Artificial Pancreas: Past, Present, and Future

Educational Objectives

The goal of this program is to improve the management of diabetes. After hearing and assimilating this program, the clinician will better be able to:

1. Discuss the state of research on a fully automated artificial pancreas.

Summary

Historical background

In the 1920s, Dr. William D. Sansum first purified and administered insulin. Most subsequent developments involved altering the time frame of insulin action (eg, short-acting, long-acting) and greater purification of insulin.

In the late 1950s, a physician at the Cleveland Clinic began considering using engineering and feedback loops to mimic how the body naturally controls glucose levels.

In the 1970s, Albisser et al helped to create the Biostator. This large device uses intravenous (IV) glucose monitoring and infuses insulin and/or glucose to optimize glucose levels. It continues to be used for insulin sensitivity calculations when new drugs are introduced. It is impractical for long-term use because of the large size of the device and the reliance on IV measurement.

Insulin pumps

The development of insulin pumps was a major advance. Over the years, the pumps have become more sophisticated, smaller, and more accurate. Physicians can set the pumps to deliver the appropriate amount of insulin at the appropriate time. The pumps also give patients more flexibility (eg, they can decrease their insulin dose when they exercise or give a correction bolus).

Continuous glucose monitors

About 10 years ago, continuous glucose monitors (CGM) became available. These devices have small wires that go under the skin. They use the same enzyme as glucose strips (ie, glucosidase). A chemical reaction produces hydrogen peroxide and electrons. The sensing wire counts electrons. Calibration values are input using a glucometer. With CGM, it becomes possible to obtain glucose readings hundreds of times a day.

Artificial pancreas system

Once input data from CGMs became available, a closed loop system became possible.

Every 5 minutes a glucose value is obtained from the CGM. A program (on a laptop, tablet, or smartphone) makes decisions about insulin delivery, and the pump delivers the dose.

About 5 years ago, Zisser et al began developing the Artificial Pancreas System (APS), which involved working with device manufacturers to test the control algorithms.

Issues of accuracy and delays

Because the CGM is reading glucose levels in the interstitial fluid, there can be a delay of 5, 10, or 15 minutes, depending on the rate of change of glucose. Newer sensors are more accurate.

There also is a delay in insulin action. Initially, subcutaneous insulin was used. To address delays in insulin action, intraperitoneal insulin delivery using the DiaPort is being tested. Regular insulin is delivered via a pump through a port in the abdominal wall. The advantage is that insulin is delivered to the liver in 4 to 5 minutes. The system can be turned on and off more quickly.

The second-generation DiaPort overcomes problems with local skin irritation and infection that were present with the first-generation device. Patients should be able to keep the port in place for several years and change the catheter every 6 to 12 months.

Inhaled insulin

A study is underway using inhaled insulin as a first-phase insulin. In people who do not have diabetes, the smell of food causes a small secretion of insulin from the pancreas. In the study, a small inhaled insulin dose is given at mealtimes to replicate that effect. Subcutaneous insulin is otherwise used.

Zisser et al also are considering combining intraperitoneal insulin with inhaled insulin to see if that will help turn insulin on and off faster.

Correcting hypoglycemia

Automatically correcting hypoglycemia is a difficult problem. An automated glucagon rescue system is being worked on. If the patient has profound hypoglycemia and is not responding, glucagon is delivered. One problem with this approach is that glucagon is not very stable in liquid.

Some investigators are working on a dual hormone control artificial pancreas that control delivery of both insulin and glucagon.

Some insulin pump companies are working on low-glucose suspend products that will stop insulin delivery if glucose is too low.

Sensor accuracy

The first day of use of most sensors tends to be the most inaccurate, which may relate to trauma associated with implantation, bleeding, or an inflammatory response.

In general, sensors have become more accurate. Today, the mean absolute relative difference is 12% to 15%, whereas it was ≈20% in the past.

There is a quandary, however. The sensor is in the interstitial space. It is calibrated with a fingerstick test, and a laboratory reference machine is used to determine the standard. Among the three different spaces used to measure, how is it possible to know which one is correct?

Summary

All aspects of the artificial pancreas are being worked on; it is not one thing. It may involve, for example, a low-glucose suspend device, remote monitoring of the glucose and insulin levels of a loved one, overnight control, or a missed-meal bolus alert. Work is progressing on a system that is fully automated all the time.

Readings

Peripheral arterial disease in people with diabetes. Diabetes Care 2003;26:3333-41; Breton M et al: Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose control maintains near normoglycemia. Diabetes 2012;61:2230-7; Dassau E et al: Clinical evaluation of a personalized artificial pancreas. Diabetes Care 2013;36:801-9; Diehm C et al: High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 2004;172:95-105; DiPietro L et al: Three 15-min bouts of moderate postmeal walking significantly improves 24-h glycemic control in older people at risk for impaired glucose tolerance. Diabetes Care 2013;36:3262-8; Faglia E et al: Screening for peripheral arterial disease by means of the ankle-brachial index in newly diagnosed Type 2 diabetic patients. Diabet Med 2005;22:1310-4; Fowkes FG et al: Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329-40; Gregg EW et al: Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care 2004;27:1591-7; Jaiswal M et al: Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort: A pilot study. Diabetes Care 2013;36:3903-8; Jude EB et al: Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care 2001;24:1433-7; Kovatchev BP et al: Feasibility of outpatient fully integrated closed-loop control: first studies of wearable artificial pancreas. Diabetes Care 2013;36:1851-8; Takahara M et al: The influence of glycemic control on the prognosis of Japanese patients undergoing percutaneous transluminal angioplasty for critical limb ischemia. Diabetes Care 2010;33:2538-42; Wassel CL et al: Family history of peripheral artery disease is associated with prevalence and severity of peripheral artery disease: the San Diego population study. J Am Coll Cardiol 2011;58:1386-92.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following was disclosed: Dr. Anderson reported relationships with Amylin Pharmaceuticals (B), Daichii Sankyo Company. (B), Eli Lilly and Company (B), Novo Nordisk (B), and sanofi-aventis US (A). Dr. Zisser reported a relationship with Abbot Diabetes Care (C), Animas Corporation (A), Artificial Pancreas Technologies (A), Cellnovo (A), Dexcom, Inc. (C), Eli Lilly and Company (C), GluMetrics, Inc. (C), Insulet Corporation (A), Lifescan, Inc. (C), MannKind Corporation (A), Medtronic (C), Novo Nordisk, Inc. (C), Roche Pharmaceuticals (A), sanofi-aventis (C). The members of the planning committee reported nothing to disclose.

A=Advisory panel B=Speakers bureau C=Consultant G=Grant or other research support

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

DI050304

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.