Sangeeta R Kashyap1, Abdullah Osme2, Serguei Ilchenko2, Makan Golizeh2, Kwangwon Lee2, Shuhui Wang3, James Bena4, Stephen F Previs5, Jonathan D Smith3, Takhar Kasumov2,6. 1. Department of Endocrinology and Metabolism, Cleveland Clinic, Cleveland, Ohio. 2. Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio. 3. Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, Ohio. 4. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio. 5. Merck Research Laboratories, Kenilworth, New Jersey. 6. Department of Hepatology, Cleveland Clinic, Cleveland, Ohio.
Abstract
Context: Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications of diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation of apolipoprotein I (ApoAI). The mechanism(s) of these changes is largely unknown. Objective: To study the role of hyperglycemia-induced glycation on ApoAI kinetics and stability in patients with diet-controlled T2DM. Design: 2H2O-metabolic labeling approach was used to study ApoAI turnover in patients with diet-controlled T2DM [n = 9 (5 F); 59.3 ± 8.5 years] and matched healthy controls [n = 8 (4 F); 50.7 ± 11.6 years]. The effect of Amadori glycation on in vivo ApoAI stability and the antioxidant and cholesterol efflux properties of HDL were assessed using a proteomics approach and in vitro assays. Results: Patients with T2DM had increased turnover of ApoAI and impaired cholesterol efflux and antioxidant properties of HDL. Glycated hemoglobin was negatively correlated with the half-life of ApoAI and cholesterol efflux function of HDL. Proteomics analysis identified several nonenzymatic early (Amadori) glycations of ApoAI at lysine sites. The kinetics analysis of glycated and native ApoAI peptides in patients with T2DM revealed that glycation resulted in a threefold shorter ApoAI half-life. Conclusions: The 2H2O method allowed the detection of early in vivo impairments in HDL metabolism and function that were related to hyperglycemia-induced glycation of ApoAI in T2DM.
Context:Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications of diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation of apolipoprotein I (ApoAI). The mechanism(s) of these changes is largely unknown. Objective: To study the role of hyperglycemia-induced glycation on ApoAI kinetics and stability in patients with diet-controlled T2DM. Design: 2H2O-metabolic labeling approach was used to study ApoAI turnover in patients with diet-controlled T2DM [n = 9 (5 F); 59.3 ± 8.5 years] and matched healthy controls [n = 8 (4 F); 50.7 ± 11.6 years]. The effect of Amadori glycation on in vivo ApoAI stability and the antioxidant and cholesterol efflux properties of HDL were assessed using a proteomics approach and in vitro assays. Results:Patients with T2DM had increased turnover of ApoAI and impaired cholesterol efflux and antioxidant properties of HDL. Glycated hemoglobin was negatively correlated with the half-life of ApoAI and cholesterol efflux function of HDL. Proteomics analysis identified several nonenzymatic early (Amadori) glycations of ApoAI at lysine sites. The kinetics analysis of glycated and native ApoAI peptides in patients with T2DM revealed that glycation resulted in a threefold shorter ApoAI half-life. Conclusions: The 2H2O method allowed the detection of early in vivo impairments in HDL metabolism and function that were related to hyperglycemia-induced glycation of ApoAI in T2DM.
Authors: R Kozyraki; J Fyfe; M Kristiansen; C Gerdes; C Jacobsen; S Cui; E I Christensen; M Aminoff; A de la Chapelle; R Krahe; P J Verroust; S K Moestrup Journal: Nat Med Date: 1999-06 Impact factor: 53.440
Authors: David J Kennedy; W H Wilson Tang; Yiying Fan; Yuping Wu; Shirley Mann; Michael Pepoy; Stanley L Hazen Journal: J Am Heart Assoc Date: 2013-04-04 Impact factor: 5.501
Authors: Arthur McCullough; Stephen F Previs; Jaividhya Dasarathy; Kwangwon Lee; Abdullah Osme; Chunki Kim; Serguei Ilchenko; Shuhui W Lorkowski; Jonathan D Smith; Srinivasan Dasarathy; Takhar Kasumov Journal: Am J Physiol Endocrinol Metab Date: 2019-09-10 Impact factor: 4.310