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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #139: The Genetics of Type 2 Diabetes Part 1

Aug 21, 2018

The diabetic spectrum

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.


There are several types of diabetes with differing disease mechanisms and clinical characteristics (Figure 26.1). Type 2 diabetes (T2DM) is the most common form, constituting 80–90% of all diabetics. T2DM develops when pancreatic β-cells can no longer increase their insulin secretion enough to compensate for increasing insulin resistance imposed by increasing obesity. There is no formal definition of T2DM; instead diabetes patients who do not fulfill the criteria of any other form of diabetes (see later) are considered to have T2DM. While T2DM onset is usually after the age of 35, it is not uncommon that T2DM is diagnosed already in adolescents in high-risk regions such as Asia, the Middle East, and USA.

Type 1 diabetes (T1DM) affects ∼8% of diabetes patients and is due to autoimmune destruction of pancreatic β-cells and is characterized by complete lack of insulin secretion, presence of autoantibodies to glutamic acid decarboxylase (GAD) and, usually, onset of disease before age 35. LADA (latent autoimmune diabetes in adults) accounts for about 7% of all diabetic patients in Europe and is usually defined as GAD antibody-positive diabetes with onset greater than 35 years of age [1]. These disease types could be divided further into subtypes possibly representing different disease mechanisms. In addition there are less common diabetes types including MODY (maturity onset diabetes of the young), representing a monogenic form of diabetes with well-defined mutations in more than six different genes, as well as neonatal and secondary diabetes.These forms of diabetes represent a range of genetic etiologies from the monogenic MODY variants to T2DM, which is a highly complex multigenic disease with a very strong environmental component.

The diabetes epidemic

Worldwide prevalence figures estimate that there were 371 million diabetic patients in 2012 and more than 500 million are expected in 2030 (www.diabetesatlas.org). In Europe, ∼ 8% of the population suffer from diabetes and up to 90% of these have T2DM, making this the fastest increasing disease in Europe and worldwide. The T2DM epidemic can largely be ascribed to the worldwide increase in obesity during the last 30 years, for example more than 60% of individuals older than 15 in the UK and US are overweight (BMI>25). This in turn has been ascribed to a collision between genes and the environment. In a situation of affluence most people tend to overconsume m calories and gain excess weight. One possible reason for this is that genetic selection has favored energy-preserving genotypes (so called thrifty genotypes); individuals living in an environment with unstable food supply could maximize their probability of survival by efficiently storing energy in times of surplus [2]. While this hypothesis provides an  appealing explanation to the obesity and T2DM epidemic, formal proof for this hypothesis is still lacking.

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