for-gestational-age also increases the chance of developing NIDDM. Ethnic background has a role in disease susceptibility for all types of diabetes, due to both genetic and environmental factors that may in part be affected by cultural practices.

Multiple genetic factors, both between individuals and often within a single affected individual, increase susceptibility to IDDM and NIDDM. Genetic factors are thought to be most important in individuals with a family history of the disease.

Heritability is the term that describes the genetic component causing a disease. It is a measure of the extent to which disease expression is the result of underlying genetic factors. One indication of the relative contribution of heritability in the causation of a particular disease is concordance.

Concordance describes the rate of similarity in disease expression between identical twins that share the same genetic material. As a general rule, the higher the concordance between identical twins, the greater the contribution of genetic factors to disease development. For example, the concordance for all types of diabetes ranges from 45-96%, indicating this percentage of diabetes can be attributed to genetic factors, with the remaining due to environmental factors. The specific genetic factors involved and their relative contributions toward diabetes development vary depending on the type of diabetes.

IDDM

Type I diabetes occurs when one's own immune system attacks and destroys the body's insulin-producing cells. There is a general population risk of 1/500 for developing IDDM. This risk increases when there is a family history or the presence of known genetic risk factors. The concordance for IDDM is generally thought to be less than 50%, suggesting that environmental factors must be present to trigger the development of the disease in individuals with genetic susceptibility. Even given this relatively low concordance, several genetic factors have been identified as established or suspected causes of IDDM susceptibility.

HLA ASSOCIATIONS HLA stands for human leukocyte antigens (also called major histocompatibility complex). HLA describes a group of proteins—genetically-determined and unique in each individual—that are important in helping the immune system distinguish 'self' from 'non-self' (foreign). Given their role in immunity, it seems intuitive that HLA types would be involved in susceptibility to this autoimmune form of diabetes. However, it is not yet clear if it is the HLA types themselves, or another closely linked gene, that increases risk.

There are several genes in the HLA gene family. Specific HLA-associations—consisting of variations of the HLA-DR gene—are thought to account for 60-70% of genetic susceptibility in IDDM. There is a significant understanding about the role of the HLA types, DR3 and DR4, in IDDM susceptibility.

HLA-DR alleles DR3 and DR4 are common in the general population. Almost half of all people in the United States have one or the other, which leads to a risk of 1/300 to 1/400 for developing IDDM. Two copies of DR3 or two copies of DR4—occuring in a very small percentage of the population—gives a risk of 1/150. Individuals having one copy each of DR3 and DR4 (1-3% of the population) is a combination that results in a 1/40 risk for developing IDDM. While less than 1% of individuals with these HLA types will develop diabetes, DR3 and/or DR4 are present in about 95% of all individuals with IDDM. While these HLA types confer susceptibility

to IDDM, other genetic or environmental factors must also be present in order for an individual to develop diabetes.

OTHER GENES ASSOCIATED WITH IDDM SUSCEPTIBILITY A genetic variation near the regulatory region of the insulin gene on chromosome 11 is widely accepted as a factor that confers IDDM susceptibility. This variation—called the 5' VNTR (variable number tandem repeat)—may contribute to susceptibility by influencing the regulation of the insulin gene, or by some other mechanism.

Several other genes or chromosomal locations have been identified and are being investigated as candidates that may contribute to genetic susceptibility for IDDM.

• Insulin receptor gene on chromosome 19
• Beta chain of the T-cell receptor on chromosome 7
• Immunoglobulin heavy chain (Gm) on chromosome 14
• Kidd blood group on chromosome 8
• IDDM3: chromosome 15 region
• IDDM4: chromosome 11 region near the fibroblast growth factor 3 gene
• IDDM5: chromosome 6 region
• IDDM7: chromosome 2 region near the HOXD8 gene
• IDDM8: chromosome 6 region
• Others: regions on chromosomes 3, 4, 13, and 18

It is thought that disease susceptibility is the result of these and other genetic factors acting independently and/or interacting with one another. There is still much to be learned about the identities, functions, and role in disease susceptibility for each of these implicated genes and chromosome regions.

