Type 2 diabetes mellitus (T2DM) is associated with oxidative stress and perturbed iron metabolism. Serotransferrin (Trf) and ceruloplasmin (Cp) are two key proteins involved in iron metabolism and anti-oxidant defense. Non-enzymatic glycation and oxidative modification of plasma proteins are known to occur under hyperglycemia and oxidative stress. In this study, shotgun proteomics and (2)H2O-based metabolic labeling were used to characterize post-translational modifications and assess the kinetics of Trf and Cp in T2DM patients and matched controls in vivo. Six early lysine (Amadori) and one advanced arginine glycation were detected in Trf. No glycation, but five asparagine deamidations, were found in Cp. T2DM patients had increased fractional catabolic rates of both Trf and Cp that correlated with HbA1c (p \textless 0.05). The glycated Trf population was subject to an even faster degradation compared to the total Trf pool, suggesting that hyperglycemia contributed to an increased Trf degradation in T2DM patients. Enhanced production of Trf and Cp kept their levels stable. The changes in Trf and Cp turnover were associated with increased systemic oxidative stress without any alteration in iron status in T2DM. These findings can help better understand the potential role of altered Trf and Cp metabolism in the pathogenesis of T2DM and other diseases.
Glycation Reduces the Stability of ApoAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes.
Creator
Kashyap Sangeeta R; Osme Abdullah; Ilchenko Serguei; Golizeh Makan; Lee Kwangwon; Wang Shuhui; Bena James; Previs Stephen F; Smith Jonathan D; Kasumov Takhar
Publisher
The Journal of clinical endocrinology and metabolism
Date
2018
2018-02
Description
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.
Temporal Dynamics of High-Density Lipoprotein Proteome in Diet-Controlled Subjects with Type 2 Diabetes.
Creator
Kheniser Karim G; Osme Abdullah; Kim Chunki; Ilchenko Serguei; Kasumov Takhar; Kashyap Sangeeta R
Publisher
Biomolecules
Date
2020
2020-03-30
Description
We examined the effect of mild hyperglycemia on high-density lipoprotein (HDL) metabolism and kinetics in diet-controlled subjects with type 2 diabetes (T2D). (2)H2O-labeling coupled with mass spectrometry was applied to quantify HDL cholesterol turnover and HDL proteome dynamics in subjects with T2D (n = 9) and age- and BMI-matched healthy controls (n = 8). The activities of lecithin-cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), and the proinflammatory index of HDL were quantified. Plasma adiponectin levels were reduced in subjects with T2D, which was directly associated with suppressed ABCA1-dependent cholesterol efflux capacity of HDL. The fractional catabolic rates of HDL cholesterol, apolipoprotein A-II (ApoA-II), ApoJ, ApoA-IV, transthyretin, complement C3, and vitamin D-binding protein (all p < 0.05) were increased in subjects with T2D. Despite increased HDL flux of acute-phase HDL proteins, there was no change in the proinflammatory index of HDL. Although LCAT and CETP activities were not affected in subjects with T2D, LCAT was inversely associated with blood glucose and CETP was inversely associated with plasma adiponectin. The degradation rates of ApoA-II and ApoA-IV were correlated with hemoglobin A1c. In conclusion, there were in vivo impairments in HDL proteome dynamics and HDL metabolism in diet-controlled patients with T2D.
Subject
apolipoproteins; HDL dysfunction; heavy water; proteomics; type 2 diabetes