Does zinc-dependent regulation of sEH contribute to sex differences in diabetes and heart failure?

Code: BC-DTP_2026_56

Title: Does zinc-dependent regulation of sEH contribute to sex differences in diabetes and heart failure?

Primary Supervisor: Rebecca Charles

Email: r.charles@qmul.ac.uk

Institute: William Harvey Research Institute

Secondary Supervisor: Dunja Aksentijevic

Email: d.aksentijevic@qmul.ac.uk

Institute: William Harvey Research Institute

Lay Summary:

Diabetes develops when the body can no longer produce enough insulin to control blood sugar levels. Over time, this greatly increases the risk of heart disease and heart failure, especially in women, who we have recently shown develop more severe diabetes-related heart muscle problems and poorer recovery after heart attacks. However, the biological reasons behind these sex differences remain unclear.

This project focuses on zinc, a natural metal released together with insulin from specialised pancreatic beta cells. Zinc was recently discovered to block the activity of an enzyme called soluble epoxide hydrolase (sEH), which regulates lipid molecules involved in cell function and stress responses. We have created a mouse model in which sEH cannot be blocked by zinc. Surprisingly, these mice are better protected from diabetes: they clear sugar from the blood more quickly and have healthier insulin-producing cells. We have also established male and female models of diabetic heart disease that mirror key features of human diabetic cardiomyopathy.

The aim of this research is to understand why preventing zinc from blocking sEH improves insulin production, and whether this process works differently in males and females with diabetes. By studying insulin-producing cells, whole-body sugar control, and heart function, we will investigate how zinc, insulin release, and sEH interact during diabetes.

By uncovering a previously unrecognised way in which zinc affects insulin-producing cells, this research may help explain why diabetes harms men and women differently and could guide the development of new treatments that protect the pancreas and reduce the risk of heart disease.

Aims:

Aim 1: Define how zinc–sEH interactions regulate β-cell function and insulin secretion.

Aim 2: Determine whether zinc–sEH–EET signalling underlies sex differences in β-cell biology and diabetes risk.

Aim 3: Test whether preventing zinc-mediated sEH inhibition protects against diabetic cardiomyopathy in a sex-specific manner.

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