Uppsala university: Faculty of Medicine: Department of medical cell biology: Research: Erik Gylfe

Physiology of pancreatic islet hormone secretion

Diabetes
Diabetes is widespread disease with rapidly increasing prevalence currently affecting >5 % of the world population. Diabetes is primarily due to insufficient or absent secretion of the blood glucose-lowering hormone insulin resulting in elevated blood glucose and glucose in the urine. Even if the acute symptoms of diabetes can be reversed by different therapies there are long-term complications like heart disease, stroke, kidney disease, eye complications with blindness, skin problems, nerve damage causing foot complications, gastrointestinal and sexual dysfunction.

Type 2 diabetes, which preferentially affects adult individuals, is the most common form and accounts for more than 90% of all diabetes. Type 2 diabetes is primarily characterized by insufficient insulin secretion from the pancreatic beta cells. Current therapy aims at maintaining or improving the secretory capacity of the beta cells and increasing the insulin sensitivity of the target organs. Elucidation of the mechanisms underlying insulin secretion and the malfunctions causing type 2 diabetes is expected to provide new strategies for restoring insulin secretion.

Type 1 diabetes mainly affects young individuals. It is a more severe disease than type 2 diabetes, since the beta cells are destroyed by an autoimmune attack. Apart from the lack of insulin, increased secretion of the blood glucose-elevating hormone glucagon contributes to rise of blood glucose in diabetes. Another dysfunction is that glucagon secretion is not appropriately stimulated when blood glucose falls to very low levels, as sometimes happens in insulin-treated type 1 diabetic patients. Clarification of the mechanisms underlying the failure of low glucose to stimulate glucagon release and the paradoxical hypersecretion of glucagon at high blood glucose may reduce acute illness and death after over-injection of insulin and help to prevent high blood glucose.

 

Experimental diabetes research
The research in our group aims at clarifying the mechanisms regulating the release of insulin, glucagon and other hormones from the islets of Langerhans. We are focussing specifically on the following issues:

Processes important for the role of Ca2+ as a universal cellular messenger
The Ca2+ concentration in the cytoplasm
controls a large number of cellular processes including secretion. Studies of the mechanisms by which the Ca2+ concentration is regulated is therefore important for understanding how secretion and other specific functions can be individually controlled by a common messenger.
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Generation of pulsatile insulin secretion
Insulin is released in a pulsatile fashion from the beta cells in the islets of Langerhans. These pulsations are important for a proper action of the hormone on the target cells. By analyzing Ca2+ signals in isolated beta cells we try to understand how this rhythmicity is generated.
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Synchronization of pulsatile insulin secretion among millions of pancreatic islets
Pulsatile insulin secretion from the pancreas requires co-ordination of the secretory activity in millions of islets. We are studying how neuro¬transmitters and other diffusible factors contribute to the synchroniza¬tion of Ca2+ signals in beta cells lacking physical contact.
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Signalling via plasma membrane phosphoinositides
It is the coordinated action of a number of second messengers and signalling molecules that determine the magnitude and kinetics of insulin secretion. In this project, messengers derived from plasma membrane phosphoinositide lipids via phospholipase C and PI3-kinase are studied using fluorescent translocation biosensors together with confocal and evanescent wave microscopy.
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Spatio-temporal dynamics of cAMP signals
Cyclic AMP is another ubiquitous second messenger which plays a key role in insulin secretion but little is known about the kinetics of cAMP signals. Using a new technique developed in our laboratory we are investigating how the concentration of cAMP is regulated in beta cells by nutrients, hormones and neurotransmitters, and how the spatio-temporal pattern of the messenger is involved to control beta cell function.
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Mechanisms controlling the release of glucagon, somatostatin and pancreatic polypeptide
The pancreatic islet is a complex endocrine organ containing also other cells than beta cells. Using Ca2+ imaging and other techniques, we are analyzing isolated alpha, delta and PP-cells, releasing glucagon, somatostatin and pancreatic polypeptide, respectively.
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Contact persons are found under the project links. For general information contact: Erik.Gylfe@mcb.uu.se or Anders.Tengholm@mcb.uu.se

Study group members
Helene Dansk -Research engineer
Oleg Dyachok – Postdoctoral fellow
Eva Grapengiesser - Associate professor
Erik Gylfe - Professor
Bo Hellman - Professor
Olof Idevall Hagren – Graduate student
Lisen Kullman - Assistant professor
Jia Li - Project student
Ing-Marie Mörsare - technician
Jenny Sågetorp – Graduate student
Anders Tengholm - Associate professor
Geng Tian – Graduate student
Anne Wuttke – Graduate student

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©2003 Department of Medical Cell Biology | Last updated: 2006-11-08
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