Each year, surgeon Jose Oberholzer frees a few people with type 1 diabetes from daily insulin injections by giving them a transplant of the insulin-secreting β-cells that the disease attacks. But it is a frustrating process.Harvested from a cadaver’s pancreas, the β-cells are in short supply and vary in quality. And the patients must take drugs to suppress their immune response to the foreign cells, which can in turn cause kidney failure.
On 9 October, stem-cell researcher Douglas Melton of Harvard University in Cambridge, Massachusetts, and his colleagues reported an advance that has the potential to overcome Oberholzer’s frustrations and allow many more people with type 1 diabetes to receive transplants. Melton and his team have achieved a long-term goal of stem-cell science: they have created mature β-cells using human stem cells that can be grown from a potentially unlimited supply, and that behave like the real thing (F. W. Pagliuca et al. Cell 159, 428–439; 2014). The next challenge is to work out how to shield these β-cells from the body’s immune response.
Researchers had previously created immature β-cells from stem cells and transplanted them into diabetic mice. But they take months to mature into insulin-secreting cells, and it is unclear whether they would do so in humans.
The β-cells reported by Melton’s team were grown from adult cells that had been reprogrammed to resemble stem cells. In response to glucose, the β-cells quickly secreted insulin, which the body uses to regulate blood sugar. When implanted in diabetic mice, the cells relieved symptoms within two weeks. The β-cells even formed clusters that are similar to those found in a pancreatic structure called the islet of Langerhans. “If you took these cells and showed them to somebody without telling them what they are, I guarantee you an expert would say that is a perfect human islet cell,” says Oberholzer, who is working with Melton’s team to test the cells in non-human primates.
A remaining hurdle is shielding the cells from immune attack. This is necessary if the treatment is to become more widely available, because immunosuppressant drugs can be justified only in the most severe cases of diabetes. And although mature β-cells could be derived from a patient’s own skin cells, type 1 diabetes is an autoimmune disease, so transplanted cells would still be vulnerable to attack.
One solution might be to encapsulate the cells in a credit-card-sized, biocompatible sheath made by ViaCyte of San Diego, California. The company will implant its first device — loaded with immature β-cells — in a patient on 21 October. Studies in animals have been promising, but some researchers worry that the cells inside the device are packed too densely and might become starved of oxygen and nutrients.
Another option is to coat cells in a protective hydrogel, which results in thousands of separate balls of cells. But a potential drawback is that it would be much harder to remove such cells if there was a safety concern, says Albert Hwa, director of discovery science at JDRF, a diabetes-research foundation in New York.
Neither technique avoids the body’s tendency to enclose foreign bodies inside scar tissue, which could cut the transplanted cells off from nutrients. Bioengineer Daniel Anderson of the Massachusetts Institute of Technology in Cambridge and his team are screening chemical compounds for a hydrogel that does not trigger this. Some, used with Melton’s cells, have shown promise in unpublished studies of diabetic primates, he says.
Still, for those people with diabetes who face life-threatening changes in blood-sugar level each day, mature β-cells could offer a big improvement without such devices, says Oberholzer. Many of his patients are relieved to be free of insulin injections: “They would much rather take immunosuppression,” he says.]]>
The results were presented here at the American Diabetes Association (ADA) 2014 Scientific Sessions by Kirstie K. Danielson, PhD, assistant professor of transplant surgery and epidemiology and biostatistics at the University of Illinois at Chicago.
Among 23 consecutive adult patients with type 1 diabetes who received allogeneic pancreatic islet-cell transplants, the 11 who received islets from female donors had significantly higher C-peptide levels, greater insulin secretion, and lower average glucose levels posttransplant than did the 12 recipients of male donor islets.
“None of the outcomes were better for recipients of male islets,” Dr. Danielson said.
Session moderator James A. M. Shaw, PhD, professor of regenerative medicine for diabetes at Newcastle University, United Kingdom, told Medscape Medical News, “I think it is tantalizing. It did seem real that female donors were leading to better transplant results.”
