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Under the Microscope

Interview with Alessia Fornoni, M.D., Ph.D.

Type 1 diabetes is an autoimmune disease in which an individual's insulin-producing beta cells are mistakenly destroyed by his/her own immune system. While the actual cause of this autoimmune attack is still under investigation, researchers are uncovering a number of key factors that lead to the onset of the disease.

In recent years, scientists have discovered that chronic inflammation plays a major role in islet loss. DRI researchers are testing numerous anti-inflammatory agents to prevent islet destruction while exploring how the different cells that make up the Islets of Langerhans function. These cell clusters are responsible for regulating and maintaining normal blood sugar levels. A better understanding of the factors that lead to beta cell loss and contribute to normal beta cell function will help in developing strategies to restore natural insulin production in those living with diabetes.

Scientists are identifying many of the key molecules involved in islet function. Among these is nephrin, a promising new therapeutic target. Nephrin, derived from the Greek nephros, or kidney, is a substance essential for optimal kidney filtration, which eliminates toxins produced by the body, as well as for the retention of certain molecules needed for a person's survival.

Although nephrin was thought to be a kidney-specific molecule, scientists recently discovered it in the pancreas, where its actual function still needs to be fully understood. However, recent findings suggest that there is a link between the development of type 1 diabetes and nephrin, thought to be a target of autoimmune attack.

At the DRI, Dr. Alessia Fornoni, assistant professor of Clinical Medicine in the Division of Nephrology and Hypertension, and her colleagues have generated preliminary results showing that beta cells express nephrin and that this molecule is vital for beta cells to secrete insulin in response to blood sugar.

In diabetes, nephrin expression in the kidneys is reduced, which contributes to the development of diabetic kidney disease. Dr. Fornoni has demonstrated that this decrease of nephrin is also seen in beta cells of patients with diabetes.

To further investigate this connection, Dr. Fornoni and her team are using mice, lacking nephrin in the pancreas, to assess the protein's potential to prevent type 1 diabetes and also to delay the need for insulin injections in those with type 2 diabetes.

How does your research fit in to the DRI's cure-focused mission?
Evidence that both type 1 and type 2 diabetes are chronic inflammatory states led me to study the function of novel anti-inflammatory agents for the treatment of diabetes. Inflammation affects the ability of insulin to signal through its own receptor and to maintain proper cell function and survival. If we overcome insulin's inability to signal, we can recover islet survival, function and viability after exposure to inflammatory stimuli. We have generated preliminary evidence that this could also be the mechanism by which nephrin facilitates islet cell function. Ensuring effective insulin signaling and maintaining proper islet cell function is probably one of the best ways to go about finding a cure.

Can nephrin facilitate the development of insulin-producing cells?
Nephrin expression is critical for mature kidney cell development. Knowing this, we are planning studies in collaboration with DRI's stem cell development team to explore the role of nephrin in the generation of insulin-producing cells from immature cells known as precursors.

What brought you to the DRI?
I obtained my M.D. and Ph.D. in Medical Pharmacology at the Universita' degli Studi di Pavia in Italy. I later joined the Renal Cell Biology lab in the Vascular Biology Institute at the University of Miami Miller School of Medicine. I continued my medical education at UM, where I currently work as a clinical nephrologist treating many diabetic patients. After being appointed assistant professor in clinical medicine at UM in 2005, I had a strong desire to join a research institution committed to curing diabetes, and I was very fortunate to have the opportunity to join the DRI team. I've always thought of diabetes as a slow but persistent “Pac Man” that will slowly take over patients' bodies and souls. Here, my training and research successes in diabetes and diabetic complications can be quickly translated from the lab to patients. The commitment of the DRI's scientific director, Dr. Camillo Ricordi, to finding a cure and his ability to harness talent from multidisciplinary areas of expertise are among the DRI's biggest strengths and was a major reason for my joining the institute.

How does this multidisciplinary environment benefit your research efforts?
At the DRI, my interaction with cell biologist Dr. Per Olof Berggren is critical to characterizing the role of nephrin in insulin secretion. The enthusiasm and encouragement of Dr. Ricordi; expertise of immunologists Drs. Luca Inverardi and Alberto Pugliese; intellectual support and technical assistance of Dr. Antonello Pileggi and molecular biologist Dr. Ricardo Pastori; as well as mentoring of physician scientists, such as Dr. Daniel Mintz, will be instrumental in finding a cure. I also have a close interaction with Dr. Jochen Reiser, recently recruited from Harvard Medical School to become chief of nephrology and hypertension at UM; Dr. Peter Mundel, basic science research director of UM's Division of Nephrology; and Dr. Karl Tryggvason, the scientist who discovered nephrin in the kidney. I'm excited about the recruitment of researchers with different scientific backgrounds and believe this strategy will be pivotal in leading to new discoveries.

What are your future research plans and how will that help find effective treatments?
I believe that understanding and improving beta cell function is necessary for finding a cure for diabetes. By knowing more about how beta cells work, we can develop strategies to better preserve islets and protect cells from the dangerous effects of anti-rejection drugs, inflammatory agents and the immune system. Nephrin is probably just one of the pieces of the puzzle but, once the puzzle comes together, a cure will be found. My patients are the driving force of my research.

Alessia Fornoni, M.D., Ph.D.
Alessia Fornoni, M.D., Ph.D.

 

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