SYNDROMES WITH IDDM AS A FEATURE In addition to susceptibility genes, there are several distinct syndromes that have IDDM as a potential feature. Additional characteristic features, aside from IDDM, mark these syndromes. The genetic basis for many of these conditions is known or suspected. These include syndromes with pancreatic disease (i.e. congenital absence of the pancreas and cystic fibrosis). There are multiple syndromes characterized by glucose intolerance due to or associated with a variety of other conditions including obesity, disease of the endocrine system, or diseases of metabolism. IDDM may also be seen in syndromes caused by mutations of the DNA of mitochondria—the cellular organelles that create energy. Mitochondrial DNA is only transmitted from the mother to each of her children, so such syndromes show a characteristic pattern of inheritance. IDDM (and NIDDM) tend to appear in conjunction with other features that are characteristic of these mitochondrial syndromes in affected families. MELAS syndrome—which is characterized by stroke-like episodes, muscle disease, and other symptoms—is one such example. It is caused by a mutation in the mitochondrial gene called tRNA Leu. Mutations in this gene can also result in a diabetes and deafness syndrome. A similar syndrome can also be caused by a large deletion of the mitochondrial DNA, called the 10.4kb deletion.

NIDDM

The genetic or heritability component of non-insulin dependent diabetes is thought to be greater than in IDDM. Studies estimate a concordance of up to 100%, with most studies estimating greater than 70%. Most experts interpret this relatively high concordance to reflect a somewhat high heritability. High concordance may also partly reflect the fact that the environment of all those studied—for example, in the United States—is highly uniform. Therefore, all those who have genetic susceptibility can be considered to be exposed to a sufficient number environmental risk factors to trigger NIDDM.

GENES ASSOCIATED WITH NIDDM SUSCEPTIBILITY Genetic susceptibility in NIDDM is highly heterogeneous—meaning that variations in many different genes contribute to disease susceptibility. Although multiple susceptibility genes have been established or are suspected, major genes that confer a clearly high susceptibility do not play a major role—such as that seen with DR3 and DR4 in IDDM. NIDDM-associated genes include, but are not limited to, those found in the table.

NIDDM due to insulin gene mutations

In some families, NIDDM appears to be inherited in an autosomal dominant fashion. Late onset of the disease may occur together with characteristic lab values. Some such families have been shown to carry specific mutations in the insulin gene. Three mutations are known and produce altered forms of the insulin protein that apparently do not function as well as the usual type of insulin. These include Insulin Los Angeles, Insulin Wakayama, and Insulin Chicago. Although only present in about 0.5% of people with NIDDM, these mutations can lead to a dominant form of the disease. Other alterations in the insulin gene—including other point mutations and a variation outside the gene called the 5' VNTR—may also contribute to NIDDM development or susceptibility in some populations.

Syndromes with NIDDM as a feature

As seen in IDDM, there are several distinct syndromes that have NIDDM as a potential feature. Aside from NIDDM, other characteristic features are present in each of these syndromes. The genetic basis for many of these conditions is known or suspected. These include syndromes with pancreatic disease (i.e. hemochromatosis and thalassemia) and syndromes due to mutations of the DNA of mitochondria—the cellular organelles that create energy. The latter includes MELAS syndrome, as well as a large deletion of mitochondrial DNA associated with diabetes and deafness. There are multiple syndromes with glucose intolerance resulting from or in association with a variety of other conditions. These include obesity, chromosomal imbalances, diseases of the endocrine system, or diseases of metabolism. As might be expected, mutations in the insulin receptor gene account for an increased risk for NIDDM. About 0.1% to 1% of the population carries such mutations, which leads to insulin resistance in some instances. Individuals who inherit two mutated copies of the insulin receptor gene may have extreme insulin resistance or diabetes. Some such individuals may have one of two rare syndromes. Donohue syndrome usually leads to death in the newborn period due to many serious complications resulting from very extreme insulin resistance. Rabson-Mendenhall syndrome is another very rare syndrome that affects multiple body systems and has been associated with the insulin receptor gene. Finally, mutations in this gene can lead to an inherited form of diabetes with acanthosis nigricans, a highly pigmented skin condition.

