T1D
Artificial Pancreas Improves Blood Glucose Control in Young Kids with Type 1 Diabetes
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Last week brought some great news for parents of small children with type 1 diabetes (T1D). It involved what’s called an “artificial pancreas,” a new type of device to monitor continuously a person’s blood glucose levels and release the hormone insulin at the right time and at the right dosage, much like the pancreas does in kids who don’t have T1D.
Researchers published last week in the New England Journal of Medicine [1] the results of the largest clinical trial yet of an artificial pancreas technology in small children, ages 2 to 6. The data showed that their Control-IQ technology was safe and effective over several weeks at controlling blood glucose levels in these children. In fact, the new device performed better than the current standard of care.
Two previous clinical trials of the Control-IQ technology had shown the same in older kids and adults, age 6 and up [2,3], and the latest clinical trial, one of the first in young kids, should provide the needed data for the U. S. Food and Drug Administration (FDA) to consider whether to extend the age range approved to use this artificial pancreas. The FDA earlier approved two other artificial pancreas devices—the MiniMed 770G and the Insulet Omnipod 5 systems—for use in children age 2 and older [4,5].
The Control-IQ clinical trial results are a culmination of more than a decade-long effort by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and many others to create technologies, such as an artificial pancreas, to improve blood glucose control. The reason is managing blood glucose levels remains critical for the long-term health of people with T1D.
What exactly is an artificial pancreas? It consists of three fully integrated components: a glucose monitor, an insulin pump, and a computer algorithm that allows the other two components to communicate. This automation frees people with T1D from checking their blood glucose levels multiple times a day and from many insulin dosing decisions, though they still interact with the system at mealtimes.
In this clinical trial, led by Marc D. Breton, University of Virginia School of Medicine, Charlottesville, researchers tested their Control-IQ technology (manufactured by Tandem Diabetes Care, San Diego, CA), also known as a hybrid closed-loop control system. Thanks to an algorithm developed at the University of Virginia Center for Diabetes Technology, insulin doses are administered automatically every few minutes based on readings from a continuous glucose monitor.
But treating younger children with T1D presents its own set of age-specific challenges. Younger kids generally require smaller doses of insulin more frequently. They also tend to have a more unpredictable schedule with lots of small snacks and random bursts of physical activity.
On top of all that, these young children have a tougher time than kids a few years older when it comes to understanding their own needs and letting the adults around them know when they need help. For all these reasons, young children with T1D tend to spend a greater proportion of time than older kids or adults do with blood glucose levels that are higher, or lower, than they should be. The hope was that the artificial pancreas might help to simplify things.
To find out, the trial enrolled 102 volunteers between ages 2 and 6. Sixty-eight were randomly assigned to receive the artificial pancreas, while the other 34 continued receiving insulin via either an insulin pump or multiple daily injections. The primary focus was on how long kids in each group spent in the target blood glucose range of 70 to 180 milligrams per deciliter, as measured using a continuous glucose monitor.
During the trial’s 13 weeks, participants in the artificial pancreas group spent over 12 percent more time—approximately three more hours per day—with blood glucose in a healthy range compared to the standard care group. The greatest difference in blood glucose control was seen at night while the children should have been sleeping, from 10 p.m. to 6 a.m. During this important period, children with the artificial pancreas spent 18 percent more time in normal blood glucose range than the standard care group. That’s key because nighttime control is especially challenging to maintain in children with T1D.
Overall, the findings show benefits to young children similar to those seen previously in older kids. Those benefits also were observed in kids regardless of age, racial or ethnic group, parental education, or family income.
In the artificial pancreas group, there were two cases of severe hypoglycemia (low blood glucose) compared to one case in the other group. One child in the artificial pancreas group also developed diabetic ketoacidosis, a serious complication in which the body doesn’t have enough insulin. These incidents, while unfortunate, happened infrequently and at similar rates in the two groups.
Interestingly, the trial took place during the COVID-19 pandemic. As a result, much of the training on use of the artificial pancreas system took place virtually. Breton notes that the success of the artificial pancreas under these circumstances is an important finding, especially considering that many kids with T1D live in areas that are farther from endocrinologists or other specialists.
Even with these clinical trials now completed and a few devices on the market, there’s still more work to be done. The NIDDK has plans to host a meeting in the coming months to discuss next steps, including outstanding research questions and other priorities. It’s all very good news for people with T1D, including young kids and their families.
References:
[1] Trial of hybrid closed-loop control in young children with type 1 diabetes. Wadwa RP, Reed ZW, Buckingham BA, DeBoer MD, Ekhlaspour L, Forlenza GP, Schoelwer M, Lum J, Kollman C, Beck RW, Breton MD; PEDAP Trial Study Group. N Engl J Med. 2023 Mar 16;388(11):991-1001.
[2] A randomized trial of closed-loop control in children with type 1 diabetes. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza GP, Cengiz E, Schoelwer M, Ruedy KJ, Jost E, Carria L, Emory E, Hsu LJ, Oliveri M, Kollman CC, Dokken BB, Weinzimer SA, DeBoer MD, Buckingham BA, Cherñavvsky D, Wadwa RP; iDCL Trial Research Group. N Engl J Med. 2020 Aug 27;383(9):836-845.
