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.

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.

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

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.