December 4, 2017

People with Diabetes May Be Missing Out on HDL Cardiovascular Protections

Glycation lowers ApoA1 stability, destroys HDL in T2DM


A Cleveland Clinic study for the first time revealed a mechanism that rapidly destroys high-density lipoprotein (HDL) in people with Type 2 diabetes, negating cardiovascular protections of the so-called good cholesterol.


Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Sangeeta Kashyap, MD, in Cleveland Clinic’s Endocrinology & Metabolism Institute, and co-author Jonathan D. Smith, PhD, the Geoffrey Gund Endowed Chair for Cardiovascular Research in the Department of Cellular & Molecular Medicine in the Lerner Research Institute, and senior author Takhar Kasumov, PhD, adjunct in Gastroenterology and Hepatology at Cleveland Clinic and fulltime faculty at NEOMED, published a clinical research article in The Journal of Clinical Endocrinology & Metabolism.

The study, “Glycation Reduces the Stability of APOAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes,” looks at the role of hyperglycemia-induced glycation on ApoA1 kinetics and stability in patients with diet-controlled type 2 diabetes mellitus (T2DM).

Derailing ApoA1

The study found that in people with diabetes, glycation of the ApoA1 molecule causes it to degrade three times faster than in a person without diabetes.

“When ApoA1 is destroyed faster, it is not able to perform its main function for reverse cholesterol uptake, which means taking the bad cholesterol and disposing of it,” says study co-author Sangeeta Kashyap, MD. “The bottom line is that it does not just matter how much good cholesterol you have, but how the cholesterol works to protect you. In people with diabetes, good cholesterol does not work normally to protect them from atherosclerotic heart disease.”

From a clinical perspective, Dr. Kashyap says, the data highlights that normal, or even elevated, HDL levels in T2DM does not equate to adequate functionality. Glycation of ApoA1, she says, is a marker for hyperglycemia-induced HDL dysfunction that blunts the anti-atherogenic and anti-oxidant functions of HDL.


These findings were reached using 2H20-metabolic labeling – a novel heavy water-based non-radioactive technique that looks at the kinetics of HDL by measuring the production and destruction of ApoA1. They study also found ApoA1 instability is related to early glycation of lysine on ApoA1 and associated with glycated hemoglobin (HbA1c) levels – a measure of long-term hyperglycemia.

When Good Cholesterol Goes Bad

“The important clinical piece for practitioners is that even if you see normal or high HDL levels, don’t think it’s working in their favor,” Dr. Kashyap says. “If they have high blood sugar, that’s a marker that HDL is not working to protect them from the atherogenic process.

Dr. Kashyap says lowering glucose levels could be a way to restore HDL functionality in people with diabetes. While previous articles theorized that high triglycerides were related to good cholesterol, this study found that HDL functionality is related to ambient glucose levels.

Reversing the Damage

Next steps involve looking at various glucose lowering interventions, including the effects of the diabetic drug Metformin and insulin, to lower glucose levels.

“We’re interested in looking at specific interventions to lower glucose levels to see if these defects are reversible. We believe they are,” Dr. Kashyap says. “This is an early glycation process. If we are able to lower blood sugar levels, we can reverse levels of lysine glycation of ApoAI and restore functionality of HDL.”


Apo A1 turnover in Hyperglycemia

Reduced cholesterol efflux of glycated ApoA1

The study was supported by the American Diabetes Association.

Related Articles

August 10, 2023
Endocrinopathies from Checkpoint Inhibitors

Incidence, outcomes and management

Hyperglycemia in hospital setting
May 22, 2023
Multi-Pronged Strategies Key to Reducing Hospital-Related Hyperglycemic Events

Cleveland Clinic endocrinologists work to identify protocols for improving care

kidneys and diabetes
January 6, 2023
Kidney Disease in Diabetes: Updates and Recommendations

Cleveland Clinic’s Endocrinology & Metabolism Institute is working to offer novel opportunities and therapies for diabetes and kidney disease

Woman sleeping
April 29, 2022
Exploring the Relationship Between Sleep Amount and Type 1 Diabetes

New findings indicate the importance of achieving sufficient sleep levels in regard to personal glucose targets

March 31, 2022
Reexamining the Role of Preoperative Biochemical Values in Predictive Models in Primary Hyperparathyroidism

A recent study evaluates the correlation between preoperative calcium and parathyroid hormone values as predictors of gland volume and multi-gland disease

February 11, 2022
Elevated hCG Can Be a Benign Finding in Perimenopausal and Postmenopausal Women

A look at how to asses hCG elevation

Keto-friendly dish
January 13, 2022
Ketogenic Diets in the Management of Type 1 Diabetes: Safe or Safety Concern?

As the diet’s popularity rises, certain considerations need to be taken when recommending it for patients with Type 1 diabetes

Diabetes care
October 14, 2021
Systematic Review Reinforces the Importance of Empowering Non-Physician Providers in Diabetes Care

Findings suggest that the effectiveness of interventions may depend more on the frequency and delivery methods of the intervention rather than who is delivering the intervention