AstraZeneca/ Karolinska Institutet research points to novel targets for next generation medicines for type 2 diabetes, obesity and other metabolic disorders

STOCKHOLM, 27-Sep-2016 — /EuropaWire/ — New understanding of how hormone-producing cells in the pancreas decode their genetic instructions is pointing to novel targets for next generation medicines for type 2 diabetes, obesity and other metabolic disorders.

A large scale analysis of gene expression in individual islet cells of the pancreas suggests insulin-producing beta cells are not the only sub-class of cells important for glucose control and diabetes treatment as previously thought. The research, carried out at the AstraZeneca/ Karolinska Institutet Integrated Cardiometabolic Center (ICMC), Stockholm, Sweden, has shown that other types of islet cells, notably alpha and delta, may also play a significant role.

“Our study has shown that all types of islet cell have distinct and unique gene expression profiles that changes in type 2 diabetes. It’s time to consider how to restore normal function to the entire network in patients instead of simply trying to make beta cells work harder,” explains Dr Carina Ämmälä, Innovative Medicines & Early Development (IMED) Biotech Unit, at AstraZeneca, and a member of the ICMC team.

At the ICMC, scientists from AstraZeneca’s IMED Biotech Unit and the Karolinska Institutet work together to improve understanding of cardiometabolic disease – a key AstraZeneca priority for advancing patient care.

The new data are published this week in Cell Metabolism and were presented recently to a packed session at the annual congress of the European Association for the Study of Diabetes (EASD).

At the forefront of research
The ICMC team was one of several leading groups aiming to report large scale, single-cell gene expression profiling in human pancreatic islets for the first time. The ICMC team brought together cutting-edge skills and techniques for islet cell preparation and gene expression characterisation.

“It’s been a really good, enjoyable and productive collaboration from the start. We shared the same enthusiasm for using basic science to gain fresh insights into the way islet cells work and interact, and our complementary skills helped to expedite the research. Our results can form the basis for new hypotheses about regulation of hormone secretion and identification of drug discovery targets,” says Dr Ämmälä.

Thousands of islet cells were painstakingly separated to ensure that only the highest quality, individual cells were analysed. Some were from healthy individuals and some from patients with type 2 diabetes.

RNA sequencing was then carried out on over 2,200 islet cells to ascertain which genes were expressed and actively involved in cell functions.
“It has been exciting to molecularly dissect the human pancreas and we were thrilled to discover that rare and seldom studied cell types turned out to express large numbers of important genes. We hope that the single-cell transcriptomic resource will catalyse the worldwide efforts to develop better treatments for metabolic disorders, e.g. by turning more efforts to understand the interplay of cell types within the Langerhans islets,” says Dr Rickard Sandberg, Head of Cell and Molecular Biology and Principal Investigator at AZ/ICMC, Karolinska Institutet.

This type of comprehensive single-cell gene expression profiling initiative can be applied to other therapy areas. Similar techniques can be used to improve understanding of faulty gene expression in many diseases.

The riddle of GPR119 solved?
Some genes were found to be expressed in surprising places. One was the gene for G-protein coupled receptor 119 (GPR119) – a previously hot target for novel diabetes drugs.

Dr Ämmälä explains that during the early days of the Human Genome Project, the GPR119 gene, coding for a 7TM receptor, was identified and shown to have a unique pattern of expression in pancreatic islets and in some regions of the gastrointestinal tract in humans. The distribution profile and the suggestion that GPR119 is related to glucose homeostasis, raised the hope it would be expressed in beta cells and play a role in diabetes. Both pharmaceutical industry and academic research was initiated to discover and develop GPR119 agonists as antidiabetes agents to boost glucose-stimulated insulin secretion from beta cells. However, the clinical results did not live up to expectations.

“Our data have shown, for the first time, that GPR119 is selectively expressed in alpha cells, not beta cells, and is most likely involved in regulating glucagon secretion not insulin secretion directly. This may explain why the results with GPR119 agonists were so disappointing,” says Dr Ämmälä.

If the new ICMC islet cell gene expression ‘directory’ had been available when researchers first thought of developing GPR119 agonists, they would have realised they were on the wrong track.

Spotlight on delta and epsilon cells
The ICMC research has also shed light on possible functions for the less well understood islet cells, such as delta and epsilon, which are found in smaller numbers in the pancreas than the better known alpha and beta cells.

In delta cells, genes were found to be switched on coding for receptors for both gherelin and leptin – the hormones that affect whether we feel hungry.
“In the past, there has been a lot of controversy over whether leptin stimulates or inhibits insulin secretion. But, having shown that the leptin receptor is expressed on delta cells, not beta cells, we can now direct our attention at how the different islet cells work together rather than just focusing on beta cells, as we have in the past,” says Dr William Haynes, Vice President & Head of Bioscience Diabetes, IMED Biotech Unit, AstraZeneca at AstraZeneca.

Gene expression clues to type 2 diabetes
Comparing gene expression in cells from healthy individuals and those with type 2 diabetes yielded some valuable clues to potential drug targets for the future. Expression of some genes was up-regulated in islets from patients with type 2 diabetes. Other genes, such as FXYD2, were down-regulated. In previous studies, mice lacking FXYD2 were more glucose tolerant and had higher beta cell numbers and plasma insulin levels. The down regulation of FXYD2 in humans could indicate an attempt to stimulate beta cell proliferation in order to increase insulin secretion and combat raised blood glucose.

An open access resource
All the data from the ICMC single-cell gene expression profiling study are available to other researchers through a user-friendly and searchable web portal (http://sandberg.cmb.ki.se/pancreas).

By putting this ground breaking resource at the disposal of the entire cardiometabolic research community, the ICMC team hope it will help to advance understanding of the complete islet cell network in the pancreas.

“The ICMC is a unique research collaboration which is committed to extending our knowledge of the science of cardiovascular and metabolic disease. By enabling scientists to formulate new hypotheses about the underlying mechanisms of type 2 diabetes, this new islet cell research may help to speed up development of innovative therapies for this increasingly common and life-limiting condition,” says Marcus Schindler, Vice President, Head of Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca.

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SOURCE: AstraZeneca