Interaction of intracellular CD59 isoform IRIS-1 with DNA in pancreatic islets- a potential involvement in regulation of gene transcription
(2023) MOBN02 20231Degree Projects in Molecular Biology
- Abstract
- Type 2 diabetes is a growing health problem. 537 million people had diabetes in 2021 and the number is continuously increasing. Our group previously showed that the isoforms of the complement inhibitor CD59, named IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are localized in the cytoplasm of pancreatic ß-cells, where they are needed for insulin secretion. A downregulation in the protein level expression of IRIS-1 and 2 has been seen in islets isolated from type 2 diabetes donors, as compared to healthy, age-matched controls, suggesting that hyperglycemia and subsequent decrease in IRIS-1/2 expression may lead to relative insulin deficiency seen in type 2 diabetic patients. IRIS-1 was also found to be localizing in the... (More)
- Type 2 diabetes is a growing health problem. 537 million people had diabetes in 2021 and the number is continuously increasing. Our group previously showed that the isoforms of the complement inhibitor CD59, named IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are localized in the cytoplasm of pancreatic ß-cells, where they are needed for insulin secretion. A downregulation in the protein level expression of IRIS-1 and 2 has been seen in islets isolated from type 2 diabetes donors, as compared to healthy, age-matched controls, suggesting that hyperglycemia and subsequent decrease in IRIS-1/2 expression may lead to relative insulin deficiency seen in type 2 diabetic patients. IRIS-1 was also found to be localizing in the nuclei of the ß-cell, where it possibly interacts with DNA and affects the expression of various genes. In this thesis, we investigated a function of nuclear IRIS-1 in ß-cells. Immunofluorescent staining followed by sub-cellular fractionation and proximity ligation assay confirmed IRIS-1 nuclear localization. Intact IRIS-1 was found in the nuclei. We have also subjected healthy and T2D islets to high glucose and palmitic acid concentrations to stimulate glucotoxicity, gluco-lipotoxicity and ER stress. Obtained results indicate translocation of IRIS-1 from the nucleus during diabetic conditions. Nuclear IRIS-1 seems to act as a transcription factor in the ß-cells, however further studies are needed to confirm this. Expression of ß-cells maturation markers was significantly higher in IRIS-1 overexpressing cells, as compared to CD59 KO, suggesting that IRIS-1 might be needed for maintaining mature and functional ß-cells. Further studies are needed in order to fully understand functions of nucleic IRIS-1, which could in the future lead to new therapeutics maintaining healthy ß-cells (Less)
- Popular Abstract
- Involvement of nuclear IRIS-1 in beta cells function and diabetes
In 2021 537 million adults suffered from diabetes, with this number continuously rising. Type 2 diabetes makes up 90 – 95 % of all diabetes cases and is caused by insufficient insulin secretion by the pancreas or when the body stop responding to produced insulin. Prolonged high blood glucose level is the main characteristic of diabetes, and if left untreated may cause organs damage and premature death. The current treatments of type 2 diabetes are insufficient, often ending up with insulin injections, therefore new therapeutics are needed.
IRIS-1 and IRIS-2 proteins are new variants of the CD59 protein and are found inside the insulin producing beta cells in the... (More) - Involvement of nuclear IRIS-1 in beta cells function and diabetes
In 2021 537 million adults suffered from diabetes, with this number continuously rising. Type 2 diabetes makes up 90 – 95 % of all diabetes cases and is caused by insufficient insulin secretion by the pancreas or when the body stop responding to produced insulin. Prolonged high blood glucose level is the main characteristic of diabetes, and if left untreated may cause organs damage and premature death. The current treatments of type 2 diabetes are insufficient, often ending up with insulin injections, therefore new therapeutics are needed.
