Tribology & lubrication technology : TLT ; systems, strategies & research for lubrication professionals

<div><p>The relationship between lipid metabolism with prediabetes (impaired fasting glucose and impaired glucose tolerance) and type 2 diabetes mellitus is poorly defined. We hypothesized that a lipidomic analysis of plasma lipids might improve the understanding of this relationship. We performed lipidomic analysis measuring 259 individual lipid species, including sphingolipids, phospholipids, glycerolipids and cholesterol esters, on fasting plasma from 117 type 2 diabetes, 64 prediabetes and 170 normal glucose tolerant participants in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) then validated our findings on 1076 individuals from the San Antonio Family Heart Study (SAFHS). Logistic regression analysis of identified associations with type 2 diabetes (135 lipids) and prediabetes (134 lipids), after adjusting for multiple covariates. In addition to the expected associations with diacylglycerol, triacylglycerol and cholesterol esters, type 2 diabetes and prediabetes were positively associated with ceramide, and its precursor dihydroceramide, along with phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. Significant negative associations were observed with the ether-linked phospholipids alkylphosphatidylcholine and alkenylphosphatidylcholine. Most of the significant associations in the AusDiab cohort (90%) were subsequently validated in the SAFHS cohort. The aberration of the plasma lipidome associated with type 2 diabetes is clearly present in prediabetes, prior to the onset of type 2 diabetes. Lipid classes and species associated with type 2 diabetes provide support for a number of existing paradigms of dyslipidemia and suggest new avenues of investigation.</p></div

Associations of lipid classes with T2D and prediabetes in the AusDiab and SAHFS cohorts.

<p>Logistic regression of T2D and prediabetes on lipid species adjusted for age, sex, waist circumference and SBP were performed. Bars show the odds ratio for each lipid class, whiskers are the 95% confidence intervals. Panel A – T2D vs. NGT; panel B – prediabetes vs. NGT. Dark bars – AusDiab; light bars – SAFHS.</p

Logistic regression of lipid classes against diabetes and prediabetes in the AusDiab cohort.

a<p>Logistic regression of T2D (n = 116) against NGT (n = 168) on lipid classes adjusted for age, sex, waist circumference and SBP.</p>b<p>Logistic regression of prediabetes (n = 64) against NGT (n = 168) on lipid classes adjusted for age, sex, waist circumference and SBP.</p>c<p>Odds ratio (95% confidence intervals) based on an interquartile range increase in predictor lipid class measurement.</p>d<p>Benjamini-Hochberg corrected p-value. Bold type indicates corrected p<0.05.</p>e<p>% difference in means between groups.</p

Baseline characteristics of the AusDiab study cohort.

a<p>BMI, body mass index; SBP, systolic blood pressure; FPG, fasting plasma glucose; 2h-PLG, 2 hour-post load glucose; HbA1c, glycated haemoglobin; Chol, total cholesterol; HDL, high density cholesterol; LDL, low density cholesterol.</p>b<p>Prediabetes group consists of 24 IFG and 45 IGT.</p>c<p>Values expressed as % (number/total), p-values (Chi-squared test).</p>d<p>Data are expressed as median (interquartile range), p-values (Mann-Whitney U test with Dunn-Sidak correction).</p

The relationship between AusDiab and SAFHS in the odds ratios (T2D) and odds ratios (prediabetes).

<p>Logistic regression of T2D and prediabetes on lipid species adjusted for age, sex, waist circumference and SBP were performed in the AusDiab and SAFHS cohorts. Each data point represents a pair of the odds ratios (AusDiab and SAFHS) for a single lipid species. Panel A – Odds ratios for T2D; panel B – Odds ratios for prediabetes.</p

The relationship between beta-coefficients (FPG) and beta-coefficients (2h-PLG) in AusDiab and SAFHS.

<p>Linear regression of FPG and 2h-PLG on lipid species adjusted for age, sex, waist circumference and SBP were performed. Each data point represents a pair of the beta coefficients (FPG and 2h-PLG) for a single lipid species. Panel A – AusDiab; panel B – SAFHS.</p

Metabolic pathways altered in type 2 diabetes.

<p>Partial lipid metabolic pathways show the major lipids associated with T2D (blue boxes) and the enzymes involved (green boxes). The sphingolipid (blue arrows), cardiolipin (orange arrows), triacylglycerol (black arrows), plasmalogen (red arrows) and phosphatidylcholine/phosphatidylethanolamine (green arrows) biosynthetic pathways are shown. The direction of association between lipids and T2D is indicated by the red arrows in yellow circles. Only partial pathways have been shown for clarity. <b>Metabolite abbreviations:</b> Cho, choline; DG, diacylglycerol; DHAP, dihydroxyacetonephosphate; Etn, ethanolamine; LPC(O), lysoalkylphosphatidylcholine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PC(O), alkylphosphatidylcholine; PC(P), alenylphosphatidylcholine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate; PI, phosphatidylinositol; TG, triacylglycerol. <b>Enzyme abbreviations:</b> A4GALT, lactosylceramide 4-alpha-galactosyltransferase; B4GALT6, beta-1,4-galactosyltransferase 6; CDIPT, CDP-diacylglycerol-inositol 3-phosphatidyltransferase; CDS1, phosphatidate cytidylyltransferase; CerS, ceramide synthasecls, cardiolipin synthase; CPT1, diacylglycerol cholinephosphotransferase; DEGS, sphingolipid delta-4 desaturase; DGAT, diacylglycerol O-acyltransferase; EPT1, PEMT, phosphatidylethanolamine N-methyltransferase; ethanolaminephosphotransferase, pgpA, phosphatidylglycerophosphatase A; pgsA, CDP-diacylglycerol – glycerol-3-phosphate 3-phosphatidyltransferase; PPAP2, phosphatidate phosphatase; SMGS, sphingomyelin synthase; UGCG, ceramide glucosyltransferase.</p

The relationship between odds ratios (T2D) and odds ratios (prediabetes) in AusDiab and SAFHS.

<p>Logistic regression of T2D and prediabetes on lipid species adjusted for age, sex, waist circumference and SBP were performed. Each data point represents a pair of the odds ratios (T2D and prediabetes) for a single lipid species. Panel A – AusDiab; panel B – SAFHS.</p

Baseline characteristics of the SAHFS study cohort.

a<p>BMI, body mass index; SBP, systolic blood pressure; FPG, fasting plasma glucose; 2h-PLG, 2 hour-post load glucose; HbA1c, glycated haemoglobin; Chol, total cholesterol; HDL, high density lipoprotein cholesterol; LDL, low density lipoprotein cholesterol.</p>b<p>NGT group contains 12 individuals on lipid lowering medication.</p>c<p>Prediabetes group consists of 14 IFG and 112 IGT, 4 individuals were on diabetes or lipid lowering medication.</p>d<p>Type 2 diabetes group consists of 69 untreated and 73 treated (diabetes or lipid lowering medication).</p>e<p>Values expressed as % (number/total), p-values (Chi-squared test).</p>f<p>Expressed as median (interquartile range), p-values (Mann-Whitney U test with Dunn-Sidak correction).</p

Linear regression of lipid classes in the AusDiab and SAFHS cohorts.

a<p>Linear regression of FPG on lipid classes adjusted for age, sex, waist circumference and SBP.</p>b<p>Linear regression of 2h-PLG on lipid classes adjusted for age, sex, waist circumference and SBP.</p>c<p>Beta coefficient (95% confidence intervals) based on an interquartile range increase in predictor lipid class measurement.</p>d<p>Benjamini-Hochberg corrected p-value. Bold type indicates corrected p<0.05.</p