The Influence of Genetic Variations in ELAPOR1 or ELAPOR2 on Insulin Secretion and Glucose Regulation in Humans

Overview

Insulin resistance and the depletion of insulin secretion are major pathogenetic aspects of type 2 diabetes mellitus. Recently, inceptor, a receptor on the surface of beta cells was dicovered. Inceptor promotes beta cell resistance to insulin and IGF-1. In humans, the inceptor is encoded by the two genes ELAPOR1 and ELAPOR2. Whether functional mutations in these genes affect insulin secretion and glucose regulation in humans has not been investigated so far. In this study we investigate the influence of genetic variations in ELAPOR1 or ELAPOR2 on insulin secretion and glucose regulation in humans by hygerglycemic glucose clamp technique and oral glucose tolerance test respectively.

Type 2 diabetes mellitus is a heterogenic disorder with a complex pathogenesis. Although, loss of beta cell function is crucial for the manifestation of the disease. Genome-wide association studies identified more than 400 genetic variations associated with a reduced beta cell function. Interestingly, beta cells are not only responsible for the secretion of insulin, but are also insulin sensitive cells, whereby insulin secretion and proliferation is regulated. It is well known that an insulin and insulin-like growth factor (IGF-1) resistance lead to the manifestation of type 2 diabetes. Underlying mechanism are mostly unknown. Recently, a new receptor on the surface of beta-cells was identified which mediates the resistance of beta cells to insulin and IGF-1. This insulin inhibitory receptor (Inceptor) induces its inhibitory function via clathrin-mediated endocytosis of the INSR-IGF-1R complex. In mice, inceptor is encoded by lir and its knock-out leads to beta cell proliferation and an increased insulin secretion. In animal models, treatment with monoclonal antibodies against the extracellular domain of inceptor, leads to a significantly improved glucose regulation. Thus, pharmacological interventions on the inceptor could represent a novel therapeutic approach for the treatment of type 2 diabetes mellitus. In humans, inceptor is encoded by genes ELAPOR1 and ELAPOR2. So far, there are no studies in humans that investigate if functional mutations in these genes affect insulin secretion and glucose regulation. The aim of this study is to investigate, whether subjects with genetic variants in ELAPOR1 or ELAPOR2 have altered insulin secretion and thus altered glucose regulation. For this purpose, the study results are compared with a reference cohort without variants in ELAPOR1 or ELAPOR2 (matched for age, sex, waist to hip ratio and BMI) from our databases of previous studies (e.g. PLIS: NCT01947595, PREG: NCT04270578, KNOMA: NCT04950283). Insulin secretion is assessed by hyperglycemic glucose clamp technique. An oral glucose tolerance test will be performed to assess glucose tolerance.