The Influence of Genetic Variations in ELAPOR1 or ELAPOR2 on Insulin Secretion and Glucose Regulation in Humans
Study Details
Study Description
Brief Summary
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 a insulin and Insulin-like growth factor (IGF-1) resistance lead to the manifestation of type to diabetes. Underlying mechanism were still 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 his 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, which investigate, if functional mutations in these genes effect on 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 "healthy" reference cohort (matched for age, sex, waist to hip ratio and BMI) from our databases of previous studies (e.g. PLIS: NCT01947595, PREG: NCT04270578, KNOMA: NCT04950283).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Patients with rare genetic variant in ELAPOR1 or ELAPOR2 Patients undergo several examinations. Beside anthropometric measurements, bioelectrical impedance analysis, an 2h-oral glucose tolerance test (OGTT) and a hyperglycemic clamp is performed. |
Outcome Measures
Primary Outcome Measures
- Insulin secretion capacity [-15 minutes - 130 minutes]
Glucose stimulated insulin secretion adjusted for insulin sensitivity during an hyperglycemic clamp in subjects with genetic variants in ELAPOR1 and ELAPOR2 compared to a control cohort without genetic variants.
Secondary Outcome Measures
- Glucose tolerance status [0-120 minutes]
Glucose tolerance status examined by 2h-oral glucose tolerance test in subjects with genetic variants in ELAPOR1 and ELAPOR2 compared to a control cohort without genetic variants.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
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subjects with genetic variations in ELAPOR1 and ELAPOR2
Exclusion Criteria:
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Women during pregnancy and lactation
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Treatment with any medication effecting on glucose metabolism like anti-diabetic drugs or steroids
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Any pancreatic disease
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Known current presence or history of severe neurological or psychiatric diseases, schizophrenia, bipolar disorder
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hopsital Tübingen | Tübingen | Germany | 72076 |
Sponsors and Collaborators
- University Hospital Tuebingen
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- INCEPTOR