Abstract
BackgroundThere is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats.MethodsFasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein–protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM.ResultsFasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up-regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein–protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM.ConclusionsNon-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0424-3) contains supplementary material, which is available to authorized users.
Highlights
There is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic
Metabolic characterization of non‐obese T2DM In order to verify the development of T2DM in male GK rats, concentrations of several serum metabolites were measured at weeks 7, 11 and 15 (Fig. 1)
homeostasis model assessment-estimated insulin resistance (HOMA-IR) was significantly increased at weeks 7 and 11 in GK rats when compared to controls showing insulin resistance in GK animals (Fig. 1d)
Summary
There is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. A significant proportion of T2DM patients are non-obese and they have an increased risk of cardiovascular diseases. The non-obese T2DM phenotype is characterized by a more pronounced reduction in insulin secretion and less severe insulin resistance as compared to obese T2DM patients [7]. It is well known that diabetic patients have an increased risk of developing a number of co-morbidities including cardiovascular diseases (CVD). It has been reported that T2DM patients have a two to fourfold increased risk of CVD in general [7, 11, 12]. CVD are estimated to be responsible for more than 50 % of deaths among T2DM population [15]
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