PDE3B in Metabolic Regulation

The Role of Phosphodiesterase 3B in the Regulation of Human Adipose Tissue Biology and Systemic Glucose and Lipid Homeostasis

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Cardiovascular Diseases; Type 2 Diabetes; Cardiometabolic Syndrome

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 Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Participants with heterozygous for PDE3B LoF variants will be recruited from existing research cohorts (i.e., the Oxford Biobank, the NIHR BioResource at the University of Cambridge and the Fenland study populations (1:700 frequency of the LoF variant). Subsequently, individuals without the variant of interest will be recruited from the same cohorts to establish a WT group of individuals matched for age, sex, race/ethnicity, and body fat percent.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
PDE3B LoF group; Individuals heterozygous for a loss-of-function variant in the PDE3B gene
Wild type group; Individuals who do not carry the loss-of-function variant for PDE3B gene but otherwise matched for age, sex, race/ethnicity, and body fat percent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipolysis	Lipolysis will be assessed as the palmitate rate of appearance by using infusion of stable isotope tracers.	baseline

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: July 17, 2024
• First Submitted That Met QC Criteria: July 29, 2024
• First Posted (Actual): August 1, 2024

Study Record Updates

• Last Update Posted (Actual): November 24, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Insulin Resistance; Hyperinsulinism; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Metabolic Syndrome
• Other Study ID Numbers: 343566

Drug and device information, study documents

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