Glycation of apoA-I and Diabetic Atherogenesis

The Impact of Glycation Modification of apoA-I on HDL Function and Atherogenesis in Type Diabetes Mellitus

The goal of this study is to determine the relationship of apoprotein A-1 (apoA-I) glycation and development of diabetic atherosclerosis.

ApoA-I is crucial for reverse cholesterol transport and anti-inflammation/anti-atherosclersis functions of HDL. However, apoA-I is easily subjected to non-enzymatic glycation modification in diabetic milleu. Our preliminary study has shown that apoA-I in HDL from type 2 diabetes mellitus (T2DM) patients with coronary artery disease (CAD) is significantly glycated, and site specific glycation of apoA-I impairs HDL function and is related to the development of atherosclerosis. To the best of our knowledge, less clinical information regarding apoA-I glycation and CAD has been reported. In this cross-sectional study, by consecutively enrolling diabetic patients with (two to three hundred) or without CAD (controls, six to eight hundred) in our hospital, we will isolate their serum HDL and perform a qualitative and quantitative proteomic analysis of apoA-I glycation. The relation of apoA-I glycation and HDL function and angiography-determined severity of CAD will be evaluated. Later, we will follow these diabetic patients to analyze the influence of apoA-I glycation on the outcome including plaque progression.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Other: overnight fasting

Detailed Description

The goal of this study is to determine the relationship of apoprotein A-1 (apoA-I) glycation and development of diabetic atherosclerosis.

ApoA-I is crucial for reverse cholesterol transport and anti-inflammation/anti-atherosclersis functions of HDL. However, apoA-I is easily subjected to non-enzymatic glycation modification in diabetic milleu. Our preliminary study has shown that apoA-I in HDL from type 2 diabetes mellitus (T2DM) patients with coronary artery disease (CAD) is significantly glycated, and site specific glycation of apoA-I impairs HDL function and is related to the severity of atherosclerosis. To the best of our knowledge, less clinical information regarding apoA-I glycation and CAD has been reported. In this cross-sectional study, we will consecutively enroll several hundred diabetic patients (two to three hundred) with no CAD (less than stenosis of 25% in coronary CTA) as controls. And we will also consecutively enroll several hundred (six to eight hundred) angiographically established T2DM patients with CAD (stenosis of >50% in coronary angiography). Serum HDL of all participants will be isolated and a qualitative and quantitative proteomic analysis of apoA-I glycation will be performed by mass spectrometry. The relation of apoA-I glycaiton and HDL function and angioraphy-determined severity of CAD will be evaluated. Later, we will follow these diabetic patients for approximately two years to analyze the influence of apoA-I glycation on the clinical outcomes (stroke, myocardial infarction, hospitalization for heart failure, death due to cardiovascular causes, etc) including plaque progression.

• Study Type: Observational
• Enrollment (Actual): 2000

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital, Shanghai Jiaotong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study is a single-center cohort study. Patients with type 2 diabetes and suspected coronary artery disease undergone coronary angiography at Ruijin Hospital, Shanghai, China are consecutively enrolled.

Description

Inclusion Criteria:

Type 2 diabetes diagnosed by one of the following criteria:

HbA1c >/= 6.5% Fasting plasma glucose >/= 7.0 mmol/l (confirmed) 2h plasma glucose value during OGTT >/= 11.1 mmol/l Already receiving glucose-lowering agents; Receiving coronary angiography for clinically suspected CAD (T2DM with CAD), Receiving CCTA for suspected CAD or other causes (T2DM without CAD).

Exclusion Criteria:

Severe liver failure (Child-Pugh grade B to C)； Severe anemia (hemoglobin < 60g/L)； Familial hypercholesterolemia； Active malignant tumor； Active autoimmune diseases on corticosteroids； Acute or chronic infection； Death.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
T2DM with CAD; Diagnosis of T2DM was made according to the criteria of the American Diabetes Association. The patients were tested by angiography, with CAD diagnosed if luminal diameter narrowing was estimated visually at ≥50% in a major epicardial coronary artery.	Other: overnight fasting; All blood samples were taken on the day of cardiac catheterization after overnight fasting.
T2DM without CAD; Diagnosis of T2DM was made according to the criteria of the American Diabetes Association. These subjects had no history of ischemic heart disease (acute myocardial infarction, unstable angina, chronic stable angina, previous percutaneous or surgical coronary revascularization, heart failure) and received CCTA in the outpatient clinics due to suspected CAD or other causes. And the luminal diameter narrowing was estimated by CCTA at ≤30%.	Other: overnight fasting; All blood samples were taken on the day of cardiac catheterization after overnight fasting.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Qualitative and Quantitative Mapping ApoA-I Glycation Modification Profiles	One of aims is understanding the importance of apoA-I glycation modification in HDL dysfunction and the progression of diabetic CAD, a comprehensive analysis of apoA-I glycation modification requires numerous levels of information, including (1) the type of glycation modification, (2) glycation localization, (3) glycation frequency in the subject cohort, and (4) the extent of glycation. The other aim is identifying the crucial pathogenic glycation sites of apoA-I based on apoA-I glycation modification profiles. Defining the chemistry of the pathologic glycation sites of apoA-I during progression of CAD will allow us to target specific epitopes using therapeutic antibodies or small molecules at every stage of disease.	completion date - December 2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Individual ApoA-I Glycation Profiles Variability and Cardiovascular Events	Individual ApoA-I Glycation Profiles Variability is evaluated annually，and The incidence of MACCE (major adverse cardio and cerebral vascular events), lesion associated events (target lesion myocardial infarction, target lesion faliure, target vessel Revascularization, etc. observed continuously for 3 years.	December 2023

Collaborators and Investigators

• Sponsor: Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): December 1, 2021
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: December 11, 2022
• First Submitted That Met QC Criteria: December 11, 2022
• First Posted (Actual): December 21, 2022

Study Record Updates

• Last Update Posted (Actual): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 11, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Atherosclerosis
• Other Study ID Numbers: 81870357

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No