Abstract
BackgroundGene expression alterations have previously been associated with type 2 diabetes, however whether these changes are primary causes or secondary effects of type 2 diabetes is not known. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease.Methods/Principal FindingsWe determined gene expression profiles in skeletal muscle biopsies from Caucasian males with type 2 diabetes, healthy first degree relatives, and healthy controls. Gene expression was measured using Affymetrix Human Genome U133 Plus 2.0 Arrays covering the entire human genome. These arrays have not previously been used for this type of study. We show for the first time that genes involved in insulin signaling are significantly upregulated in first degree relatives and significantly downregulated in people with type 2 diabetes. On the individual gene level, 11 genes showed altered expression levels in first degree relatives compared to controls, among others KIF1B and GDF8 (myostatin). LDHB was found to have a decreased expression in both groups compared to controls.Conclusions/SignificanceWe hypothesize that increased expression of insulin signaling molecules in first degree relatives of people with type 2 diabetes, work in concert with increased levels of insulin as a compensatory mechanism, counter-acting otherwise reduced insulin signaling activity, protecting these individuals from severe insulin resistance. This compensation is lost in people with type 2 diabetes where expression of insulin signaling molecules is reduced.
Highlights
Type 2 diabetes is a complex and multi-factorial disease involving both genetics and pre- and postnatal environmental etiological factors
Skeletal muscle biopsies from male subjects with type 2 diabetes, first degree relatives, and healthy controls were investigated at the gene expression level using the microarray technology
The elevated fasting plasma insulin levels in the first degree relatives support the notion that they are in the pre-diabetic stage probably on their way to develop overt insulin resistance
Summary
Type 2 diabetes is a complex and multi-factorial disease involving both genetics and pre- and postnatal environmental etiological factors. The underlying genetics of type 2 diabetes is very complex and it is clear that several genes play a role making this a polygenic disease. Several new type 2 diabetes gene regions have recently been identified [8,9,10]. Whether these SNPs in or close to specific genes are part of the underlying pathogenesis or markers of the disease is still not known, some of these variants have been linked to impaired b-cell function and insulin secretion [11]. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease
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