Characterization of human islet cells: functional and transcriptional studies
Lead Research Organisation:
University of Oxford
Department Name: RDM OCDEM
Abstract
Pancreatic islets play a central role in plasma glucose regulation. They do so by secreting several hormones with key role in glucose homeostasis. In addition, the islet delta-cells secrete somatostatin, a peptide hormone that inhibits both insulin and glucagon release. Type-2 diabetes involves disturbances of both insulin and glucagon release.
Studies on rodent islets have revealed the fundamental principles about how changes in plasma glucose levels stimulate or inhibit pancreatic islet hormone secretion. It is generally assumed ? without much justification - that data emanating from rodent studies can be extrapolated to man.
The Human Islet Transplantation Centre in Oxford is one of two islet isolation centres in the UK. Via this centre we now have regular supply of high-quality human pancreatic islets. Over the last two years, we have characterized the electrophysiological and secretory characteristics of human beta-cells. We have found that human beta-cells differ from mouse beta-cells in a number of important ways.
Collectively, the data obtained so far indicate that it is not possible to extrapolate rodent data to the situation in man. In order to understand the hormone secretion defects that associate with type-2 diabetes in man (rodent diabetes is a rare clinical disorder!), we require a much more detailed picture of the functional characteristics of human islet cells.
This information should be highly relevant in the ongoing efforts developing new antidiabetic medicines.
Studies on rodent islets have revealed the fundamental principles about how changes in plasma glucose levels stimulate or inhibit pancreatic islet hormone secretion. It is generally assumed ? without much justification - that data emanating from rodent studies can be extrapolated to man.
The Human Islet Transplantation Centre in Oxford is one of two islet isolation centres in the UK. Via this centre we now have regular supply of high-quality human pancreatic islets. Over the last two years, we have characterized the electrophysiological and secretory characteristics of human beta-cells. We have found that human beta-cells differ from mouse beta-cells in a number of important ways.
Collectively, the data obtained so far indicate that it is not possible to extrapolate rodent data to the situation in man. In order to understand the hormone secretion defects that associate with type-2 diabetes in man (rodent diabetes is a rare clinical disorder!), we require a much more detailed picture of the functional characteristics of human islet cells.
This information should be highly relevant in the ongoing efforts developing new antidiabetic medicines.
Technical Summary
Pancreatic islets play a central role in plasma glucose regulation. They do so by secreting several hormones with key role in glucose homeostasis. Among these, insulin with a hypoglycaemic action) from the beta-cells and glucagon (hyperglycaemic) from the alpha-cells are the two most important ones. In addition, the islet delta-cells secrete somatostatin, a peptide hormone that inhibits both insulin and glucagon release. Type-2 diabetes involves disturbances of both insulin and glucagon release.
Studies on islets isolated from rodent islets have revealed the fundamental principles about how changes in plasma glucose levels stimulate or inhibit pancreatic islet hormone secretion. The roles of pathways and proteins identified by such experiments have subsequently been characterized further in mouse models in which key proteins have been genetically ablated. It is assumed that data emanating from rodent studies can be extrapolated to man but this has not been unequivocally confirmed.
In parallel with the functional studies, efforts to elucidate the genetics of type-2 diabetes have been ongoing. The genome wide scan studies have revolutionized our understanding of the polygenic nature of type-2 diabetes and led to the identification of several novel diabetes genes. However, the interpretation of the genetic data depends heavily on information about gene expression. Obviously, a gene variant is unlikely to affect islet cell function directly if it is not expressed in the islet and vice versa.
We will i) determine gene transciption in islet cells to document the complements of ion channels, membrane receptors and other genes of interest, ii) perform an electrophysiological characterization of human islet cells and iii) study pancreatic islet hormone seretion from intact human islets in response to glucose in the absence and presence of ion channel and receptor agonists/antagonists.
Studies on islets isolated from rodent islets have revealed the fundamental principles about how changes in plasma glucose levels stimulate or inhibit pancreatic islet hormone secretion. The roles of pathways and proteins identified by such experiments have subsequently been characterized further in mouse models in which key proteins have been genetically ablated. It is assumed that data emanating from rodent studies can be extrapolated to man but this has not been unequivocally confirmed.
In parallel with the functional studies, efforts to elucidate the genetics of type-2 diabetes have been ongoing. The genome wide scan studies have revolutionized our understanding of the polygenic nature of type-2 diabetes and led to the identification of several novel diabetes genes. However, the interpretation of the genetic data depends heavily on information about gene expression. Obviously, a gene variant is unlikely to affect islet cell function directly if it is not expressed in the islet and vice versa.
We will i) determine gene transciption in islet cells to document the complements of ion channels, membrane receptors and other genes of interest, ii) perform an electrophysiological characterization of human islet cells and iii) study pancreatic islet hormone seretion from intact human islets in response to glucose in the absence and presence of ion channel and receptor agonists/antagonists.
