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01-04-2012 | Diabetes | Article

Obesity susceptibility genes linked to insulin sensitivity


Free abstract

MedWire News: The SH2B adaptor protein 1 gene (SH2B1) previously shown to be associated with body mass index (BMI) is also associated with insulin sensitivity, show study findings.

In addition, two other BMI-susceptibility loci (neuronal growth regulator 1 [NEGR1] and mitochondrial carrier 1 [MTCH1]) may also play a role in sensitivity to insulin, say Tove Fall (Karolinska Institutet, Stockholm, Sweden) and colleagues.

"Genome-wide association studies have been very successful in identifying common genetic Type 2 diabetes loci and, to date 44 such loci have been identified," says the team. "However, the vast majority of these loci have been associated with β-cell dysfunction or are of unknown function, whereas the number of loci associated with insulin sensitivity is unexpectedly low, prompting further identification."

As it is well established that obesity and insulin resistance are highly correlated, the authors hypothesized that some loci that have been discovered as BMI-susceptibility loci may primarily act through an effect on insulin sensitivity.

To investigate, they evaluated available data for participants from the Uppsala Longitudinal Study of Adult Men. The study cohort comprised 926 men (aged 71 years) without diabetes, who underwent a euglycemic-hyperinsulinemic clamp and genotyping for 32 BMI-susceptibility loci.

The team used linear regression modelling to assess the effects of these loci on the insulin sensitivity index (M/I ratio).

As reported in Diabetic Medicine, the investigators found that three single nucleotide polymorphisms (SNPs) in or near SH2B1, NEGR1, and MTCH2 were inversely related to insulin sensitivity, after adjusting for BMI. "The variance explained for M/I ratio of these three SNPs were 0.2 to 0.6% when added to a model including age and BMI," report the authors.

The team also performed an in silico replication by extracting results for the three SNPs from the Meta-analyses of Glucose and Insulin-related traits Consortium (MAGIC) analyses of homeostatic model assessment of insulin resistance (HOMA-IR). They discovered that the BMI-increasing allele of rs7359397 in SH2B1 also significantly increased HOMA-IR in the MAGIC data set. However, no such significant associations were observed for the NEGR1 and MTCH2 loci.

"The lack of replication of associations of the MCTH2 and NEGR1 loci could be attributable to a true null effect, or the quite low correlation of HOMA-IR to gold standard measurement of insulin sensitivity," write the researchers.

"Further studies are needed to identify additional loci involved in insulin sensitivity pathophysiology," they conclude.

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Sally Robertson