Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven (dihydro)ceramide network to T2D and CVD risk. Controlling for confounding by other (dihydro)ceramides, ceramides C18:0 and C22:0 and dihydroceramides C20:0 and C22:2 are associated with higher and ceramide C20:0 and dihydroceramide C26:1 with lower T2D risk. Ceramide C16:0 and dihydroceramide C22:2 are associated with higher CVD risk. Genome-wide association studies and Mendelian randomization analyses support a role of ceramide C22:0 in T2D etiology. Our results also suggest that (dh)ceramides partly mediate the putative adverse effect of high red meat consumption and benefits of coffee consumption on T2D risk. Thus, (dihydro)ceramides may play a critical role in linking genetic predisposition and dietary habits to cardiometabolic disease risk.

OBJECTIVEShort leg length, a marker of early childhood deprivation, has been used in studies of the association of early life conditions with adult chronic disease risk. The objective of this study was to determine the cross-sectional associations of leg length with measures of insulin sensitivity and -cell function.RESEARCH DESIGN AND METHODSSubjects (n = 462) at risk for type 2 diabetes were recruited into the PROspective Metabolism and ISlet cell Evaluation (PROMISE) longitudinal cohort. Leg length was calculated from sitting and standing height at the 3-year clinical examination. Glucose tolerance status was determined using an oral glucose tolerance test. Insulin sensitivity was assessed using homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda insulin sensitivity index (ISI), while the insulinogenic index over HOMA-IR (IGI/IR) and the insulin secretion sensitivity index 2 (ISSI-2) determined -cell function. Multiple linear regression analysis was conducted, adjusting for covariates including age, sex, ethnicity, family history of diabetes, waist, and weight.RESULTSLeg length and leg-to-height ratio were significantly associated with HOMA-IR ( = -0.037, = -10.49, respectively; P < 0.0001), ISI ( = 0.035, = 8.83, respectively; P < 0.0001), IGI/IR ( = 0.021, P < 0.05; = 7.60, P < 0.01, respectively), and ISSI-2 ( = 0.01, P < 0.03; = 3.34, P < 0.01, respectively) after adjustment for covariates. The association of shorter leg length with lower insulin sensitivity was most evident for those with high waist circumferences.CONCLUSIONSShorter legs were independently associated with lower insulin sensitivity and -cell function, suggesting that early childhood deprivation may increase the risk of developing diabetes.

Objective: To evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D). Research design and methods: Adults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (IC_FASTING) and areas under the curve of C peptide-to-insulin (IC_AUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC. Results: IC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in IC_FASTING and IC_AUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia. Conclusions: Our findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

Context: Specific serum fatty acid (FA) profiles predict the development of incident type 2 diabetes; however, limited longitudinal data exist exploring their role in the progression of insulin sensitivity (IS) and β-cell function.Objective: To examine the longitudinal associations of the FA composition of serum phospholipid (PL) and cholesteryl ester (CE) fractions with IS and β-cell function over 6 years.Design: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort is a longitudinal observational study, with clinic visits occurring every 3 years. Three visits have been completed, totaling 6 years of follow-up.Setting: Individuals (n = 477) at risk for diabetes recruited from the general population in London and Toronto, Canada.Main Outcome Measures: Values from an oral glucose tolerance test were used to compute 1/HOMA-IR and the Matsuda index for IS, the insulinogenic index over HOMA-IR, and the insulin secretion-sensitivity index-2 for β-cell function. Thin-layer chromatograph and gas chromatograph quantified FA. Generalized estimating equations were used for the analysis.Results: IS and β-cell function declined by 8.3–19.4% over 6 years. In fully adjusted generalized estimating equation models, PL cis-vaccenate (18:1n-7) was positively associated with all outcomes, whereas γ-linolenate (GLA; 18:3n-6) and stearate (18:0) were negatively associated with IS. Tests for time interactions revealed that PL eicosadienoate (20:2n-6) and palmitate (16:0) and CE dihomo-γ-linolenate (20:3n-6), GLA, and palmitate had stronger associations with the outcomes after longer follow-up.Conclusions: In a Canadian population at risk for diabetes, we found that higher PL stearate and GLA and lower cis-vaccenic acid predicted consistently lower IS and β-cell function over 6 years.

The Internet should, in theory, facilitate access to peer-reviewed scientific articles for orthopaedic surgeons in low-income countries (LIC). However, there are major barriers to access, and most full-text journal articles are available only on a subscription basis, which many in LIC cannot afford. Various models exist to remove such barriers. We set out to examine the potential, and reality, of journal article access for surgeons in LIC by studying readership patterns and journal access through a number of Internet-based initiatives, including an open access journal (“PLoS Medicine”), and programs from the University of Toronto (The Ptolemy Project) and World Health Organization (WHO) (Health InterNetwork Access to Research Initiative [HINARI]). Do Internet-based initiatives that focus on peer-reviewed journal articles deliver clinically relevant information to those who need it? More specifically: (1) Can the WHO’s program meet the information needs of practicing surgeons in Africa? (2) Are healthcare workers across the globe aware of, and using, open access journals in a manner that reflects global burden of disease (GBD)? We compared actual Ptolemy use to HINARI holdings. We also compared “PLoS Medicine” readership patterns among low-, middle-, and high-income regions. Many of the electronic resources used through Ptolemy are not available through HINARI. In contrast to higher-income regions, “PLoS Medicine” readership in Africa is proportional to both the density of healthcare workers and the GBD there. Free or low-cost Internet-based initiatives can improve access to the medical literature in LIC. Open access journals are a key component to providing clinically relevant literature to the regions and healthcare workers who need it most.