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Final Report Summary - INSGEN (The incretin system: From genetic determinants to impact on early development of type 2 diabetes in the population)

The overall research objective was to establish a new understanding of how disturbances in the gut incretin system interact with genetic and pathophysiological mechanisms to drive the development of type 2 diabetes. To accomplish this I have carried out a unique combination of state-of-the-art phenotyping and genotyping in a large, well-characterized cohort (Addition-Pro) of individuals at key stages of increased diabetes risk. This cohort includes 2,082 individuals who have undergone an extensive examination including detailed characterization of glycemic status based on a 3-point oral glucose tolerance test (OGTT). The specific research objectives were:
1. To determine the effect of genetic variants on the gut incretins and glucagon responses during a 3-point oral glucose challenge.
2. To validate new potential targets for individualized prevention and treatment of type 2 diabetes.
The incretin hormones (GLP-1 and GIP) are secreted from the gut in response to food intake and their primary role is to amplify nutrient-induced insulin release. Most of this effect is lost in obesity and type 2 diabetes. Glucagon acts as a counter-regulatory hormone to insulin and may therefore also be essential in type 2 diabetes pathophysiology.
I have genotyped a large panel of more than 500,000 genetic markers in 2,082 individuals with varying levels of glucose tolerance, either normal glucose tolerance, impaired fasting glycaemia, impaired glucose tolerance or type 2 diabetes. In addition, I have measured plasma levels of GLP-1, GIP and glucagon at 0, 30 and 120 minutes during an oral glucose tolerance test in the same individuals. I have then examined the effect of these genetic markers on incretin and glucagon levels during the oral glucose challenge. After imputation of genotypes, a total of 30.8 million markers have been analyzed for each phenotype in a so called genome-wide association study (GWAS). The results of the GWASs were followed up in a family-based study including 249 individuals and a cohort of 553 children to mothers with gestational diabetes. Both replication cohorts consisted of individuals of Danish descent and an increased risk of developing type 2 diabetes. In addition to measurements on glucose, insulin, GLP-1, GIP and glucagon during the OGTT, we have also performed metabolic measurements using the NMR technique at all three time points in the original cohort.
We investigated the role of glucose-stimulated release of GLP-1 in the development of type 2 diabetes and obesity and found that compared to individuals with normal glucose tolerance, individuals with pre-diabetes or type 2 diabetes had lower GLP-1 concentrations during the OGTT, independent of age and obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes (Færch et. al. Diabetes 2015;64:2513-2525).
We examined the association between GIP and lipid metabolism in individuals with low to high risk of developing type 2 diabetes and assessed whether the associations were modified by or mediated through insulin. The result showed that GIP may be associated with improved low-density lipoprotein clearance, but with an unhealthy fat distribution independent of insulin. The effect of GIP on obesity measures was substantially different between men and women. The potential effect of GIP on visceral and subcutaneous adipose tissue physiology warrants further examination (Møller J Clin Endocrinol Metab 2016;101(2):485-493).
Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaption to insulin resistance. The results indicated that increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia, but also on the ability to suppress glucagon early after glucose intake (Færch et. al. under review in Diabetes).
Large-scale GWASs have up to date successfully identified 68 validated genetic determinants of type 2 diabetes. For many of those validated variants, it is unclear through which mechanisms they exert their effect and little is known whether these genes also affect incretin levels and/or alpha-cell function. I examined the impact of known type 2 diabetes associated variants on the circulating levels of GLP-1, GIP and glucagon during the OGTT. We did not observe any significant associations of the 68 known type 2 diabetes risk variants with circulating plasma levels of GLP-1, GIP or glucagon during the oral glucose challenge after adjusting for the number of tests performed. However, we found nominal associations for 19 out of the 68 variants with either one or several of the investigated phenotypes (manuscripts under preparation).
The analyses of the GWASs for circulating levels of GLP-1, GIP and glucagon during the OGTT have been completed and we have a few genome-wide significant signals we would like to follow up on in further cohorts. Based on the acquired genotypes, we have also calculated the heritability of the three hormones in the Addition-Pro cohort. Heritability is usually estimated in family based cohorts, but with the use of a Genetic Relatedness Estimation through Maximum Likelihood model (GREML), it can be estimated out of GWAS data. We found heritabilities that were lower than those estimated from family studies, which might be due to inflated estimates in the family based studies due to factors such as shared environment (manuscript under preparation). GWASs of the different metabolites are ongoing and a first manuscript on branched-chain amino acids is under preparation.

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