In 1964, Dr. Arnold Kadish used real-time glucose monitoring to adjust insulin infusion in a patient with diabetes and introduced the concept of a closed-loop system of insulin delivery. A decade later, several research groups developed closed-loop systems that linked glucose monitors with insulin pumps and determined how much insulin to deliver based on calculations from a set of algorithms [1, 2]. These big, bulky machines depended on intravenous routes of glucose sensing and insulin infusion. While the products in development today have evolved, they utilize the same basic components: a glucose sensor, a complex algorithm, and an insulin pump. This automated closed loop system of insulin delivery is also known as an artificial pancreas.
Further research in insulin treatment includes selective islet cell transplantation and the molecular engineering of liver cells to create new beta cells.
Let’s take a look at these recent advances in treatments for type 1 diabetes, starting with the artificial pancreas.
The artificial pancreas
Currently, some individuals with type 1 diabetes use subcutaneous insulin pump therapy along with continuous glucose monitoring, in what is known as a “sensor-augmented insulin pump.” There are various insulin pumps and continuous glucose monitor systems (CGMS) available. In addition to subcutaneous insulin pumps (which a patient must manually change every 3 days), there are also intraperitoneal insulin pumps that are implanted by a minor surgical procedure. These are less common, though they may offer some benefits compared to subcutaneous pumps (such as faster onset of insulin action) . However, after implantation, these pump reservoirs need to be refilled transcutaneously at least every 3 months, a procedure performed in a clinic setting. For CGMS, as opposed to finger stick checking, people with diabetes can purchase a glucose sensor and place it under the abdominal skin to measure interstitial glucose concentration in real-time.
At present, a glucose sensor can alert the patient of high or low blood sugar, but the patient must make the necessary adjustments to modify their insulin treatment. Researchers are racing to “close the loop” between glucose sensors and insulin pumps. With newer technologies, the information from a glucose sensor is transmitted to a receiver, the “brain” of the system, which tells the pump how much insulin to deliver. The goal would be to have a device that is the size of a cell phone that would automatically deliver physiologic amounts of insulin. Besides removing the burden of self-monitoring glucose and insulin administration, an artificial pancreas could also be an effective way to achieve intensive glycemic control in type 1 diabetes. Intensive insulin therapy is currently the standard of care to obtain tight glycemic control for younger, healthier patients, using either multiple daily injections of insulin or insulin pumps. Intensive control has been shown to decrease the rates of retinopathy, nephropathy, and neuropathy in type 1 diabetes, as well as decrease fatal and nonfatal cardiovascular events [4, 5]. Of note, the optimal level of glycemic control should still be individualized, as older patients with multiple comorbidities or limited life expectancies are unlikely to benefit from the long-term effects of intensive glycemic control. One of the major complications of intensive glycemic control is an increased risk of hypoglycemia . Could an artificial pancreas reduce the incidence of hypoglycemic events in these patients?
Another recent study published in the New England Journal of Medicine compared the efficacy and safety of using an artificial pancreas system to a sensor-augmented pump in 56 subjects with type 1 diabetes at a diabetes camp . Campers were 10 to 18 years of age, on insulin pump therapy for at least 3 months, had a hemoglobin A1c of 7 to 10%, and a BMI below the 97th percentile. This randomized crossover trial was conducted on two consecutive nights. Participants in one group received treatment with an artificial pancreas on the first night (the MD-Logic Artificial Pancreas system) and a sensor-augmented insulin pump on the second night (Medtronic’s Paradigm VeoÒ) and participants in the second group received the same treatments in the opposite order. The primary outcome of the study was the number of hypoglycemic events (defined as a sensor value <64 mg/dL for at least 10 consecutive minutes). On the night when the artificial pancreas was used, there were significant decreases in the number of hypoglycemic events (7 vs. 22, p=0.003) and the time during which the glucose level was below 60 mg/dL (p=0.02). There were no significant differences in the median overnight glucose levels. In this study, the artificial pancreas caused fewer nocturnal episodes of hypoglycemia than the sensor-augmented pump. This could have been due to a number of factors, such as better control of quantity and timing of insulin delivery. Though the length of the study was limited, this study again demonstrates important potential benefits of using an artificial pancreas in the treatment of type 1 diabetes.
Hovorka et al. also compared conventional insulin pump therapy to a closed loop delivery of insulin overnight in two randomized controlled crossover studies . In these studies, subcutaneous glucose was measured by a continuous glucose monitoring system, and the insulin pump was a study pump. The two studies created two different eating scenarios for participants. In the first study, participants mimicked “eating in” for dinner, and in the second they mimicked “eating out” a heavier meal with wine included. The study included 24 adults, aged 18-65 years, who had used an insulin pump for at least 3 months. In the closed loop system in this study, glucose measurements were transmitted into a computer algorithm, which guided insulin pump infusion rates at 15-minute intervals. The primary outcome was the time that plasma glucose levels were at goal. The investigators found that the closed loop delivery system significantly increased this duration by a median of 22 percent (3-37%, P<0.001). The closed loop system also significantly reduced nocturnal hypoglycemia by a median 3 percent (p=0.04). During the trial, study personnel transmitted data manually from the continuous glucose monitor to the computer running the closed loop system and from the computer to the insulin pump. A research nurse entered the data and adjusted the insulin pump, so the system was not fully automated. Nonetheless, this study shows the potential for an automated insulin pump system to effectively control glucose in this population.
