News & Research

    University of Miami School of Medicine, Miami, Florida

Role of nephrin in insulin secretion

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Islet Biology\Hormone Secretion and Exocytosis

Type of Grant: Junior Faculty

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

Nephrin is a protein that allows proper function of podocytes, the cell type responsible for the filtration abilities in the kidney. Diabetes is characterized by a reduction of nephrin expression and function in the kidney. The objective of the proposed research is to investigate the function of nephrin in the pancreas, where its expression has recently been reported.

We hypothesize that, in pancreatic beta cells, nephrin contributes to the secretion of insulin. We have developed several techniques that allow us to manipulate the quantity of nephrin that is expressed by human islets and cells in culture. This tool will allow us to identify the specific function of nephrin in pancreatic beta cells. Because several key players responsible for insulin secretion have been identified, we will further investigate the interaction of nephrin with those proteins.

We have generated preliminary data suggesting that nephrin augments insulin secretion at baseline and after glucose stimulation. We have also described a colocalization of nephrin with secretory vescicles in human pancreas and cells in culture. Furthermore, we have developed an in vivo imaging system that allows us to see how nephrin moves inside a live beta cell, giving us the ability to study real time the function of nephrin.

The long-term objectives of this grant proposal are to understand how molecules that are relevant to podocyte function in diabetes may also affect pancreatic beta cell function. The outcome of the proposed research may allow for the identification of a common mechanism linking diabetes and its major debilitating complication (diabetic nephropathy). Furthermore, nephrin may become a novel target for the development of a new cure for diabetes.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

The proposed study is highly relevant to the area of diabetes research investigating the function of insulin-producing pancreatic beta cells. Experimental and clinical studies have revealed some of the mechanisms by which beta cells secrete insulin in response to an increase in glucose concentration; however, the fine mechanisms responsible for insulin secretion remain to be determined.

The novel finding in this study is the identification of a protein named nephrin on the surface of insulin containing granules in the pancreatic beta cell, where nephrin regulates insulin release in response to glucose. The expression of nephrin was thought to be confined to the kidney, and in the kidney, nephrin is essential for the structural and functional integrity of the glomerulus, the kidney's filtration unit. Nephrin expression and function are impaired in the kidneys of diabetic patients. Hence, studying the mechanisms by which nephrin may affect beta cells' function may lead to the identification of novel therapeutic targets for the cure of diabetes. In addition, characterization of nephrin function in beta cells may allow for the discovery of unexplored kidney-specific nephrin functions. Thus, a common pathogenetic pathway linking beta cell function and kidney function in diabetes may be found. The work proposed has broad significance in the long-term, since it may lead to the identification of a cure for diabetes and for its major devastating complication, diabetic nephropathy.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

From the prospective of a physician seeing patients with diabetes on a daily basis, I feel highly committed to research that may lead to a cure. In fact, my motivation to work as a scientist in the field of diabetes stems from the fact that many patients, despite being very adherent to modern treatment protocols, still develop life-threatening cardiovascular complications of diabetes and experience kidney failure. I expect that my research in the foreseeable future will lead to the development of new medications that target nephrin and help maintain the ability of pancreatic beta cells to secrete insulin, thus delaying or perhaps abolishing the need to initiate insulin therapy in diabetic patients.

Nephrin may have important application also in patients with type 1 diabetes, where insulin production is impaired due to a self-destruction of insulin-producing cells. When the immune system attacks beta cells, it develops antibodies directed against specific proteins, and nephrin has been recognized to be one of the targets. Interestingly, auto-antibodies directed against nephrin can also cause a leakage of proteins through the kidney filter, which is the early phenomenon that characterizes diabetic kidney disease. Thus, developing therapeutic strategies that protect nephrin from being a target of the immune system may prevent diabetes and also diabetic kidney disease.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

I have been involved in diabetes research since I was a medical student. As a nephrologist, I see a lot of patients with diabetes, since diabetes is the major cause of end-stage renal disease leading to the need for dialysis or transplantation in the United States. I remember as student seeing patients with diabetes on dialysis who would lose their toes, legs, and their sight. I just cannot tolerate this slow but relentless disease progression that involves a large percentage of patients with diabetes. Thus, I truly feel committed to find a cure.

The award provided by ADA will be essential at this stage of my career to compile enough data to become a strong competitive independent investigator in the field. The University of Miami has granted me 80 percent of protected time from clinical duties to advance in my research, and I have a strong institutional support to continue my promising work as a physician-scientist. Finally, I truly believe that as long as my enthusiasm and passion for research prevail, along with compassion for the patients I care for, my efforts will translate into a successful academic career in the field of diabetes.

In what direction do you see the future of diabetes research going? 

Diabetes is a complex and multifactorial disease that calls for a multidisciplinary approach. Scientists with diverse backgrounds must come together, taking advantage of different perspectives and unique capabilities, working towards the common goal: finding a cure. I strongly believe that we have to understand how the body works if we want to develop rational interventions for complicated diseases such as diabetes. Hence, I have decided to investigate the physiology of the insulin-producing pancreatic beta cells, because it is the dysfunctional beta cell that triggers the disease cascade in patients with diabetes.

I also believe new treatment options will be based on molecular medicine, the study of molecules as they relate to health and disease, and the manipulation of those molecules to improve the diagnosis, prevention, and treatment of disease. I focus on a set of molecules that are known to have important functions in the healthy and diseased kidney; my research will show that they play a vital role in the regulation of beta cells as well. While each scientist concentrates on a small piece of the puzzle, the entire picture comes into focus, making the cure of diabetes more attainable.