Genetics of Diabetes Mellitus (Type 2)

 

DNA Sciences Article

This article attempts to answer some of the more common questions about type 2 diabetes and its genetics. As with all conditions, consult your physician about specific issues regarding yourself or your family.

 

What is type 2 diabetes?

 

People who develop diabetes mellitus have too much sugar in their bloodstream. Normally, the hormone insulin signals the body's tissues to remove sugar from the blood. So, if the blood sugar level is abnormally high, at least one of the following two conclusions can be made: (1) not enough insulin is being made, or (2) the body's tissues are not responding properly to insulin.

 

In this article, we are going to discuss a type of diabetes mellitus resulting from both conditions. This type of diabetes is called "typical type 2 diabetes mellitus." (The "Advanced" box, below, defines the other types of diabetes.) Typical type 2 diabetes occurs in overweight adults. For reasons that are only now becoming understood, obesity makes the body's tissues less sensitive to insulin.

 

There are many classifications for the subtypes of diabetes mellitus. The following is just one example:

 

*        Type 1 -- Too little insulin is produced because of damage to the pancreas. The damage is due to the body's own immune system attacking the insulin-producing areas of the pancreas. Most, but not all, cases of type 1 diabetes occur in children. This type of diabetes can run in families. Several relevant genes have been identified.

*        Type 2 "Typical" -- This was defined above. Typical type 2 diabetes accounts for 55% to 75% of all diabetes mellitus [1]. Typical type 2 diabetes is also known, somewhat imprecisely, as "non-insulin-dependent diabetes mellitus" (NIDDM).

*        Type 2 "MODY" -- MODY is the diagnosis given to youngsters who, were they adults, would be diagnosed with typical type 2 diabetes. MODY stands for "maturity onset diabetes of youth." This type of diabetes can run in families, too. Several relevant genes have been identified.

*        Secondary -- The word "secondary" implies that diabetes is not the only feature of the disorder. For example, physical trauma to the pancreas, including alcohol toxicity, can lead to diabetes. Diabetes is also a part of some genetic syndromes, which we will mention later.

 

The word "diabetes" comes from the Greek word meaning "passing through." This refers to the large amounts of urine passed by untreated diabetics. The word "mellitus" comes from the Latin word for "honey," a reference to the sweet character of the sugar-laden urine.

 

There are other types of diabetes in addition to diabetes mellitus. Diabetes insipidus can occur after a brain injury. There is little to the urine except water. Diabetes inositus is an extremely rare condition in which the chemical inositol is passed in large amounts of urine. Diabetes mellitus is so much more common than the other types, that when used alone, "diabetes" means diabetes mellitus.

 

Can type 2 diabetes run in families?

 

Yes. It is well-established that type 2 diabetes can run in families. Here are some statistics:

 

*        The brothers and sisters of a type 2 diabetic have almost a 40% risk of developing type 2 diabetes or near-diabetes (glucose intolerance).

*        The children of a type 2 diabetic have a 33% chance of developing type 2 diabetes or near-diabetes.

*        The identical twin of a type 2 diabetic has a 70% to 80% chance of developing type 2 diabetes.

 

When type 2 diabetes runs in families, is the reason genes or environment?

 

As in most human disease, type 2 diabetes has genetic components and environmental components. So, it's a matter of nature and nurture, not nature versus nurture.

 

Type 2 diabetes also runs within larger "human families." For example, 34% of the natives on the Pacific island of Nauru have type 2 diabetes. In Arizona, 40% of the Pima Native Americans have it. By contrast, in American whites, the number is around 1% to 2%.

 

The high frequencies for Nauruans and Pimas are new, and resulted from a change in their pattern of food intake. Until recently, food was scarce in these populations. Obesity and, therefore, type 2 diabetes were rare. When food became abundant, both abnormalities became common.

 

Food is abundant in the United States, yet the frequency of type 2 diabetes is much lower than on Nauru or for the Pimas. Why the difference in frequencies? Most likely, the Nauruans and the Pimas have gene variants that give them a tendency toward obesity and type 2 diabetes when food is plentiful. Presumably, these gene variants may help the Nauruans and the Pimas function when food is scarce, or help them survive starvation.