The effect appeared to be related to estrogen, as other study findings included worse beta-cell function in current users of oral contraceptives (which suppress circulating estrogen) compared with nonusers; better function among premenopausal compared with postmenopausal female recipients; and better function in postmenopausal women who used hormone-replacement therapy (HRT) compared with nonusers.
Islet-Cell Transplant Success Improving
Dr. Shaw told Medscape Medical News that islet-cell transplantation is a “very safe and effective” procedure for patients with type 1 diabetes who have severe hypoglycemic unawareness. The need for immunosuppression is the primary factor preventing its wider use, he said.
“It mustn’t be seen as a short-term cure. It’s a real cure for people with severe hypoglycemia,” he said, pointing to data from another paper presented during the same oral abstract session in which continuous glucose monitoring demonstrated significantly better glucose control and reduced glycemic variability among islet-cell recipients than among type 1 patients using the best currently available medical therapy.
“The big thing in America is [Food and Drug Administration] approval. There is no doubt success is getting better and better,” he noted.
In Dr. Danielson’s study, both the deceased islet donors and the recipients had a mean age of 46 years. Half of the donors and more than three-quarters of the recipients were female. Among the female recipients, 9 were postmenopausal (5 of whom were on HRT) and 5 were premenopausal contraceptive users.
Half of the recipients (11) achieved insulin independence at some point posttransplant, and 13 eventually required a second transplant. The current study focused on multiple measures taken during the 64 weeks following the first transplant.
After adjustment for a variety of potential confounders, including donor and recipient age and weight, cause of donor death, cold ischemia time, and number of islets received, measures of fasting C-peptide function (335 separate tests) were significantly better among the recipients of female donor islets (P = .02), as were measures of glucose-stimulated C-peptide at 0 minutes (31 measurements, P = .02) and at 6 minutes (32 measures, P = .03).
Both insulin and glucose responses to oral glucose tolerance tests were also better among the female islet recipients (P = 0.01 and P = .01, respectively).
Among postmenopausal women islet recipients, those who used HRT had significantly better insulin responses to oral glucose tolerance tests (P = .04), lower insulin dose requirements (P = .04), and higher fasting C-peptide levels (P = .006).
Dr. Shaw said: “It’s very interesting to know the effect that these sex hormones have on people’s diabetes and islet function, and there is other work going on about that.
“We have an opportunity with islets to really understand them before we transplant them. We need to make sure we’re giving the best islets to the best patients.…Some of these factors may come into play to improve survival and function when they’re transplanted,” he concluded.
Dr. Danielson and Dr. Shaw have reported no relevant financial relationships .
American Diabetes Association 2014 Scientific Sessions; June 14, 2014.]]>
Jorge Balderas has been riding his bike toward his hometown in Mexico since November 4th, stopping along the way raise awareness for the Chicago Diabetes Project and how the need for a cure is critical. Follow his progress via facebook at Tour de Diabetes Cure
When: Saturday, December 7th (11am open bar, 1 mile race 1:00pm, and an afternoon of Santa mayhem!)
Where: Shenanigans, 16 W. Division Street, Chicago
Who: All elves, reindeer, santas…
Attire: speedos and swimsuits encouraged… snowpants, sweatshirts, and parkas completely acceptable! Wear your best costume underneath and at the stroke of 1pm, we will strip down to the speedos and get our run on! Please note while speedos are encouraged, you don’t have to run or wear a speedo…as long as its festive!
Open bar starts at 11am and lasts 3 hours. $50 cover charge inludes domestic bottles and well drinks, and a Speedo Run Mug and Santa Hat.
Flip Cup tourney, raffle, prizes, contest and North Pole dancing!
All proceeds go to the Chicago Diabetes Project!
Darren Weissman aka Doctor Dribble ran the Bank of America Chicago Marathon and ING NYC Marathon while dribbling two basketballs the ENTIRE time! Check out an exclusive interview with Darren after his completion of the ING NYC Marathon.]]>