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The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

Diabetes mellitus (DM) is a systemic metabolic disease that affects 463 million adults worldwide and is a leading cause of cardiovascular disease, blindness, nephropathy, peripheral neuropathy, and lower-limb amputation. Lipids have long been recognized as contributors to the pathogenesis and pathophysiology of DM and its complications, but recent discoveries have highlighted ceramides, a class of bioactive sphingolipids with cell signaling and second messenger capabilities, as particularly important contributors to insulin resistance and the underlying mechanisms of DM complications. Besides their association with insulin resistance and pathophysiology of type 2 diabetes, evidence is emerging that certain species of ceramides are mediators of cellular mechanisms involved in the initiation and progression of microvascular and macrovascular complications of DM. Advances in our understanding of these associations provide unique opportunities for exploring ceramide species as potential novel therapeutic targets and biomarkers. This review discusses the links between ceramides and the pathogenesis of DM and diabetic complications and identifies opportunities for novel discoveries and applications., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The hyperinsulinemic euglycemic clamp (HEC) is the "gold standard" for measuring insulin sensitivity (Si-clamp). Here, we determined the reproducibility of serial HEC data in healthy subjects., Research Design and Methods: The Pathobiology of Prediabetes in A Biracial Cohort study assessed incident prediabetes in healthy African Americans (AA) and European Americans (EA) with parental type 2 diabetes mellitus during 5.5 years of follow-up. Assessments included anthropometry, OGTT, and HEC. Ninety subjects (44 AA, 46 EA) who underwent Year-1HEC consented to Year-3 HEC. We calculated coefficients of variation (CVs), 95% limits of agreement, and repeatability coefficients for Year-1 and Year-3 data, and assessed the association of change in Si-clamp with incident prediabetes., Results: The mean (SD) baseline age was 47.5 ± 8.13y, body mass index was 30.4 ± 9.16 kg/m 2 , fasting plasma glucose was 93.7 ± 7.82 mg/dL and 2-hrPG was 126 ± 26.8 mg/dL. Si-clamp (umol/kg/min·pmol/L -1 ) was 0.071 ± 0.04 in Year 1 and 0.067 ± 0.04 in Year 3 (P = 0.22). Year 1 and Year 3 values were strongly correlated (r = 0.81, P < 0.0001); the CV was 13.6% and repeatability coefficient was ±0.025. Intrasubject differences in serial Si-clamp were less than the repeatability coefficients and within the 95% limits of agreement. After 5.5 years of follow-up, 40 subjects progressed to prediabetes and 50 were nonprogressors. The change in Si-clamp was greater in progressors than nonprogressors (-10% vs. -2.5%, P = 0.02)., Conclusions: The HEC is reproducible over ~2 years in free-living individuals, with a temporal decline in Si-clamp that predicts prediabetes risk., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The hyperinsulinemic euglycemic clamp (HEC) is the gold standard for measuring insulin sensitivity, but glycemic recovery and stabilization after the procedure have not been well studied. Here, we assessed the physiological determinants of postclamp recovery., Methods: We analyzed data from 207 healthy subjects [102 African American (AA) and 105 European American (EA)] who underwent HEC in the Pathobiology of Prediabetes in a Biracial Cohort study. At the end of HEC, insulin infusion was stopped, and dextrose (20%) infusion was tapered and stopped when plasma glucose stabilized ≥20 mg/dL above the preclamp value (∼100 mg/dL). Glucose recovery time (GRT) was defined as the interval from cessation of insulin infusion to discontinuation of dextrose infusion. Insulin clearance was calculated under basal and clamp conditions., Results: The mean (± SD) age and body mass index were 46.3 ± 9.96 years and 30.7 ± 8.43 kg/m2, respectively. Plasma glucose (mg/dL) was 92.2 ± 6.26 preclamp and 124.2 ± 26.9 postclamp. The median GRT (minutes) was 65 (range, 30 to 270); mean GRT was 77.1 ± 42.7 (men: 82.9 ± 45.5; women: 74.4 ± 42.3; AA, 82.0 ± 49.6; EA, 72.3 ± 34.2; P > 0.1 for sex or race). The 90th percentile for GRT was 119 minutes. In regression models, significant predictors of GRT were age (P = 0.03), weight (P = 0.009), 2-hour plasma glucose (P = 0.0002), insulin sensitivity (P = 0.03), disposition index (P = 0.017), and basal insulin clearance (P = 0.02)., Conclusions: In our biracial cohort, glycemic recovery after hyperinsulinemic clamp was independent of sex or race but was significantly predicted by age, weight, and glucose tolerance and by insulin sensitivity, secretion, and clearance. We recommend that monitoring be maintained for ∼2 hours postclamp to ensure adequate glycemic stabilization.