Demographics

Worldwide, diabetes mellitus represents a large proportion of the common, chronic diseases caused by multiple factors. Between 5% and 10% of adults in the Western world are affected by some form of diabetes. About 1/10,000 people have IDDM. The incidence of NIDDM is about three-fold that of IDDM—up to 5% of the U.S. population age 20-74. Up to an additional 11% have impaired glucose tolerance (IGT), which can represent an early stage of NIDDM.

Incidence rates of all types of diabetes vary among ethnic groups—a result of differing genetic and environmental backgrounds. For IDDM, incidence rates range from less than 1/100,000 among Japanese to greater than 25/100,000 among Scandinavians. Ethnic variation follows a different pattern for diabetes overall, which consists primarily of those with NIDDM and IGT. While NIDDM rates are very low among the Eskimo, IGT is very common.

Population studies suggest that there may be one or more major genes that influence diabetes susceptibility, particularly NIDDM susceptibility, in certain populations with high to very high incidence rates of clinical diabetes. These include Mexican Americans, Pima Indians, Oklahoma Seminoles, and several populations in the South Pacific including the Nauruans.

In other populations, increased incidences of NIDDM suggest the role of environmental factors in the disease's development. Changes in diet and lifestyle are implicated as contributing factors in the increased incidence seen by members of ethnic groups who have experienced Westernization due to immigration patterns or other cultural changes. Such factors may play a role in the increased incidence of NIDDM seen in African Americans, Japanese Americans, certain Native American groups, South Pacific Nauruans, and recently Westernized aboriginal Australians. Differences in incidence rates among various populations is a reflection of the multiple underlying genetic and environmental factors that contribute to the development of all types of diabetes mellitus.

Signs and symptoms

The onset of IDDM is marked by the sudden, dramatic appearance of one or more of the following symptoms:

• Frequent urination
• Extreme thirst and/or hunger
• Rapid weight loss
• Irritability
• Weakness and exhaustion
• Nausea and vomiting

NIDDM usually develops much more gradually. Symptoms can be subtle and include any of the above symptoms, in addition to the following:

• Itching
• Blurry vision
• Obesity
• Tingling or numbness in feet
• Slow healing of the skin or gums
• Recurrent bladder infections

Diabetes can affect many of the body's organs and systems. Individuals with IDDM are prone to a potentially life-threatening complication called ketosis, in which elevated tissue and fluid levels of ketones may lead to toxic results. People with diabetes are also prone to infections. Infections of the kidney can lead to kidney disease and failure. A specific type of infection by an organism called Mucormycosis tends to occur following ketosis events in individuals with IDDM. This infection usually begins in the nasal passages and can become quite serious if it spreads to the soft tissues and bones of the face, the eye, the skull, or the brain. Gangrene can occur in individuals with poorly controlled disease and has the potential to result in limb amputation. There is an increased risk for cataracts, as well as glaucoma. Left untreated, such complications can lead to blindness. Vascular disease is common in both IDDM and NIDDM. Atherosclerosis—hardening of the arteries—can occur early and advance quickly, increasing the risk for stroke, kidney disease, and heart disease. Heart attack is the most common cause of death in diabetes. Disease of the peripheral blood vessels occurs commonly, particularly when kidney disease is also present. This can lead to increased bruising and development of ulcers, particularly in the leg.

Diagnosis

Diagnosis of diabetes can be based on the presence of suggestive symptoms, together with lab results that support the specific diagnosis.

IDDM is a distinct disease that, in most all cases, is easy to diagnose based on clinical symptoms and lab values. The identification of certain autoantibodies (immune system proteins directed against 'self' tissues) is particularly helpful in diagnosing IDDM. The onset of IDDM is almost always rapid and dramatic. Rarely, onset can be gradual and result in a diagnostic dilemma in which it is difficult to distinguish from NIDDM, particularly in an individual who is age 35-50 and not obese. Testing for autoantibodies in such individuals can help distinguish the two diseases. Although not typically done, testing for the presence of HLA-DR3 and/or HLA-DR4 may also be informative. Individuals who have a relative with IDDM are also at increased risk of a variety of other autoimmune diseases—notably thyroid disease, autoimmune gastritis, and adrenal disease.

