Altered lipid metabolism associated with insulin resistance and obesity is a major contributor to the onset and progression of type 2 diabetes

Abstract

The Australian population and indeed most of the developed world are facing an obesity epidemic, which is associated with a dramatic increase in the incidence of type 2 diabetes (T2D). Obesity and insulin resistance (IR) are strong predictors of the development of T2D. Dyslipidaemia as assessed by “traditional” measures (raised plasma triglycerides and/or decreased high-density lipoprotein cholesterol) is also a major risk factor for the onset and progression of T2D. However, the measurement of a few circulating “classical” lipids and lipoproteins alone does not adequately represent the hundreds of lipids in the circulation and tissues that may be associated with the pathogenesis of T2D. Initially, targeted lipid profiling methodology was developed to characterise lipid species that are implicated in the pathogenesis of T2D. These methods resulted in 60 species from the phosphatidylethanolamine, alkylphosphatidylethanolamine, alkenylphosphatidylethanolamine, lysophosphatidylethanolamine and cardiolipin classes/subclasses being added to the ~270 lipid species representing 20 lipid classes/subclasses that are routinely measured in our laboratory using reverse phase high performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (LC ESI-MS/MS) and established multiple reaction monitoring experiments in positive ion mode. Comprehensive lipidomic analysis was then performed to compare temporal (6, 10 and 16 weeks of age) and tissue-specific (plasma, liver, skeletal muscle, left-ventricle and adipose) lipid abnormalities in male and female leptin receptor-deficient homozygous db/db mice with a C57BL/KsJ background (an established monogenic model of diabetes) and their less affected heterozygous (db/h) and control (H/H) littermates. The independent effect of the db/db genotype on plasma and tissue lipid abnormalities was clearly superior to the separate effects of gender and age. There was a myriad of temporal and tissue-specific lipid abnormalities in db/db mice (versus corresponding H/H mice) associated with early elevations of surrogate measures of hepatic de novo lipogenesis and cardiolipin remodelling, but also with increasing oxidative stress and severity of disease. Using DNA microarray analysis with mouse whole-genome gene expression WG-6 version 2.0 BeadChips, 68 differentially expressed genes in the livers of male db/db mice (versus male H/H mice, with ages combined) were found to be linked to lipid pathway/diabetes-specific disease states. Correlation analyses revealed that elevated triacylglycerol and lysophosphaethanolamine classes/subclasses were significantly correlated with 24 and 20 genes respectively, and that many of these differentially expressed liver genes have been identified as candidate genes for human T2D. Finally, in a human study in which 80 adults were classified as lean, overweight-to-obese and insulin sensitive, overweight-to-obese and insulin resistant, or T2D, there was a gradation of fasting plasma lipid abnormalities associated with obesity, IR and combined obesity/IR, but ~85% of the lipid abnormalities in T2D subjects (versus lean group) were already present in the combined obesity/IR group prior to the onset of T2D. Some of these lipid abnormalities also occurred in the db/db mice. Taken together, these studies improve our understanding of the biological interplay that exists between lipid abnormalities, obesity and IR, and provide more opportunities to identify new therapeutic targets and possible lipid biomarkers for early detection and prevention of disease progression.