SLMS Academic Careers Office

Grand Challenges

11. Understanding the mechanisms of insulin secretion in patients with HADH mutations

Supervisor Pair: Dr Khalid Hussain and Dr Simon Eaton
Potential Student’s Home Department: Clinical and Molecular Genetics Unit, Institute of Child Health

Pancreatic beta-cells secrete insulin in response to glucose, amino acids and fatty acids. Glucose metabolism is the key for glucose induced insulin secretion and amino acids (such as leucine) control insulin secretion by regulating the activity of the enzyme glutamate dehydrogenase. The mechanism/s of how fatty acids control insulin secretion is unclear. Our preliminary clinical and biochemical data have shown that the enzyme Short Chain 3-Hydroxy-Acyl-CoA Dehydrogenase (HADH) plays a key role in regulating both fatty acid and amino acid induced insulin secretion. We have identified patients with HADH mutations that have defects in fatty acid and amino acid induced insulin secretion. However the molecular mechanisms of how HADH mutations lead to abnormalities in insulin secretion are still unclear. This project will focus on trying to unravel the genetic and biochemical basis of insulin secretion in patients with defects in HADH.

This project addresses human wellbeing. Our clinical observations on patients with HADH mutations have provided fundamental new insights into how insulin secretion is regulated by fatty acid and amino acid metabolism. We have shown for the first time that a defect in fatty acid oxidation (HADH deficiency) makes patients hypersensitive to the amino acid leucine (JCEM 2010, Orphanet J Rare Dis 2012). These clinical observations have important implications for patient management (preventing hypoglycaemia by restricting protein in the diet) and have unravelled a new biochemical pathway involved in regulating insulin secretion by fatty acid oxidation and amino acid metabolism.