Paraoxonase and HDL Qualities in Glycaemia and Inflammation

NCT ID: NCT02169518

Last Updated: 2023-04-12

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 600 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2012-07-05
• Study Completion Date: 2030-01-31

Brief Summary

The incidence of coronary heart disease (CHD) is significant in the super-obese and diabetics.

Inflammation is believed to play an important part in the development of CHD, and the large collection of abdominal fat in the obese person is a vast source of inflammation. Diabetics have abnormal glucose and cholesterol metabolism which ultimately compromise their bodies' circulatory system and nerve function.

Cholesterol plays a vital role in CHD. Low-density lipoprotein (LDL) particles carry cholesterol and deposit it in blood vessel walls which become damaged as a result. When LDL particles undergo changes chemically (called oxidation) or as a result of high circulating blood glucose (called glycation), they become more harmful to the body. High-density lipoprotein (HDL) particles have a protective function in CHD. Not only do they transport cholesterol away from the blood vessels to the liver to be broken down, they have properties against oxidation and inflammation. These properties are related to the activity of an enzyme on HDL called paraoxonase 1(PON1).

Super-obese patients are increasingly treated by weight-reducing surgery (bariatric surgery). In this study we examine whether weight loss following bariatric surgery results in reduced inflammatory state, improved HDL function (higher PON1 activity), better control of blood glucose and less nerve damage.

We will study PON1 activity, inflammation and glucose control in patients with type 1 diabetes (with and without kidney damage) and type 2 diabetes. We will also study the effects of rapidly rising blood glucose levels on PON1 and glycated LDL in patients undergoing oral glucose tolerance test.

Detailed Description

High-density lipoprotein (HDL) is known to have a protective role in cardiovascular disease. Apart from transporting cholesterol from peripheral blood vessels back to the liver where it is processed, HDL has the ability to inhibit chemical changes (called oxidation) to low-density lipoprotein (LDL) which would make the latter more toxic to the body. HDL can also stop inflammatory particles from damaging the vessel walls. The anti-oxidation and anti-inflammatory properties of HDL are associated with an enzyme on HDL called paraoxonase 1 (PON1). It is not the level of measured HDL but the level of PON1 activity that is important in preventing cardiovascular disease. PON1 activity determines the quality of HDL and the effect against vascular disease.

Obese patients accumulate most of the fat within their abdomen (termed visceral fat). It is known that visceral fat produces large quantities of inflammatory particles so that obese patients have increased systemic inflammation and thus higher risk of vascular disease. The impact of heightened inflammatory status on HDL functions and PON1 activity is not known. Weight-reducing (bariatric) surgery can result in significant weight loss in obese patients. It is unclear whether the weight loss is associated with improvement in HDL functions, possible reversal of lipoprotein abnormalities and other physiological parameters. We plan to study a population of obese patients scheduled to have bariatric surgery before and after the surgery and compare the results with a matching population of healthy control patients.

Diabetic patients are at increased risk of developing cardiovascular disease. HDL in diabetic patients is often dysfunctional. Even though HDL levels are normal, PON1 activity may be reduced. LDL is able to interact with raised levels of blood glucose (called glycation) and become more harmful to the body. Glycation of lipoproteins associated with PON1 may affect PON1 activity. We plan to study glycated lipoproteins and PON1 activity in a population of diabetic patients who have either type 1 or type 2 diabetes. Some of the type 1 diabetics will have diabetic kidney disease, these patients are known to be particularly at high risk of cardiovascular complications. We also plan to recruit a cohort of patients who do not have diabetes but who have had an abnormal blood glucose test. These patients will be having an oral glucose tolerance test (OGTT) which establishes whether they have diabetes. During the OGTT, patients are given an oral glucose load which results in a rapid rise in blood glucose. We will see if this accelerated change in blood glucose level has any effects on the glycation of lipoproteins.

Conditions

Diabetes Mellitus; Bariatric Surgery Candidate

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: OTHER

Study Groups

Diabetes Arm

Patients with Type 1 and Type 2 diabetes

No interventions assigned to this group

Bariatric Arm

Obese patients scheduled for bariatric surgery

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patients with Type 1 diabetes who are not receiving lipid-lowering drugs, omega fatty acid supplements or thiazolidinediones and without clinical and/or ECG evidence of CHD.

Type 2 diabetic patients who are not receiving omega fatty acid supplements or thiazolidinediones and without clinical and/or ECG evidence of CHD.

Patients with impaired fasting glucose undergoing oral glucose tolerance test. Patients scheduled for bariatric surgery. Healthy controls who have no major acute or chronic illness, are not receiving regular medication and not taking omega fatty acid supplements, do not have clinically overt ischaemic heart disease.

Subjects (male and female) aged between 20 and 75. Subjects who have capacity and understanding for informed consent process.

Exclusion Criteria

• Type 1 diabetics using lipid lowering therapy, thiazolidinediones, omega fatty acid supplements. History and/or ECG evidence of ST segment changes indicative of CHD.

Type 2 diabetics receiving thiazolidinediones, omega fatty acid supplements. History and/or ECG evidence of ST segment changes indicative of CHD.

Healthy controls who have any history of CHD, vascular insufficiency, or diabetes. Use of any lipid-lowering drug or omega fatty acid supplements.

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

British Heart Foundation

OTHER

Sponsor Role: collaborator

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

Manchester University NHS Foundation Trust

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Handrean Soran, MD FRCP

Role: PRINCIPAL_INVESTIGATOR

Manchester University NHS Foundation Trust

Locations

Central Manchester University Hospitals NHS Foundatioon Trust

Manchester, Lancashire, United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Handrean Soran, MD FRCP

Role: CONTACT

hsoran@aol.com

01612764843

See Kwok, MD FRCGP

Role: CONTACT

sk7@doctors.org.uk

01612768863

Facility Contacts

Jonathan Schofield, MRCP

Role: primary

jschofield@doctors.org.uk

07866529898

See Kwok, MD FRCGP

Role: backup

sk7@doctors.org.uk

01612768863

References

Yadav R, Hama S, Liu Y, Siahmansur T, Schofield J, Syed AA, France M, Pemberton P, Adam S, Ho JH, Aghamohammadzadeh R, Dhage S, Donn R, Malik RA, New JP, Jeziorska M, Durrington P, Ammori BA, Soran H. Effect of Roux-en-Y Bariatric Surgery on Lipoproteins, Insulin Resistance, and Systemic and Vascular Inflammation in Obesity and Diabetes. Front Immunol. 2017 Nov 15;8:1512. doi: 10.3389/fimmu.2017.01512. eCollection 2017.

Reference Type: DERIVED

PMID: 29187850 (View on PubMed)

Other Identifiers

PON2011

Identifier Type: -

Identifier Source: org_study_id