Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits.
OBJECTIVE
In the past 3 years, genome-wide association studies have identified many tens of common genetic variants associated with metabolic diseases and traits. Although much further research is needed to identify the target genes, the associations between gene variants and diseases are already providing biological insights. The purpose of this review is to update the reader with the most relevant findings, with a particular emphasis on type 2 diabetes (T2D) and glucose metabolism, and discuss some of the biological implications of the genetic findings.


RESULTS
Largely through recent genome-wide association studies, we now know of approximately 20 gene variants associated with T2D, 10 with body mass index (BMI) and obesity, four with fasting glucose levels in the normoglycaemic population and over 30 with lipid levels. These findings are stimulating many new important areas of research related to metabolic diseases. For T2D and glucose metabolism, we discuss a number of aspects and implications of the genetic findings, including the observations that T2D gene variants are not usually in or near obvious candidate genes, highlighting the poor prior knowledge of the biology of the disease; most T2D gene variants are associated with beta-cell function rather than insulin resistance; there is a difference between genes that influence variation in normal glucose levels compared with those influencing onset and progression of diabetes; and there is a genetic link between diabetes and foetal growth.


CONCLUSIONS
Genetic studies in the past 3 years have provided a greatly increased knowledge of the regions of the genome involved in adverse metabolic consequences. There are now over 100 common genetic variants reproducibly associated with metabolic traits, including reduced beta-cell function, obesity, increased lipid levels and increased glucose levels. These genetic findings are already altering perceptions of how these traits develop and interact to result in diseases such as T2D.
De Silva
N Maneka G
NM
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Frayling
Timothy M
TM
D000818:Animals; D001724:Birth Weight; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology
D005947:Glucose