PDE3B in Metabolic Regulation

Not yet recruiting

• Conditions: Cardiometabolic Syndrome; Cardiovascular Diseases; Type 2 Diabetes

• Registration Number: NCT06533007
• Lead Sponsor: Cambridge University Hospitals NHS Foundation Trust

Brief Summary

Phosphodiesterase 3B (PDE3B), an enzyme responsible for the degradation of cyclic AMP and GMP (two important second messengers used for intracellular signal transduction), has been associated with cardiometabolic outcomes. Results from animal studies indicate that abolishing PDE3B function may be associated with unfavourable metabolic profile; however, preliminary human studies suggest that heterozygous loss of function (LoF) variants in the PDE3B gene have been associated with cardiometabolic improvements. Therefore, the effect of PDE3B on human adipose tissue metabolic pathways remains poorly understood.

Accordingly, the investigators propose to conduct a recall-by-genotype, case-control study in a group of people with LoF variants in the PDE3B gene and a matched group without the variant (wild type, WT) to determine differences on key metabolic features: 1) adipose tissue biology (i.e., mitochondrial function, adipocyte morphology, gene expression and in vivo lipolysis in the basal and/or the insulin-stimulated state); 2) systemic lipid and glucose metabolism using the hyperinsulinemic-euglycemic clamp procedure.

The proposed investigations will elucidate the role of PDE3B on adipose tissue and systemic glucose and lipid metabolism in humans and whether modulating PDE3B activity constitutes a target for the prevention and treatment of cardiometabolic disease.

Detailed Description

Phosphodiesterase 3B (PDE3B) is a protein that plays a role in how cells handle nutrients (i.e. glucose and fats). The investigators have recently found that people who have a gene variant (i.e., change in the DNA) that reduces the function of the PDE3B protein may be protected from the development of diabetes and heart disease. However, it is unclear how this happens.

The aims of this study are to examine:

* What is the role of PDE3B in fat tissue function?

* How does PDE3B influence the way one's body handles blood sugars and lipids?

To this end, the investigators propose to study people who have a variant that reduces the function of that PDE3B and an equal number of people with the typical genotype.

Participants will be asked to attend two visits:

* a 4-h screening visit: involving a medical examination, blood tests before/after drinking a sugary drink and assessment of lifestyle (physical activity/sleep/diet) using questionnaires and smartwatch.

* a 24-h metabolic testing visit (only for eligible participants): involving an infusion of insulin and collection of blood samples and fat tissue from the lower tummy.

These investigations will provide a great opportunity to study how people with or without the variant handle fat, sugars and lipids in their bodies. They will also help the scientific community to understand the role of PDE3B in humans and possibly develop new ways to prevent or fight conditions like diabetes and heart disease.

Study Timeline

• Status Verified: 2024-07
• Study First Submitted: 2024-07-17
• Study First Submitted QC: 2024-07-29
• Last Update Submitted: 2024-07-29
• Study First Posted: 2024-08-01
• Last Update Posted: 2024-08-01
• Study Start: 2024-09
• Primary Completion: 2028-09
• Study Completion: 2029-09

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• willing and able to give informed consent for participation in the study
• aged 21-75 years
• men and women

Exclusion Criteria

• unstable weight (>5% change the last 2 months)
• type 2 diabetes or other major organ dysfunction
• cancer in last 5 years
• gastrointestinal or bariatric surgery (except cholecystectomy and appendectomy)
• conditions that render subject unable to complete all testing procedures (including individuals with known allergies or contraindications to the medications used in this study)
• use of medications that affect the study outcome measures or increase the risk of study procedures and that cannot be temporarily discontinued
• smoking
• illegal drug use
• pregnant or lactating
• unable to grant voluntary informed consent or comply with the study instructions

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Lipolysis	baseline	Lipolysis will be assessed as the palmitate rate of appearance by using infusion of stable isotope tracers.

Secondary Outcome Measures

Name	Time	Method
Insulin sensitivity	baseline	Insulin sensitivity will be assessed by using a hyperinsulinemic euglycemic clamp procedure in conjunction with infusion of stable isotope tracers.
Insulin secretion	baseline	Insulin sensitivity will be assessed by using an oral glucose tolerance test
Adipose tissue gene expression	baseline	Changes in the expression of genes will be assessed by using RNA sequencing