Physiological investigation of causal genetic variants in metabolic disease

Thesis

Type 2 diabetes (T2D) is a leading cause of morbidity and mortality. Understanding the molecular pathways that regulate glucose control and weight regulation may help predict disease course and develop novel interventions to improve health outcomes. In this thesis, I use naturally occurring genetic variation in combination with physiological tests to interrogate molecular pathways implicated in metabolic disease. Specifically, I examine impact of T2D risk alleles in peptidylglycine alpha-amidating monooxygense (PAM) on glucose physiology and the impact of phosphate and tensing homologue (PTEN) haploinsufficiency on brown adipose tissue function (BAT) and insulin sensitivity.

In Chapter 3, I demonstrate that carriers of loss of function alleles (LoF) in PAM have altered serum PAM activity and increased glucagon-like peptide-1 (GLP-1) concentrations in the postprandial period. Based on the similar glycaemic profiles despite significantly increased GLP-1 concentration, I speculate that these results may be due to GLP-1 resistance. In Chapter 4, I perform a prospective study to determine if PAM regulates GLP-1 resistance. I demonstrate that carriers of the LoF allele, S539W, have altered PAM activity, increased postprandial GLP-1 concentration but no difference in the incretin effect, suggesting GLP-1 resistance. I show that carriers of both alleles have a clinically meaningful reduction in response to GLP-1 receptor agonists but no other oral hypoglycaemic agents. I conclude that this may facilitate personalised medication choice in T2D.

In Chapter 5, I explore the role of PTEN in BAT regulation. I recruited individuals with PTEN haploinsufficiency which causes Cowden syndrome (CS). I demonstrate that individuals with CS have significantly reduced skin temperature overlying the supraclavicular BAT deposits, reduced maximal cold induced energy expenditure and reduced cold tolerance. I attribute this to reduced BAT function. I conclude that PTEN positively regulates BAT and that reduction in BAT activity contributes to the obesity phenotype seen in individual with CS.

In Chapter 6, I characterised an individual with mosaic CS to assess the importance of tissue specific regulation of the PTEN/PI3K/AKT pathway. I show that the percentage mosaicism in muscle and fat is in keeping with the impact on whole body insulin sensitivity.

In conclusion, I used a combination of physiological and genetic tools to determine how pathways under genetic regulation alter metabolic traits. The results of these studies have added to the understanding of the regulation of GLP-1 and BAT physiology and provide information that may help personalise treatment of T2D in the future and I validate PTEN as a regulator and potential target for activating BAT.

Authors: Umapathysivam, MM

• DOI: 10.5287/ora-qrgb4bka2
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: diabetes; infra-red thermographydiabetes; genetics; brown adipose tissue; pharmocogenetics; PAM; physiology; PTEN