For individuals at increased risk of diabetes, a screening glucose tolerance test is recommended periodically and may identify diabetes before symptoms become obvious. Since gestational diabetes is such a common pregnancy complication, and the impact of unmanaged disease on the fetus is serious, all pregnant women are screened between the 24th and 28th weeks of pregnancy. For those at increased risk for NIDDM due to an affected relative, increased screening for risk factors for cardiovascular disease is also recommended.

Genetic testing

IDDM The fact that only about one-half of one percent of individuals with DR3 or DR4 develop IDDM is one indicator that HLA-typing on all individuals in the population is not a useful approach for determining IDDM risk. When there is a family history of IDDM, however, HLA-typing may have a role. When considering the risk for someone with a family history to develop IDDM, using the risk figures generated from large population studies based on family history alone (not HLA typing) is most appropriate. However, these risks could potentially be modified by HLA typing results. For example, there is a 1/14 risk for IDDM in the sibling of an affected individual. If HLA typing reveals that the sibling has inherited a completely different set of HLA types, the risk can be more accurately given as 1/100. On the other hand, if there are shared DR3/DR4 HLA types, this increases the risk to 1/5-1/4. Given HLA typing results or not, an individual with a sibling with IDDM is at sufficiently increased risk to warrant increased screening and education about early signs of the disease.

NIDDM NIDDM genetic susceptibility is highly heterogeneous. There are no single genes that alone increase susceptibility to a significantly high degree that testing should be considered. Like in IDDM, it is even more appropriate in NIDDM to discuss genetic susceptibility relative to population studies that determine risk based on family history alone (not based on genetic testing). These studies indicate that individuals with a parent, sibling, or child with NIDDM is at a 10-15% risk to develop NIDDM and a 20-30% risk for IGT, which may be an early sign of developing NIDDM. Symptoms that suggest a diagnosis of NIDDM can occur in younger individuals or those that do not fit the typical profile of someone with NIDDM in other ways (i.e. not obese). In these cases, genetic testing may play a role to help determine the true diagnosis of that individual and/or allow for a more accurate risk assessment.

MODY As discussed previously, there is a unique form of NIDDM called MODY. MODY is caused primarily by mutations in the glucokinase gene. Genetic testing for this form of diabetes is available and can be very helpful in diagnosis and risk assessment for other family members, if a glucokinase mutation is detected.

NIDDM DUE TO INSULIN GENE MUTATIONS In families with late onset of NIDDM, characteristic lab values, and a dominant pattern of inheritance, insulin gene testing is available. Other lab techniques are able to distinguish variant forms of insulin that result from known mutations. A positive genetic diagnosis of this type of NIDDM can be very helpful in risk assessment for other family members.

SYNDROMES WITH DIABETES AS A FEATURE There are also several underlying syndromes and diseases of which NIDDM, IDDM, and/or IGT are potential complications. These are generally accompanied by several other signs and symptoms. If one of these syndromes is suspected, the availability, benefits, and limitations of genetic testing can be considered. Mitochondrial DNA testing may be indicated in families that show NIDDM and/or IDDM transmitted only from mothers to children together with other features characteristic of mitochondrial syndromes. In some cases, genetic testing may be appropriate and can assist in diagnosis, medical management for other potential complications, and risk assessment for other family members.

Treatment and management

Management approaches for all types of diabetes are aimed at controlling blood glucose levels, preventing complications through lifestyle changes, and treating complications symptomatically as they arise.

The first step toward controlling blood glucose levels is monitoring the levels, which is done for all types of diabetes. This can be done daily with home glucose tests, as well as every few months through a physician using a test called the hemoglobin A1c test. When levels are abnormal, adjustments can be made in the timing and or quantity of dosages of insulin for IDDM and in oral glucose-lowering medications in NIDDM. Management of blood glucose levels is particularly important when diabetes occurs in pregnancy, to avoid the potential damaging effects on the developing fetus. Increased fetal monitoring and education is also a part of this management.

