Future of type 1 diabetes: Islet cells could hold key to a cure

December 21, 2012 | by Shawn Le

Type 1 diabetes can be difficult to manage, and many patients need to stay vigilant about their blood sugar levels, strictly control their diet and keep insulin always close at hand to ensure that their blood glucose doesn’t soar too high or fall too low.

Islet cells produce insulin In type 1 diabetes, insulin-producing islet cells in the pancreas are killed by the immune system.

City of Hope researchers are among the scientists and physicians investigating treatments for type 1 diabetes that could ultimately bring an end to regular insulin injections, and prevent the long-term health problems associated with the disease.

Type 1 diabetes, also commonly known as juvenile diabetes, is an autoimmune disease in which a patient’s own immune system mistakenly destroys the insulin-producing islet cells in the pancreas.

America’s obesity epidemic has centered attention on type 2 diabetes, overshadowing an equally alarming rise in type 1 cases. The leading type 1 diabetes research foundation JDRF estimates that more than 3 million Americans have type 1 diabetes, and approximately 80 people are newly diagnosed each day.

Fouad Kandeel , M.D., Ph.D., chair of City of Hope’s Department of Division of Molecular Diabetes Research, is one of the physicians pushing to eliminate the need for synthetic insulin.

He’s been pursuing islet cell transplantation as a potential cure for type 1 diabetes. In that procedure, patients undergo a bone marrow transplant to reset their immune system, then doctors transplant new islet cells to the liver, which takes over insulin-producing duties. The treatment is still in the investigational stage, with practical obstacles that need to be addressed.

One limiting issue is that islet cells can only be collected from the pancreases of dead donors, and the current process yields low numbers of useable cells. One transplant procedure can require the islet cells from 2-5 donor pancreases. New developments in the laboratory may provide a solution.

“We can now create insulin-producing cells in the lab,” said Kandeel in a previous interview. “The hope is that one day we will be able to take a few cells from any human being and transform them into insulin-producing cells that can be used therapeutically. Through the ongoing efforts at City of Hope, we hope to accomplish these objectives in the next few years.”

Another obstacle is the arduous bone marrow transplant. Before a transplant, patients commonly undergo a regimen of chemotherapy and radiation therapy to scrub their defective immune system, enabling new donor blood stem cells to then take root. But even successful transplants have been shown to last only a limited number of years. In addition, patients can experience an auto-immune condition called graft vs. host disease, in which the new donor immune cells attack all of the patients’ own cells.

Soon, these obstacles also may fall.

Defu Zeng, M.D., associate professor in the Division of Diabetes, Endocrinology & Metabolism, is developing a new treatment approach that hopes to solve these problems without the need for radiation or donor islet cells. His strategy strives to both block the autoimmune response – preventing continued destruction of islet cells – and to stimulate the growth of new islet cells to restore healthy insulin regulation.

“While transplanting islet cells from another person can provide insulin independence, the effect lasts only about three years due to chronic rejection of the graft cells,” Zeng in a previous interview.

The combination therapy begins with timed doses of antibodies followed by an infusion of donor bone marrow to induce mixed chimerism in the patient – a condition in which a patient’s immune system is made up of both the patient’s own cells and new cells from the donor bone marrow. The patient’s defective immune cells are replaced by the healthy cells, stopping the autoimmune response. Unlike traditional bone marrow transplants, this approach does not require radiation or high-dose chemotherapy.

“We have shown that conditioning … allows for induction of mixed chimerism with no signs of graft-versus-host disease in late-stage diabetes lab models,” said Zeng. "We have also shown that combination therapy of mixed chimerism with administration of growth hormone is able to reverse late-stage diabetes, although either alone cannot.”

Because type 1 diabetic patients with chronic, unresponsive disease often have too few functional islet cells left to regenerate healthy cells on their own, the researchers follow up the mixed chimerism with growth hormones to stimulate regeneration.

Islet cell transplantation is in limited human clinical trials, and the chimerism approach is nearly ready to leave the laboratory for more advanced-stage studies. Kandeel says patients might not need to wait long for new treatment options.

“The greatest advancement I’d like to see in type 1 diabetes is elimination of the disease, and this will happen through being able to control cell biology and cell immunology,” he said. “This work hopefully will reach application in humans over the next couple of years.”

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