[3] Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, Levy CJ, Pinsker JE, Wadwa RP, Dassau E, Doyle FJ 3rd, Anderson SM, Church MM, Dadlani V, Ekhlaspour L, Forlenza GP, Isganaitis E, Lam DW, Kollman C, Beck RW; N Engl J Med. 2019 Oct 31;381(18):1707-1717.
[4] MiniMed 770G System-P160017/S076. U. S. Food and Drug Administration, December 23, 2020.
[5] FDA authorizes Omnipod 5 for ages 2+ in children with type 1 diabetes. Juvenile Diabetes Research Foundation news release, August 22, 2022
Links:
Type I Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Artificial Pancreas (NIDDK)
Marc Breton (University of Virginia, Charlottesville)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
Insulin-Producing Organoids Offer Hope for Treating Type 1 Diabetes
Posted on by Dr. Francis Collins
For the 1 to 3 million Americans with type 1 diabetes, the immune system destroys insulin-producing beta cells of the pancreas that control the amount of glucose in the bloodstream. As a result, these individuals must monitor their blood glucose often and take replacement doses of insulin to keep it under control. Such constant attention, combined with a strict diet to control sugar intake, is challenging—especially for children.
For some people with type 1 diabetes, there is another option. They can be treated—maybe even cured—with a pancreatic islet cell transplant from an organ donor. These transplanted islet cells, which harbor the needed beta cells, can increase insulin production. But there’s a big catch: there aren’t nearly enough organs to go around, and people who receive a transplant must take lifelong medications to keep their immune system from rejecting the donated organ.
Now, NIH-funded scientists, led by Ronald Evans of the Salk Institute, La Jolla, CA, have devised a possible workaround: human islet-like organoids (HILOs) [1]. These tiny replicas of pancreatic tissue are created in the laboratory, and you can see them above secreting insulin (green) in a lab dish. Remarkably, some of these HILOs have been outfitted with a Harry Potter-esque invisibility cloak to enable them to evade immune attack when transplanted into mice.
Over several years, Doug Melton’s lab at Harvard University, Cambridge, MA, has worked steadily to coax induced pluripotent stem (iPS) cells, which are made from adult skin or blood cells, to form miniature islet-like cells in a lab dish [2]. My own lab at NIH has also been seeing steady progress in this effort, working with collaborators at the New York Stem Cell Foundation.
Although several years ago researchers could get beta cells to make insulin, they wouldn’t secrete the hormone efficiently when transplanted into a living mouse. About four years ago, the Evans lab found a possible solution by uncovering a genetic switch called ERR-gamma that when flipped, powered up the engineered beta cells to respond continuously to glucose and release insulin [3].
In the latest study, Evans and his team developed a method to program HILOs in the lab to resemble actual islets. They did it by growing the insulin-producing cells alongside each other in a gelatinous, three-dimensional chamber. There, the cells combined to form organoid structures resembling the shape and contour of the islet cells seen in an actual 3D human pancreas. After they are switched on with a special recipe of growth factors and hormones, these activated HILOs secrete insulin when exposed to glucose. When transplanted into a living mouse, this process appears to operate just like human beta cells work inside a human pancreas.
Another major advance was the invisibility cloak. The Salk team borrowed the idea from cancer immunotherapy and a type of drug called a checkpoint inhibitor. These drugs harness the body’s own immune T cells to attack cancer. They start with the recognition that T cells display a protein on their surface called PD-1. When T cells interact with other cells in the body, PD-1 binds to a protein on the surface of those cells called PD-L1. This protein tells the T cells not to attack. Checkpoint inhibitors work by blocking the interaction of PD-1 and PD-L1, freeing up immune cells to fight cancer.
Reversing this logic for the pancreas, the Salk team engineered HILOs to express PD-L1 on their surface as a sign to the immune system not to attack. The researchers then transplanted these HILOs into diabetic mice that received no immunosuppressive drugs, as would normally be the case to prevent rejection of these human cells. Not only did the transplanted HILOs produce insulin in response to glucose spikes, they spurred no immune response.
So far, HILOs transplants have been used to treat diabetes for more than 50 days in diabetic mice. More research will be needed to see whether the organoids can function for even longer periods of time.
Still, this is exciting news, and provides an excellent example of how advances in one area of science can provide new possibilities for others. In this case, these insights provide fresh hope for a day when children and adults with type 1 diabetes can live long, healthy lives without the need for frequent insulin injections.
References:
[1] Immune-evasive human islet-like organoids ameliorate diabetes. [published online ahead of print, 2020 Aug 19]. Yoshihara E, O’Connor C, Gasser E, Wei Z, Oh TG, Tseng TW, Wang D, Cayabyab F, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM. Nature. 2020 Aug 19. [Epub ahead of publication]
[2] Generation of Functional Human Pancreatic β Cells In Vitro. Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA. Cell. 2014 Oct 9;159(2):428-39.
[3] ERRγ is required for the metabolic maturation of therapeutically functional glucose-responsive β cells. Yoshihara E, Wei Z, Lin CS, Fang S, Ahmadian M, Kida Y, Tseng T, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM. Cell Metab. 2016 Apr 12; 23(4):622-634.
Links:
Type 1 Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Pancreatic Islet Transplantation (National Institute of Diabetes and Digestive and Kidney Diseases)
“The Nobel Prize in Physiology or Medicine 2012” for Induced Pluripotent Stem Cells, The Nobel Prize news release, October 8, 2012.
Evans Lab (Salk Institute, La Jolla, CA)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute
