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Taming diabetes

John S. Najarian, M.D., and David E. R. Sutherland, M.D., Ph.D., are the only two recipients of the Medawar Prize (the highest honor bestowed by the international Transplantation Society) from the same department: Najarian became a Medawar laureate in 2004, Sutherland in 2012. (Photos: University Archives)

U scientists launched islet transplants 40 years ago — and their march toward a cure continues

The debilitating, often deadly disease of type 1 diabetes mellitus still has not been conquered. But 40 years ago, because seven forward-looking patients volunteered to be injected with tiny clusters of cells from donated pancreases, University of Minnesota scientists took a huge step toward taming diabetes. On February 8, 1974, the world’s first clinical trial of islet transplants — a seemingly out-of-this-world idea at the time — was launched here.

And the idea actually worked, though only temporarily back then. It would be another 16 years, and at another university, before islet transplants would give any patients full, long-term relief from diabetes. But, coming full circle, the University of Minnesota is now poised to become one of the first institutions in the United States authorized to offer islet transplants as a standard procedure.

At first, a short-lived solution

That first islet transplant series used islet allografts (islets from deceased donors); all seven recipients had previously undergone a kidney transplant and thus were already committed to taking immunosuppressive drugs for the rest of their lives. So adding an islet transplant was not dangerous or burdensome, either surgically or medically, yet it was a gamble: Would it make a lasting difference or not? The answer, at least at that time, was no. Even though those first recipients did enjoy a reduction in their insulin doses, the respite was short-lived, and they all needed to resume taking full doses of insulin.

Less than a decade earlier, in 1966, the world’s first successful pancreas transplant had been performed at the University of Minnesota. The U’s pancreas transplant program has flourished since. Still, the hope in 1974 was that an islet transplant — a far shorter and less daunting procedure than a whole-organ pancreas transplant — could cure diabetes.

The islets (sometimes called islands) of Langerhans are small structures scattered throughout the pancreas. Of the four types of cells in the islets, the most common are the insulin-secreting beta cells, whose malfunction or loss leads to diabetes.

The inaugural human islet transplant was performed by John S. Najarian, M.D., Department of Surgery chair from 1967 to 1993, and David E. R. Sutherland, M.D., Ph.D., a resident at the time who became a transplant fellow the next year, then spent the rest of his career on the faculty. (In 1977 Najarian and Sutherland also performed the world’s first autoislet transplant, using the recipient’s own islets to treat chronic pancreatitis, an excruciatingly painful disease. The procedure continues to work well for patients with chronic pancreatitis but was not successful for treating diabetes until later.)

Lessons learned on the road to success

Islet allografts, however, created a greater challenge. But the lessons learned in Minneapolis in 1974 helped advance the entire field. Today, the pancreas and islet transplant programs are thriving at the University of Minnesota, as well as at a few select centers around the world.

Both Najarian and Sutherland vividly recall the first islet transplant and the numerous milestones that followed.

Najarian describes the mid-1970s as “an exciting time that introduced a whole new area of thought and research. And we ran with it. Islet transplants opened the possibility that you could someday help millions of diabetics.”

Sutherland agrees, emphasizing that, even though none of the first seven recipients became insulin-independent, they all experienced some islet function — a true leap forward. Thanks to extensive lab work, he says, he knew that “islet transplants would be safe in humans, and we were ready.”

Passing the baton

Today, islet allograft recipients do become insulin-independent, in greater numbers and for longer periods. At the University of Minnesota, the baton has been passed to Bernhard J. Hering, M.D., who arrived on campus in 1996. A professor of surgery and medicine, he is also the scientific director of the Schulze Diabetes Institute. (Sutherland founded its precursor, the Diabetes Institute for Immunology and Transplantation.)

Hering has been a key leader in modern-era islet allograft research. The protocol changes that he and his University team pioneered have markedly improved short- and long-term outcomes; several of the changes have been adopted for the phase 3 licensure trial of human alloislets by the multicenter Clinical Islet Transplant Consortium, sponsored by the National Institutes of Health.

The University, which has considerably contributed to the consortium’s success, will now seek a biologics license from the Food and Drug Administration that would allow it to perform alloislet transplants as a nonexperimental procedure.

“What is unique about the University of Minnesota,” Hering says, “is our use of single-donor pancreases; most other groups require two or three pancreases for one islet recipient.” Moreover, the U team has made distinct strides in “the timing of the transplant and immunosuppression, as well as in the quality of islets.” He points out that “half of our islet recipients are now completely insulin-independent five years after their last islet infusion, and some for more than 10 years and counting — outcomes that match those of pancreas transplants alone.”

Looking beyond 2014, Hering is preparing for a clinical trial in human patients of pig islets and is also intrigued by the possibility of stem cell-derived islets. “We can’t become complacent,” he emphasizes, “but must develop the next treatment that’s even more impactful and more widely available.”

By Mary E. Knatterud, Ph.D., a telecommuting associate professor (based in St. Paul) for the Department of Surgery at the University of Arizona, Tucson. Previously, she worked for 21 years in the Department of Surgery at the University of Minnesota, Minneapolis.

To learn more or to support the University’s leading-edge diabetes research, contact Jean Gorell, senior director of development at the University of Minnesota Foundation, 612-625-0497 or jgorell@umn.edu.

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