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Glycosylated sphingolipids and progression to kidney dysfunction in type 1 diabetes.

ABSTRACT: BACKGROUND:Glycosphingolipids are important components of cell membranes, modulators of cell-cell interactions and cell recognition, and have recently emerged as bioactive molecules and important players in nearly all cell biological processes. We previously have shown that decreased plasma levels of long and very long species of ceramides were able to predict the development of macroalbuminuria (MA) in type 1 diabetes. OBJECTIVE:This study proposed to examine whether plasma glycosphingolipids could predict development of diabetic nephropathy, assessed as MA or chronic kidney disease (CKD). METHODS:Measurement of plasma hexosylceramides (H) and lactosylceramides (L) were conducted in the Lipidomics Core Facility of our Institution in a subcohort of 432 patients from the DCCT/Epidemiology of Diabetes Interventions and Complications cohort in plasma collected at entry into the study. Inverse probability weighted Cox proportional hazards regression models were used to assess the effect of glycosphingolipids levels on the risk of developing MA (albumin excretion rate ?300 mg/24 hours) or CKD (glomerular filtration rate <60 mL/min) over a period of 21 to 28 years. RESULTS:Decreases of several long and very long chain lactosylceramides were significantly associated with increased risk of progression to MA but not CKD. Among the hexosylceramides, the only significant association observed was between one of its minor species C18:1-H and CKD. CONCLUSION:Our findings showed that decreased levels of long and very long lactosylceramides were able to predict the development of MA in type 1 diabetes. This finding is similar to previous findings showing that low levels of long and very long ceramides were also able to predict development of MA in the same cohort. Further studies are needed to determine the changes in sphingolipid metabolism leading to the development of complications.

SUBMITTER: Lopes-Virella MF

PROVIDER: S-EPMC7218687 | biostudies-literature | 2019 May - Jun

REPOSITORIES: biostudies-literature

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Glycosylated sphingolipids and progression to kidney dysfunction in type 1 diabetes.

Lopes-Virella Maria F MF Baker Nathaniel L NL Hunt Kelly J KJ Hammad Samar M SM Arthur John J Virella Gabriel G Klein Richard L RL

Journal of clinical lipidology 20190403 3

<h4>Background</h4>Glycosphingolipids are important components of cell membranes, modulators of cell-cell interactions and cell recognition, and have recently emerged as bioactive molecules and important players in nearly all cell biological processes. We previously have shown that decreased plasma levels of long and very long species of ceramides were able to predict the development of macroalbuminuria (MA) in type 1 diabetes.<h4>Objective</h4>This study proposed to examine whether plasma glyco ...[more]

PMID: 31043336

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Project description:Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

Project description:OBJECTIVE:To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association. RESEARCH DESIGN AND METHODS:Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. In addition to traditional biomarkers of inflammation (C-reactive protein and fibrinogen), we measured interleukin-6 (IL-6) and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1/2), markers of endothelial dysfunction (soluble intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin [sE-selectin]), and fibrinolysis (total and active plasminogen activator inhibitor-1 [PAI-1]). Renal outcomes were defined as progression to incident chronic kidney disease (stage 3 or more severe) or macroalbuminuria (albumin excretion rate ?300 mg/24 h). Prospective multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals (3-year and 10-year windows). RESULTS:Multivariate event-time models indicated that several markers of inflammation (sTNFR-1/2), endothelial dysfunction (sE-selectin), and clotting/fibrinolysis (fibrinogen and PAI-1) are significantly associated with subsequent development of kidney dysfunction. Although some markers showed variations in the associations between the follow-up windows examined, the results indicate that biomarkers (sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows. CONCLUSIONS:Plasma markers of inflammation, endothelial dysfunction, and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up.

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Project description:ObjectivesGrowing evidence demonstrated that vitamin D levels had been linked to type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in light of various extraskeletal effects. Therefore, the present study aimed to evaluate the association of 25-hydroxyvitamin D [25(OH)D] level with the clinicopathological features and CKD progression in T2DM.MethodsA total of 182 patients with T2DM with CKD stages 1 through 4 (G1-G4) were retrospectively included. Identification of the serum 25(OH)D level associated with CKD progression was executed by Kaplan-Meier survival analysis and Cox proportional hazards models. We further performed sensitivity analyses with a time-weighted average (TWA) of the serum 25(OH)D level in 75 participants to reinforce the findings.ResultsThe median serum 25(OH)D level was 26 (IQR, 14; 39) nmol/L in the study participants. Median follow-up time was 42 months, during which 70 (38%) patients confronted CKD progression. Cumulative kidney outcomes were significantly higher in the lowest tertile of the serum 25(OH)D level in Kaplan-Meier analyses (P < 0.001). Consistently, the analyses of Cox proportional hazards regression models indicated a significantly greater risk for CKD progression in the lowest tertile of the serum 25(OH)D level compared with the highest tertile of the serum 25(OH)D level (P = 0.03). These relationships remained robust with further sensitivity analysis of data with TWA of the serum 25(OH)D level, showing an independent association between lower TWA of the serum 25(OH)D level and an unfavorable renal outcome in patients with T2DM with CKD.ConclusionsOur findings demonstrated that patients with T2DM with a decreased 25(OH)D level had deteriorated renal function. Both lower levels of baseline and TWA of serum 25(OH)D were associated with an increased risk of CKD progression in patients with T2DM, which suggested that the long-term maintenance of optimal vitamin D levels from early in life might be associated with reduced future risk of CKD development in T2DM.

Dataset Information

Glycosylated sphingolipids and progression to kidney dysfunction in type 1 diabetes.

Publications

Glycosylated sphingolipids and progression to kidney dysfunction in type 1 diabetes.

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