type 2 diabetes

introduction

Type 2 diabetes (T2D) (also called non-insulin dependent diabetes mellitus or adult-onset diabetes) is the most common form of diabetes.

In T2D, the body does not respond well to insulin, a hormone that helps transfer sugar out of the blood and into the body's cells and tissues, where it is used for energy. At first, the islet cells in the pancreas try to produce more insulin in an effort to make the body respond. But eventually, these cells cannot keep up and stop working altogether, so sugar stays in the blood. People with T2D have difficulty maintaining normal blood sugar levels. If blood sugar levels are not controlled, T2D can lead to the development of several life-threatening complications such as heart disease, stroke, hypertension, and kidney failure. Patients with T2D also develop blood circulation problems that can lead to blindness and even amputation of extremities in extreme cases.

It is estimated that a total of 20.8 million people, or 7% of the US population, were living with diabetes in 2005. Of those, an estimated 6 million were undiagnosed. Currently, over 1.5 million people are diagnosed with diabetes in the US each year, and the number of new cases of T2D is steadily increasing due to the growing number of older Americans, increasing obesity, and lack of exercise.

An increasing number of genetic variants have been consistently found to contribute to the risk of developing T2D. Variants in the TCF7L2 gene appear to be associated with the highest risk of developing T2D, and also can predict the likelihood that a person will convert from a state of pre-diabetes (borderline blood sugar levels) to full-blown T2D. Several studies have shown that overweight pre-diabetics who have certain TCF7L2 variants have a 55-70% chance to develop T2D within 3 to 5 years after their initial diagnosis. It has been shown by the NIH-sponsored Diabetes Prevention Program Outcome study that weight loss and treatment with metformin can prevent or delay the transition from pre-diabetes to T2D in this high-risk group.

The deCODEme Genetic Scan identifies variants in or near 12 genes: TCF7L2, CDKAL1, CDKN2A/2B, PPARG, HHEX, SLC30A8, IGF2BP2, KCNJ11, JAZF1, TSPAN8/LGR5, THADA, and NOTCH2 genes and provides interpretation of their associated risk for the development of T2D. At this time we provide this information on all variants for individuals of European descent. Information for seven out of the twelve variants is provided for East Asians. For African Americans we provide information on TCF7L2, the individually strongest genetic risk factor.

risk factors

• Overweight or obesity: Type 2 diabetes (T2D) is associated with obesity and resistance to the effects of insulin. Most people with the disease are overweight at the time of diagnosis, and they are more likely to have central obesity (fat concentrated around the waist). T2D can develop in those who are thin, especially the elderly.
• Age: Most patients are over the age of 45 at the time of diagnosis, but a growing number of children and adolescents are being diagnosed with T2D, most likely due to the rise in childhood obesity.
• Abnormal cholesterol levels: People with T2D often have high total cholesterol combined with low HDL cholesterol (less than 35 mg/dL) and high triglyceride levels (over 250 mg/dL).
• Other cardiovascular disease risk factors: High blood pressure, a history of heart disease, and lack of physical activity are also common risk factors for developing T2D.
• History of gestational diabetes: Women who develop diabetes during pregnancy are at higher risk of developing T2D later on in life.
• Ethnicity: Compared with Individuals of European origin, African-Americans, Hispanic/Latino Americans, American Indians, some Asian Americans, and Native Hawaiians or other Pacific Islanders, are at a higher risk for T2D and its complications.
• Genetics: Having a family history of T2D is associated with increased risk for developing the disease. Variants in the TCF7L2 gene appear to be associated with the highest risk of developing T2D, and also can predict the likelihood that a person will convert from a state of pre-diabetes (borderline blood sugar levels) to full-blown T2D. Several studies have shown that overweight pre-diabetics who have certain TCF7L2 variants have a 55-70% chance to develop T2D within 3 to 5 years after their initial diagnosis.

more information

• American Diabetes Association
• Centers for Disease Control and Prevention about Diabetes
• MedlinePlus Medical Encyclopedia about Diabetes
• National Diabetes Information Clearinghouse
• The National Institute of Diabetes and Digestive and Kidney Diseases
• Diabetes Information from the U.S. Food and Drug Administration
• World Health Organization – The Diabetes Programme

scientific references

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   TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med. 2006 Jul 20; 355(3): 241-50
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   Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes. 2008 Mar;57(3): 791-5.
3. Miyake K, Horikawa Y, Hara K, et al.
   Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes in 4,087 Japanese subjects. J Hum Genet. 2008; 53(2): 174-80.
4. Sale MM, Smith SG, Mychaleckyj JC, et al.
   Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes. 2007 Oct;56(10): 2638-42.
5. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al.
   A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007 Jun;39(6): 770-5.
6. Wang J, Kuusisto J, Vänttinen M, et al.
   Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia. 2007 Jun;50(6): 1192-2000
7. Weedon MN.
   The importance of TCF7L2. Diabet Med. 2007 Oct;24(10): 1062-6. Review.
8. Zeggini E, Scott LJ, Saxena R, et al.
   Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008 Mar 30; [Epub ahead of print]