Dissecting mechanisms involved in the aetiological overlap between Type 2 diabetes and cancer

Thesis

The advent of large scale genome wide association studies (GWAS) have uncovered a plethora of proposed susceptibility loci, most previously not connected to T2D pathogenesis. One of the most intriguing GWAS discoveries is the frequency with which T2D susceptibility loci map close to genes with roles in cell-cycle regulation. This previously unsuspected link between genes known for being dysregulated in cancer and T2D pathogenesis is supported by epidemiological evidence linking T2D and cancer. The aims of this thesis were to gain insight into T2D pathogenesis by studying specific examples involved in the complex interplay between T2D and cancer.

I investigated two loci already known for their roles in cancer pathogenesis: the tumour suppressor PTEN locus on chromosome 10 and the CDKN2A and CDKN2B locus at chromosome 9p21 (Chr9p21). PTEN is known to negatively regulate the phosphatidylinositol-3-kinase/AKT (PI3K-AKT) pathway which mediates many of the metabolic downstream effects of insulin signalling. Rodent data supports a role for PTEN in insulin action: tissue-specific Pten knockout and Pten haploinsufficient mice display improved glucose tolerance and insulin sensitivity. I recruited individuals with a rare cancer predisposition syndrome, Cowden syndrome, due to PTEN mutations and assessed their glucose homeostasis. Using oral glucose tolerance tests, euglycaemic hyperinsulinaemic clamp studies and adipose/muscle tissue biopsies, I have demonstrated that these PTEN haploinsufficient individuals display heightened insulin sensitivity and that this is via amplified signalling through the PI3K-AKT pathway.

The Chr9p21 T2D susceptibility loci are proximal to the tumour suppressors CDKN2A and CDKN2B. A noncoding RNA, ANRIL, is transcribed close to the regions of T2D association and a hypothesised mechanism for the T2D association is that the T2D variants affect ANRIL expression leading to altered CDKN2A/CDKN2B expression. Through a series of molecular studies I have demonstrated that ANRIL may have regulatory effects upon CDKN2A/CDKN2B expression in human islets. Although there is some rodent evidence suggesting a role for CDKN2A in regulation of beta-cell mass and glucose homeostasis, there is no direct evidence linking CDKN2A/B to glucose homeostasis in humans. I recruited individuals with rare CDKN2A mutations and performed oral and intravenous glucose tolerance tests to assess beta-cell function. The sample size precluded definitive conclusions but interesting trends were observed and further studies are planned. Collectively, the data presented in this thesis illustrate some mechanisms that may contribute to the aetiological overlap between T2D and cancer.

Authors: Pal, A

• Alternative title: Type 2 diabetes and cancer
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford