PDE3B in Metabolic Regulation

NCT06533007 | Enrolling By Invitation

• 1 other identifier: 343566
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes; Cardiometabolic Syndrome; Cardiovascular Diseases

Outcome Measures

Primary Outcomes (1)

• Lipolysis

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

  baseline

Secondary Outcomes (3)

• Adipose tissue gene expression

  baseline

• Insulin sensitivity

  baseline

• Insulin secretion

  baseline

Study Arms (2)

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.

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator

Study Sites (1)

Cambridge University Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Biospecimen

Retention: SAMPLES WITH DNA

blood samples and adipose tissue biopsies.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Metabolic Syndrome; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator and Lead for Human Nutrition

Study Record Dates

• First Submitted: July 17, 2024
• First Posted: August 1, 2024
• Study Start: September 1, 2025
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2029
• Last Updated: November 24, 2025

Record last verified: 2025-11

Locations

GB (1)