November is National Diabetes Month, a time to reflect on new ways to manage a chronic condition that affects young and old. Mayo Clinic is applying a regenerative lens to advancing diabetes care beyond routine blood checks and standard insulin therapy.

Quinn Peterson, Ph.D.; Aleksey Matveyenko, Ph.D.; and Alexander Revzin, Ph.D., are collaborating on a team science approach to finding new cell-based solutions that restore the body's ability to regulate blood sugar in people with Type 1 and Type 2 diabetes. Mayo Clinic's Center for Regenerative Medicine has brought these three experts together in a research trifecta aimed at improving diabetes care through restoration of cell function, cell replacement and improving immune protection of cells.

"As a team, we are trying to understand how pancreatic beta cells that produce insulin either die or become deficient, and how to reverse that process," says Dr. Peterson. "Each lab has a different focus that complements one another. Bringing each of these capabilities together allows us to do more than we could do in our individual laboratories. We each look at diabetes through a different lens to address problems in unique ways."

Diabetes is a growing health problem in the U.S., with a 40% increase in cases over the past decade, according to the American Diabetes Association. Approximately 34 million people, or 1 in 10 Americans, have Type 1 or Type 2 diabetes. Millions more people are classified as prediabetic, which could lead to a tsunami of diabetes cases in the future.

For more than a century, insulin has been a standard treatment for Type 1 diabetes and some forms of Type 2 diabetes. Despite improvements, insulin replacement therapy does not always sufficiently control blood glucose, leaving diabetics at risk of conditions such as neuropathy, blindness or infections that could lead to limb amputation.

Researching cell rejuvenation

Type 2 is the most prevalent form of diabetes, accounting for approximately 95% of all diabetes cases. Type 2 diabetes, which most often affects people over 40, develops when pancreatic beta cells cannot secrete enough insulin to lower blood sugar. Prolonged elevation of blood sugar could damage many organs in the body, including the heart, blood vessels and kidneys. These beta cells don't make enough insulin to control blood sugar or the insulin they do produce isn't functioning properly.

Regenerative medicine focuses on repairing or restoring diseased cells, tissues and organs. Dr. Matveyenko's research examines how to kick-start faulty pancreatic beta cells. His lab probes how genetic and environmental factors play a role in this process. For example, would proper sleep, a healthy diet, regular exercise and losing weight activate the genes that produce insulin and keep beta cells healthy? In contrast, does a sedentary lifestyle, lack of sleep or a diet rich in fat and sugar lead to malfunctioning beta cells?

"My lab is focused on faulty beta cells. We have the opportunity to work with a variety of human pancreatic specimens at Mayo Clinic, which is a huge resource for us," says Dr. Matveyenko. "In addition, we test our theories in animal models of diabetes and obesity, with goals of trying to figure out how to best treat and rejuvenate defective beta cells."

Dr. Matveyenko's long-term goal is to bring new therapies to the practice that improve the function of pancreatic beta cells so they can produce more insulin and improve the regulation of blood sugar.

"It is a passion of mine that I've been researching since I was a Ph.D. student. Diabetes is an interesting and crucially important scientific and societal problem to solve, particularly in light of the fact that the prevalence of Type 2 diabetes in America has surpassed 10% of the population," says Dr. Matveyenko.

Investigating cell replacement therapy

Type 1 diabetes is a condition in which the body attacks and destroys its own pancreatic cells, obliterating the ability to produce any insulin. Type 1 diabetes, which often develops in childhood, can only be controlled with injections of insulin. Lack of insulin can lead to hyperglycemia, diabetic ketoacidosis and ultimately death.

Dr. Peterson's lab is researching whether induced pluripotent stem cells are a safe and viable replacement for dormant beta pancreatic cells in Type 1 diabetes. Induced pluripotent stem cells are created from adult cells that are reprogrammed to behave like stem cells. Then these cells can be converted into disease-free pancreatic cells capable of producing insulin. With the help of the Center for Regenerative Medicine Biotrust, Dr. Peterson's lab can mass-produce islet cells from these induced pluripotent stem cells and transplant them in preclinical models to test their potential to cure Type 1 diabetes. Islet cells are groups of multiple different cell types that are normally involved in glucose regulation.

"The focus of my lab is on the development of a cell replacement therapy that can restore the ability of patients to produce their own insulin and regulate their own blood sugar levels," says Dr. Peterson. "What's unique about my team's approach is the integration of different endocrine cell types and the appreciation of the need for more than just a single cell type to regulate blood glucose levels. We are really trying to engineer islets."

Dr. Peterson is driven by the desire to address unmet patient needs and the hope of helping family members who have diabetes. His team is working to translate their findings to clinical application, including standardizing manufacturing processes and establishing quality control metrics to ensure safety and effectiveness of their cell products.

"Our long-term goal is to provide patients with an alternative to insulin replacement therapy that will more effectively respond to changes in blood glucose levels or changes in the physiological conditions. We hope this will do a better job of managing blood glucose levels, thereby minimizing or reducing the potential for complications as a result of diabetes," says Dr. Peterson.

Bioengineering technology to advance regenerative toolkit

Dr. Revzin's lab provides the biotechnology needed for Dr. Matveyenko's and Dr. Peterson's research. Building on his background as a bioengineer and on his deep understanding of pancreatic cells, Dr. Revzin is developing strategies to encapsulate the islet cells in Dr. Peterson's lab.

"This encapsulation technology is hopefully going to enable successful transplantation of cells by improving immune protection of cells," says Dr. Revzin. "Another goal is to develop technologies that would improve quality of stem cell-derived products and possibly decrease the cost associated with differentiating stem cells to islet cells," says Dr. Revzin.

Like his research colleagues, Dr. Revzin is driven by a passion to find new solutions to improve the health and quality of life for people with diabetes.

"I think it's a really compelling, heart-wrenching medical condition. It's a privilege to have a chance to work on a project for a condition like Type 1 diabetes that affects so many people, including small children. It is an important medical problem that needs addressing, and I am hoping I can make a difference," says Dr. Revzin.

Together and separately, this diabetes research team is trying to understand function and dysfunction of pancreatic cells to advance a regenerative approach to diabetes care. Although they are working at an accelerated pace, they are conservative with projections on when their findings could be approved for daily patient care. Their hope is to begin human clinical trials over the next few years.

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