Ceramides and Sphingolipids as Predictors of Incident Dysglycemia

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Type 2 diabetes (T2D) is a chronic metabolic disorder responsible for a number of debilitating complications such as diabetic retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Bioactive lipids like sphingolipids (SPLs) have been implicated in the pathogenesis of T2D, and recent studies specifically link ceramides (Cers) with the pathophysiology of obesity and T2D. We hypothesize that Cers and other SPLs are critical modulators of pathophysiological processes driving the progression from normal glucose regulation (NGR), through prediabetes, to T2D and associated diabetic complications. We propose to use stored specimens from the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study of normoglycemic participants with parental history of T2D and the Diabetes Prevention Program/Diabetes Prevention Program Outcome Study (DPP/DPPOS) which followed participants already diagnosed with prediabetes for the development of T2D. We will enroll and analyze samples from 200 normoglycemic individuals with no family history of diabetes, which will serve as normative controls. In Specific Aim 1, we will analyze Cer and related SPLs (glycosyl ceramides, sphingomyelins and long-chain sphingoid bases) from plasma samples of normoglycemic participants with no family history of diabetes and two cohorts from the POP-ABC study: normoglycemic participants who developed prediabetes (progressors) and who did not develop prediabetes (non-progressors), each at base line and at 5 years follow-up. We expect to determine a novel association of Cer burden with prediabetes and family history. In Specific Aim 2, like Aim 1, we will perform a comprehensive profiling of Cer and SPLs DPP/DPPOS samples longitudinally at baseline, at 2 year DPP and at 11 year DPPOS from participants who were randomized to ‘placebo’ group (no intervention). We will compare prediabetic participants who progressed to T2D with participants who had not progress to T2D by year 11 in DPPOS. In Specific Aim 3, we will evaluate SPL signatures in relation to the efficacy of interventions that reverse prediabetes and those that prevent T2D. Using three different groups from the POP-ABC and DPP/DPPOS studies, we will analyze Cer and SPLs levels as predictors of incident prediabetes and T2D during longitudinal follow-up of well-defined subgroups of participants. Our results will enable us to determine whether Cer and SPLs modulate the impact and magnitude of the interventions on glycemic outcome. In Specific Aim 4, we will analyze existing DPP/DPPOS data in a case- control design, to determine associations between Cers and microvascular and macrovascular complications of diabetes. Overall, results of the studies proposed here will advance our understanding of the role of Cers in the pathophysiology of prediabetes, diabetes and related complications. Further, our planned lipidomics analyses are designed to facilitate the discovery of novel predictive, prognostic and specific biomarkers for prediabetes, T2D, and vascular complications.