IRIS-1 and IRIS-2 proteins are new variants of the CD59 protein and are found inside the insulin producing beta cells in the pancreas. Both IRIS-1and 2 are located in the cytoplasm of the beta cells, where they help in transport/ secretion of insulin by interacting with other proteins, called SNAREs known to be involved in this process. We previously noticed that in islets isolated from people with type 2 diabetes the expression of IRIS-1 and IRIS-2 is lower than in healthy controls, suggesting that low levels of IRIS-1 and 2, and therefore lower insulin secretion, can be involved in type 2 diabetes development. However, IRIS-1 was also found in the nucleus of the beta cells, where it possibly interacts or controls the genes connected to diabetes.
In current project, the function of nuclear IRIS-1 and its involvement in diabetes development was investigated. A series of assays were performed on rat beta cells expressing human IRIS-1 to confirm the location of the IRIS-1 protein inside the nucleus. The experiments confirmed IRIS-1 presence inside the nucleus. To find its possible involvement in diabetes, islets from healthy and type 2 diabetic donors were treated with high glucose concentrations to mimic diabetic conditions. Results showed that nuclear IRIS-1 moves towards the cytoplasm, with only a small percentage of IRIS-1 staying in the nucleus during diabetic conditions. We also found that cells expressing IRIS-1 have signifyingly more of beta cells markers, suggesting the nuclear IRIS-1 might be needed to maintain the beta cells in its mature and functional state, which is needed for insulin secretion.
The exact functions of nuclear IRIS-1 still need to be explored. Understanding its function would give a possibility to develop new medicines against diabetes.
Master’s Degree Project in Molecular Biology 45 credits 2023
Department of Biology, Lund University
Advisor: Prof. Anna Blom and Dr. Ewelina Golec
Department of Translational Medicine, University Hospital, Malmö (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9140773
- author
- Karlsson, Maja
- supervisor
-
- Anna Blom LU
- Ewelina Golec LU
- organization
- course
- MOBN02 20231
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9140773
- date added to LUP
- 2023-11-02 11:38:08
- date last changed
- 2023-11-02 11:38:08
@misc{9140773,
abstract = {{Type 2 diabetes is a growing health problem. 537 million people had diabetes in 2021 and the number is continuously increasing. Our group previously showed that the isoforms of the complement inhibitor CD59, named IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are localized in the cytoplasm of pancreatic ß-cells, where they are needed for insulin secretion. A downregulation in the protein level expression of IRIS-1 and 2 has been seen in islets isolated from type 2 diabetes donors, as compared to healthy, age-matched controls, suggesting that hyperglycemia and subsequent decrease in IRIS-1/2 expression may lead to relative insulin deficiency seen in type 2 diabetic patients. IRIS-1 was also found to be localizing in the nuclei of the ß-cell, where it possibly interacts with DNA and affects the expression of various genes. In this thesis, we investigated a function of nuclear IRIS-1 in ß-cells. Immunofluorescent staining followed by sub-cellular fractionation and proximity ligation assay confirmed IRIS-1 nuclear localization. Intact IRIS-1 was found in the nuclei. We have also subjected healthy and T2D islets to high glucose and palmitic acid concentrations to stimulate glucotoxicity, gluco-lipotoxicity and ER stress. Obtained results indicate translocation of IRIS-1 from the nucleus during diabetic conditions. Nuclear IRIS-1 seems to act as a transcription factor in the ß-cells, however further studies are needed to confirm this. Expression of ß-cells maturation markers was significantly higher in IRIS-1 overexpressing cells, as compared to CD59 KO, suggesting that IRIS-1 might be needed for maintaining mature and functional ß-cells. Further studies are needed in order to fully understand functions of nucleic IRIS-1, which could in the future lead to new therapeutics maintaining healthy ß-cells}},
author = {{Karlsson, Maja}},
language = {{eng}},
note = {{Student Paper}},
title = {{Interaction of intracellular CD59 isoform IRIS-1 with DNA in pancreatic islets- a potential involvement in regulation of gene transcription}},
year = {{2023}},
}