 

This is typical of the relationship between genes and environment -- the environment determines whether a gene is helpful or harmful.

 

Studies of twins provide the clearest evidence for genes and environment both having a role. For example, in one study researchers looked at 56 pairs of twins in which at least one twin had type2 diabetes.

 

Type of twin pair         Number of twin pairs   Twin pairs in which

both twins had type 2 diabetes

("concordance rate")

Identical twins                         46                                 80%

(37 of 46 pairs)

Non-identical twins                  10                                 40%

(4 of 10 pairs)

 

If type 2 diabetes were governed only by genes, then every time one identical twin had it, the other should have it, too. (Because identical twins have the same genes.) In other words, the "concordance rate" should be 100%. The table shows, however, that instead of a 100% concordance, there is an 80% concordance between identical twins. This shows that type 2 diabetes has a small environmental component.

 

If type 2 diabetes were purely an environmental condition, then genes should make no difference at all. The concordance rate would be the same for identical twins and non-identical twins. The table shows, however, that the concordance rate is twice as high in identical twins (80%) as in non-identical twins (40%). This shows that type 2 diabetes has a strong genetic component.

 

In summary, type 2 diabetes has a genetic component that is subject to a major influence from the environment.


 

What genes are involved in type 2 diabetes?

 

For the overwhelming majority of persons with typical type 2 diabetes, a single gene variant is not responsible. Instead, the genetic component of their disease is the result of multiple genes acting together. Scientists haveidentified some gene variants that contribute to type 2 diabetes, but have not yet found the variants that contribute to most cases.

Gene Name        Chromosome      Comments

insulin         11      Insulin, of course, is a critical part of diabetes. Yet, only a few variants of the insulin gene have been discovered, and they are not common.

insulin receptor     19      In order to send its signal to the body's tissues, insulin must chemically react with another protein -- the insulin receptor. (It's like putting a key into a lock.) In contrast to the insulin gene, more than 40 variants of the insulin receptor gene have been found. Most of these variants reduce the efficiency of the insulin "signal." Thus, people who have variants of the insulin receptor gene are partially resistant to the effects of insulin -- a key step on the road to developing type 2 diabetes.

NIDDM1      2       This gene was found after analyzing the DNA of 330 pairs of Mexican-American siblings near the Rio Grande in Texas [3]. In this group, the gene is a major contributor to the development of type 2 diabetes. There is some evidence that a second gene must work in combination with this one in order for diabetes to develop.

NIDDM2      12      This gene has not been precisely identified. It was "discovered" in a group of 26 families from an isolated area in western Finland. The NIDDM2 gene is near a gene that is responsible for some cases of type 2 MODY [4]. Thus, some scientists suspect that NIDDM2 may be a different variant of the MODY gene.

NIDDM3      20      This gene was found by analyzing 477 Finnish families. It has not been precisely identified [2].

HNF4A        20      At least five variants of this gene are associated with diabetes. Four are related to type 2 MODY, and one is related to typical type 2 diabetes. None of the gene variants have been found in more than one or two families.

GLUT4        17      In a study of 6 patients with type 2 diabetes, one proved to have a unique variant of this gene. The gene is a blueprint for a protein that is involved in sugar processing.

NEUROD1   2       Unique variants of this gene have been found in two families. In one of the families, there were some people with the variant, but without diabetes. It appears that this gene affects the way the pancreas develops as an organ.

MAPK8IP1  11      A variant of this gene was found in a single family in which type 2 diabetes was present in 4 generations. Some people in the family who carried the variant gene did not have diabetes. This gene is the blueprint for a protein that has an effect on the movement of sugar in the pancreas and other organs.

tRNA-LEU   mito.  Different variants of this gene produce different diseases. For example, one variant causes the MELAS syndrome and another causes the MERRF syndrome. Type 2 diabetes is a part of the MERRF syndrome, which also includes a type of epilepsy and eye disease.

 

What environmental factors are involved in type 2 diabetes?

 

Body weight would seem to be the most obvious environmental factor involved in type 2 diabetes. However, as we discuss at length in the article on obesity, body weight is largely under genetic control.

 

As we mentioned earlier, damage to the pancreas can bring on or hasten the appearance of diabetes. Alcohol, trauma, pancreatitis, and perhaps some toxins are capable of damaging the pancreas.

 

Learning more about the genetics of type 2 diabetes will make it easier to identify and understand environmental contributions to the disease.

 

When type 2 diabetes runs in families, why don't all family members have it?

 

It helps to frame this question a little differently.... All members of a family do not have the same height, weight, and face. So, it makes sense that they don't all have the same conditions and diseases -- or the same susceptibility to various diseases.

 

Here again, it's genetic and environmental differences that explain differences in our appearance and health. Some family members will inherit genes that predispose to diabetes, and others will not. Some family members will be exposed to environmental agents that trigger disease, and others will not.

 

There is no type 2 diabetes in my family. Does this mean it will never occur in my family?

 

No. Anyone can develop diabetes. Most people with diabetes do not have a parent, brother, sister, or child with diabetes. But if someone in your family does have diabetes, you are at greater risk.

 

How will discoveries about DNA help people and families with type 2 diabetes?

 

Further discoveries about diabetes genes will lead to more individualized medicine. Prevention, diagnosis, treatment, and prognosis will be personalized, based largely on the strengths and weaknesses found in a person's genes.

 

*        Treatment -- better use of existing treatments

 

Several medicines have been approved to treat diabetes. How does your physician know which is best for you? Part of the answer may be in your genes.

 

In this article, we've seen how specific genes influence the development and progression of a complex condition -- diabetes. Similarly, specific genes may influence the responses to different treatments. Better genetic information could explain why some drugs work better in some people than others. This will make choosing treatments less hit-and-miss than in the past.

 

*        Treatment -- discovery of new treatments

 

Whenever scientists discover a gene involved in diabetes, it's a doorway to designing new treatments. If the gene is over-active, then scientists can look for ways to turn it off or interfere with its activity. If the gene is under-active or broken, then scientists can look for ways to turn it on or increase its activity.

 

*        Prevention, Diagnosis, Prognosis

 

Prevention, diagnosis, and prognosis all improve when our ability to calculate risk improves. Scientists believe genes will tell us a lot about the risk of developing diabetes and the progression of diabetes.

 

 

How can I help other people and families with type 2 diabetes?

 

To help those who are already ill, consider donations of money or time to charitable causes sponsoring research into diabetes. We also hope you will consider participating in The Gene Trust.

 

What other web sites deal with type 2 diabetes

 

*        Diabetes web site at the National Institute of Diabetes and Digestive and Kidney Diseases:

http://www.niddk.nih.gov/

 

 

*        The MedlinePlus web site for diabetes:

http://www.nlm.nih.gov/

 

 

*        The Centers for Disease Control's frequently asked questions about diabetes:

http://www.cdc.gov/

 

 

*        The Joslin Diabetes Center:

http://www.joslin.harvard.edu/

 

References used in this article

 

1.      Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998 Aug;19(4):491-503. [Medline]

2.      Ghosh S, and 39 others. Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci U S A 1999 Mar 2;96(5):2198-203. [Medline] [Full text]

3.      Hanis CL, and 32 others. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161-6. [Medline]

4.      Mahtani MM, and 20 others. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90-4. [Medline]

5.      Unger RH, Foster DW. Diabetes mellitus. Chapter 21 in: Williams Textbook of Endocrinology. 9th ed. Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Philadelphia: Saunders, 1998.

 

Professional-level resources:

 

*        For OMIM search on diabetes, click here.

 

 

*        For Medline search on twin studies in diabetes, click here.

 

 

*        For Medline search on famous persons with diabetes, click here.

Revised: July 21, 2000 by JS 

 

© 2001 DNA Sciences, Inc. All rights reserved.