Lifestyle changes include changes in diet aimed at maintaining ideal body weight, lowering blood glucose levels, and preventing heart and blood vessel disease. Exercise also helps to maintain ideal body weight and helps the cardiovascular system remain healthy. In addition, exercise is important for helping insulin to function more efficiently in some forms of diabetes.

The acute and chronic complications of diabetes should be recognized and managed properly. Ketosis is an acute, potentially life-threatening complication that can be identified in its early stages by the presence of ketones in the urine. Home urine ketone tests are available and should be used—particularly in individuals with IDDM—when a person is sick or has a highly elevated blood glucose level prior to eating. Other medical complications—including infection, cataracts, and cardiovascular disease—are treated with conventional medicine as they arise.

Since diabetes can affect multiple body systems and has an impact on lifestyle on a daily basis, the disease is best managed by a multidisciplinary approach to care. Such an approach may involve many types of specialists, including physicians, dieticians, psychologists, high-risk obstetricians, genetic counselors, ophthalmologists, cardiologists, kidney specialists, and others.

Potential future treatments may include the long-range goal of gene therapy, particularly for IDDM. This therapy may be aimed at preventing or repairing damage to the insulin-producing pancreas, or restoring insulin production by some other means. There are several significant technical challenges that must be overcome, however, before gene therapy could become a reality.

Prognosis

As with many common chronic diseases, early diagnosis and treatment is very important to prevent diabetes-associated complications. Particularly for NIDDM, recognizing and modifying risk factors related to lifestyle plays a very important role and can often lead to the avoidance of complications or even the development of disease. With all types of diabetes, appropriate management can lead to increased quality of life and health.

BOOKS

Jorde, L.B., et al. Medical Genetics. 2nd ed. St. Louis: Moseby, 1999.

Raffel, L.J., et al. "Diabetes Mellitus." Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Ed. D.L. Rimoin, J.M. Connor, and R.E. Pyeritz, 479–504. New York: Churchill Livingston, 1997.

PERIODICALS

Efrat, S. "Prospects for gene therapy of insulin-dependent diabetes mellitus." Diabetologia 41 (1998): 1401–09.

Lynn, S., et al. "Mitochondrial diabetes: investigation and identification of a novel mutation." Diabetes 47 (1998): 1800–02.

Permutt, M.A., et al. "Genetics of type II diabetes." Recent Progress in Hormone Research. 53 (1998): 201–16.

Sankaranarayanan, K., et al. "Ionizing radiation and genetic risks. VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease, essential hypertension and diabetes." Mutation Research 436, no. 1 (1999): 21–57.

She, J.X., and M.P. Marron. "Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses." Current Opinion in Immunology 10 (1998): 682–89.

Velho, G., and P. Froguel. "Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young." European Journal of Endocrinology. 138 (1998): 233–39.

Zimmet, P.Z. "The pathogenesis and prevention of diabetes in adults: genes, autoimmunity, and demography." Diabetes Care 18, no. 7 (1995): 1050–64.

ORGANIZATIONS

American Diabetes Association. 1701 N. Beauregard St., Alexandria, VA 22311. (703) 549-1500 or (800) 342-2383. <http://www.diabetes.org>.

Diabetes Action Research and Education Foundation. 426 C St. NE, Washington, DC 20002. <http://www.daref.org>.

Juvenile Diabetes Foundation International (JDF). 120 Wall St., New York, NY 10005. (212) 785-9500 x708 or (800) 533-2873. <http://www.jdf.org>.

WEBSITES

"Ask NOAH About: Diabetes." New York Online Access to Health. <http://www.noah-health.org/english/illness/diabetes/diabetes.html>.

"Diabetes in Pregnancy." Fact sheet from March of Dimes. <http://www.modimes.org/HealthLibrary2/FactSheets/DiabetesInPregnancy.htm>.

"Diabetes Public Health Resource." Center for Disease Control <http://www.cdc.gov/diabetes/faqs.htm>.

National Diabetes Information Clearinghouse of the National Institute of Diabetes & Digestive & Kidney Diseases. <http://www.niddk.nih.gov/health/diabetes/pubs/dmover/dmover.htm>.

Jennifer Denise Bojanowski, MS, CGC