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8.04.2011

UM Researchers Grace the Covers of Three Prestigious Journals

In the past two months three University of Miami Miller School of Medicine researchers from the Diabetes Research Institute have had their study findings grace the covers of three prestigious scientific journals. The journals are Science Translational Medicine, Cell Metabolism and Nature Medicine.

In June, a study by Alessia Fornoni, M.D., Ph.D., DRI scientist and assistant professor of medicine in the Division of Nephrology and Hypertension, was featured on the cover of Science Translational Medicine. Her research unlocked the mechanism of a drug used to prevent recurrent kidney disease. The finding, which has implications for the diagnosis and treatment of many other diseases, involves the action of rituximab, a B-cell lymphoma therapy, in treating recurrent focal segmental glomerulosclerosis (FSGS) in children and young adults.

Rayner Rodriguez-Diaz, senior research associate at the DRI, and Alejandro Caicedo, Ph.D., a former DRI scientist and associate professor of medicine in the Division of Endocrinology, Metabolism and Diabetes, had cover stories published simultaneously in the July issues of Cell Metabolism and Nature Medicine.

The findings in Cell Metabolism and Nature Medicine significantly advance our understanding of islet cell function and lay the groundwork for discovering new treatments to preserve and prolong natural insulin production in patients with type 2 diabetes.

“To have three UM studies on the covers of such prestigious journals at the same time is an extraordinary accomplishment,” said Pascal J. Goldschmidt, M.D., Senior Vice President for Medical Affairs and Dean of the Miller School and CEO of UHealth, the University of Miami Health System. “Our investigators are leading the way in making the scientific discoveries that will impact all of our fellow humans in the decades to come.”

Fornoni showed not only that rituximab is a valid treatment strategy in preventing recurrent FSGS in kidney transplant patients, but also uncovered a previously unknown mechanism of action of rituximab.

Focal segmental glomerulosclerosis often leads to end-stage renal disease in pediatric and adult patients. While kidney transplantation can improve the mortality rate, as many as 80 percent of patients suffer a recurrence of the kidney disease and lose the transplanted organ. Therefore, there is a great need to find effective, long-lasting therapies.

Co-corresponding authors George W. Burke III, M.D., professor of surgery and director of the Division of Kidney and Pancreas Transplantation, and Jochen Reiser, M.D., Ph.D., professor and vice chair for research in the Department of Medicine and chief of the Division of Nephrology and Hypertension, have been collaborating on how to change the rate of recurrence of FSGS in their young patients following transplantation. Reiser says they began “an ideal collaboration” working with Fornoni, merging the disciplines of nephrology and surgery with science in an effort to find a solution.

Fornoni says the finding is also unique as it uncovers an assay that can be used before transplant to identify patients at risk for recurrent disease and to guide therapeutic decisions, allowing for a personalized medicine approach. The discovery, Fornoni says, “will likely unveil new clinical indications for rituximab beyond its original function and lead to new pathways involved in regulating cell function.”

The Cell Metabolism study, titled “Autonomic Axons in the Human Endocrine Pancreas Show Unique Innervation Patterns,” illustrates what represents a paradigm shift in the understanding of islet cell anatomy. The autonomic nervous system influences insulin secretion by sending nerves to the pancreatic islet. The innervation of the islet, long believed to be similar in mice and humans, is found to be drastically different. The mouse islet is much more “hard wired” with nerve fibers penetrating broadly across each islet to reach beta cells and other endocrine cells. In humans, nerve fibers are less prominent and contact blood vessels.

“Given these differences in islet innervation, it is likely that animals and humans use different mechanisms to achieve nervous control of insulin secretion,” said first author Rodriguez-Diaz. “Implications for future research and understanding of human endocrine response are great, including improved beta cell function through better targeting of therapeutic agents.”

The study in Nature Medicine, which moves the research forward from the Cell Metabolism study, is titled “Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans.” One of the endocrine cells, the alpha cell, surprisingly showed expression of a neuronal molecule, acetylcholine. Acetylcholine is widely understood to be essential for the support of beta cell health and insulin production. Unlike the mouse model, alpha cells within pancreatic islet cells include all elements needed for cholinergic input directly to surrounding endocrine cells. Physiology models utilizing biosensor “sniffer” cells were applied to test the hypothesis that alpha cells secrete acetylcholine. Beta cell response was measured and found to improve in the presence of acetylcholine.

These discoveries build on previous work by the same team that showed that alpha and beta cells within human islet cells are closely associated, whereas in mouse islet they are segregated. Implications for diabetes and prevention are vast.

“These findings pave the way for highly focused targeting of pancreatic islet alpha cells to improve beta cell health and function,” said senior author Caicedo. Previously the entire autonomic nervous system was believed to be involved. Targeted support of alpha and beta cells can prolong healthy insulin production in patients suffering from type 2 diabetes.

The research represented in both papers was a cross-collaboration between the Karolinska Institute in Sweden and Professor Per-Olof Berggren’s Signal Transduction Laboratory at the Diabetes Research Institute at the Miller School. Rodriguez-Diaz is finishing his doctoral studies at the Karolinska Institute under Professor Berggren’s supervision.

“Signals generated by the nervous system play a fundamental role for the insulin secretory process,” explains Professor Berggren. “Demonstrating that the innervation pattern is different between mouse and man and that the hormone secreting cells themselves can generate these signals in the human endocrine pancreas is essential and may lay the foundation for novel pharmacological treatment regimens for diabetes.”

Both studies also benefited from a collaboration with Stephen D. Roper, Ph.D., professor of physiology and biophysics, and Robin Dando, Ph.D., a postdoctoral associate in Dr. Roper’s lab.

“These are exciting discoveries from the Diabetes Research Institute and our collaborators, indicating once again the power of multidisciplinary teamwork and the overall impact of the DRI’s translational research strategy at UM and worldwide,” said Camillo Ricordi, M.D., Director of the University of Miami’s Diabetes Research Institute and Cell Transplant Center.

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