To make this technology more accessible, a study showed that a smart phone is capable of running a closed-loop control system in the outpatient setting . This research was not conducted to test the clinical outcome of the device, but was done to show the technology was feasible to treat outpatients at four different centers in the U.S., Italy and France. This study used the OmnipodÒ insulin pump and a sensor, with a device that transmitted data through either 3G or WiFi to servers that allowed for remote observation. A total of 20 adults (age 21-65 years) were monitored over 42 hours. On the first night of the study, the “Diabetes Assistant” was used in an open-loop mode using the subjects’ home insulin parameters. The next morning, the system was switched to a closed loop model. The system was reported to work 90% of the time. Participants could wear the device while using a treadmill or riding a bike, demonstrating that they could move about freely. Patients could shower, but only if the device was kept outside of the shower. There were also some other issues that cannot be neglected. For example, one subject dropped the communication tablet and attempts to restart it were unsuccessful. And even though the system worked most of the time, a few patients did develop mild ketosis or hypoglycemia. While the technology might be almost ready, there are certainly many kinks to work out.
There are a number of limitations to the current models for an artificial pancreas, such as what happens when your computer malfunctions. In addition, the accuracy of CGMS is questionable. A continuous glucose monitor measures glucose in the interstitial fluid. However, there is a known delay between the interstitium and plasma. How much of a lag time between a change in a patient’s blood glucose, and a response of the system, could a patient tolerate? And what are these mysterious algorithms, anyway? While the details of such algorithms are beyond the scope of this article, the general principle is that an algorithm should control insulin infusion rates based on a patient’s recent glucose values, recent insulin infusion, and individual-specific information on insulin sensitivity. Also, often more insulin is required in the pre-dawn hours in persons with well-controlled type 1 diabetes . The algorithm is the brain of this operation, and would need to be perfected to account for physiologic changes like the dawn phenomenon. Other studies are investigating the potential benefit of a multi-hormonal artificial pancreas that regulate glucose levels . Finally, how much would an artificial pancreas cost? Would an artificial pancreas ultimately be more or less expensive than a pump and its supplies? A pump and its supplies often cost more than $5000 per year, and a sensor can cost $1000 per year.
Pancreatic and Islet cell transplantation
Since there are many obstacles to creating a bionic pancreas, other researchers are investigating the possibility of curing diabetes with a transplant. The availability of whole pancreases for transplantation is low. Major surgery is involved, the recipients require steroid treatment that increases the demands of the new organ, and there is a long list of patients waiting for scarce donor organs.
Another option is to perform more selective islet cell transplantation, which requires minimally invasive surgery . In 2000, researchers in Edmonton, Canada, published the first research of the infusion of islet cells into the liver through a catheter in the portal vein in seven patients, who were then maintained on an immunosuppressive regimen that did not include steroids . This study and other reports of successful islet cell transplantation created hope for a cure of diabetes. However, in many cases the “Edmonton procedure” has failed to live up to its expectations. Multiple donors are needed for each islet cell infusion, and patients require repeated transplants to achieve insulin independence. An international trial of islet cell transplants found that 66% of the recipients required conventional insulin therapy within a year and 75% after 2 years . Recipients also need to be maintained on lifelong immunosuppression, which is associated with a myriad of complications. While there are ongoing clinical trials to improve islet cell transplantation, other researchers are exploring further options to cure diabetes, including molecular engineering .
Most attempts to prevent beta cell destruction in the early stages of type 1 diabetes with immunosuppressive drugs targeting T lymphocytes have not been successful; a patient is forced to trade off diabetes for the risks of life-long immunosuppressive therapy with its attendant risks . On the other hand, a research team led by investigators Dr. Fiaschi-Taesch and Dr. Andrew Stewart discovered a novel way to stimulate the replication of beta cells. Human beta cells contain a protein called cdk-6. When the level of cdk-6 is increased, beta cells multiply. This could be translated into clinical use by either targeting this pathway to generate new beta cells in patients with diabetes, or by creating drugs that turn on beta cell replication . Such a technique might be especially effective in the early stages of type 1 diabetes, while there are still some remaining beta cells. Given the current limitations to long-term success with islet cell transplantation, and the limited supply of donor pancreatic cells, researchers are also investigating the molecular engineering of beta cells for diabetes therapy. Sapir et al. were able to induce human hepatocytes to transdifferentiate into functioning beta cells using a single gene (the pdx-1 gene) . Perhaps, in the future, with this technique, a patient’s own liver cells could be turned into insulin-secreting cells, eliminating the need for immunosuppression. These are exciting biologic areas of research with the potential to replace artificial insulin pumps.
About 5-10% of patients with diabetes in the United States have type 1 diabetes. Each year, more than 13,000 young people are diagnosed with type 1 diabetes, and its incidence is rising . An artificial or new bionic pancreas would undoubtedly change the lives of thousands of people, whether computer generated, harvested from donor islet cells or grown in a laboratory from stimulated or transdifferentiated cells. Even if this revolutionary advance succeeds in the reproduction of native insulin, it still might lack the fine tuning of the normal pancreas, in which insulin production is regulated by other islet hormones: glucagon, somatostatin and amylin. For now, there is more work to be done, but a recreated endocrine pancreas seems closer to a reality.
Dr. Karin Katz is a 3rd year resident at NYU Langone Medical Center
Dr. Loren Wissner Greene is an Clinical Associate Professor of Medicine and ObGyn, NYU School of Medicine
Image courtesy of Wikimedia Commons
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