Mid-Term Report Summary - GENE TARGET T2D (General and targeted approaches to unravel the molecular causes of type 2 diabetes)
Type 2 diabetes (T2D) is the fastest increasing disease worldwide affecting 350 million people today with an estimated 550 million in 2030. This epidemic has been ascribed to a collision between genes and an affluent society. While genetics of T2D during recent years has identified > 60 variants increasing susceptibility to T2D, these variants explain only 15% of the heritability of T2D. The current project presents some novel approaches to dissect this missing heritability of T2D.
Given the rapid development of next generation sequencing technology, the sequencing part (general approaches) has been expanded to provide answers to some key questions, among them explanation of the best replicated linkage between T2D and a region on chromosome 18. This linkage was strongest in individuals with the highest BMI and we have now by exome sequencing identified the underlying genetic variation, which regulates expression of a non-coding RNA, and thereby expression of a protein involved in the development of T2D. At the time when the linkage studies were performed non-coding RNAs were unknown which explains why this has not been found before.
We have also applied a systems genetics approach of gene expression in human islets; the 20 top-ranked genes could explain 25% of the variance in HbA1c, which is 10 times more than could be seen only by studying genetic variation of HbA1c. We also provided the first genome-wide catalogue of allelic imbalance of expression and RNA editing events in human pancreatic islets. Among targeted approaches we have focused on the TCF7L2 gene, which shows the strongest association with T2D. By disrupting TCF7L2 in rat and human beta-cell lines we could demonstrate that not only synthesis of proinsulin is regulated by TCF7L2, but also processing of proinsulin and insulin in a genotype dependent manner. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing the strongest association with T2D.
After a meal, redistribution of blood flow from the periphery to the gut is thought to be influenced by the hormone GIP (glucose-dependent insulinotropic peptide). We hypothesize that alteration in splanchnic blood flow underlies the rapid resolution of T2D after gastric bypass surgery (GBP) and that GIP mediates these effects. We have now shown that GIP exerts such effects by altering pancreatic and islets blood flow.
To demonstrate that alterations in blood flow explain the normalisation of glucose tolerance after GBP we have collaborated with expertise in Finland measuring splanchnic blood flow using PET-MRI imaging (position-emission tomography combined with magnetic resonance imaging). Preliminary data show that pancreatic blood flow is altered by GIP-infusion and markedly influenced by GBP.
Given the rapid development of next generation sequencing technology, the sequencing part (general approaches) has been expanded to provide answers to some key questions, among them explanation of the best replicated linkage between T2D and a region on chromosome 18. This linkage was strongest in individuals with the highest BMI and we have now by exome sequencing identified the underlying genetic variation, which regulates expression of a non-coding RNA, and thereby expression of a protein involved in the development of T2D. At the time when the linkage studies were performed non-coding RNAs were unknown which explains why this has not been found before.
We have also applied a systems genetics approach of gene expression in human islets; the 20 top-ranked genes could explain 25% of the variance in HbA1c, which is 10 times more than could be seen only by studying genetic variation of HbA1c. We also provided the first genome-wide catalogue of allelic imbalance of expression and RNA editing events in human pancreatic islets. Among targeted approaches we have focused on the TCF7L2 gene, which shows the strongest association with T2D. By disrupting TCF7L2 in rat and human beta-cell lines we could demonstrate that not only synthesis of proinsulin is regulated by TCF7L2, but also processing of proinsulin and insulin in a genotype dependent manner. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing the strongest association with T2D.
After a meal, redistribution of blood flow from the periphery to the gut is thought to be influenced by the hormone GIP (glucose-dependent insulinotropic peptide). We hypothesize that alteration in splanchnic blood flow underlies the rapid resolution of T2D after gastric bypass surgery (GBP) and that GIP mediates these effects. We have now shown that GIP exerts such effects by altering pancreatic and islets blood flow.
To demonstrate that alterations in blood flow explain the normalisation of glucose tolerance after GBP we have collaborated with expertise in Finland measuring splanchnic blood flow using PET-MRI imaging (position-emission tomography combined with magnetic resonance imaging). Preliminary data show that pancreatic blood flow is altered by GIP-infusion and markedly influenced by GBP.