these blog posts are written by Dr. alfredo G. Tomasselli, a Retired bio-Chemist and Bio-physicist who spent his life in Academia and The Pharmaceutical Industry researching cures and treatments for diseases such as HIV/Aids, Diabetes, and Rheumatoid arthritis. His daughter sara inspires this blog and helps to write posts. sara was diagnosed with type 1 diabetes on april 4th, 2014 at the age of 30. 

2016 Closing the loop: the “Artificial Pancreas” is approaching approval for use in Type 1 Diabetes people

This document is for informational purposes only and cannot be taken to make medical or other personal decisions

Summary

 People with Type 1 Diabetes (T1D) have lost the ability to make sufficient insulin to control their blood glucose. Managing the disease properly to avoid, or at least delay, long-term health complications is difficult and annoying as it requires monitoring glucose levels with multiple finger pricks and injecting insulin manually to match carbohydrates ingested and exercise performed. A complete automated system, the “artificial pancreas”, is being developed by various companies; it is an automated multifunctional wearable device that continuously monitors glucose levels and sends real-time data to an algorithm center (a smart-phone) which is able to instruct a pump to subcutaneously deliver precise amounts of insulin only when needed.  “Artificial pancreases” capable to deliver glucagon to better cope with hypoglycemic episodes are also in development. Indeed, the “artificial pancreas” expectation is to keep body glucose levels within a fixed range while minimizing hypo- and hyper-glycemia and providing relief to the patient. However, to be widely accepted, this multifunctional device incorporating such a high level of technology needs to be both easily wearable and operable by the patient. It must also demonstrate the ability to carry out its multiple tasks in an efficient, seamless, and SAFE way.  Moreover, it should be affordable and/or acceptable to insurance agencies for expense reimbursements. It is expected that the first “artificial pancreas” on the market will be followed by continuously improved systems in terms of varieties of tasks they can perform, efficiency, precision, size, and patients’ operability to become used by a sizable number of people with T1D.  The medical devices company Medtronic has now completed a US key clinical trial of its MiniMed 670G/Enlite 3 hybrid closed loop system for insulin delivery. This system is not yet completely automatic as it still requires some manual operations to control glucose properly, but it is an interesting start.  An application has been sent to the Food and Drug Administration (FDA) for approval of this system for marketing. If the approval procedure goes smoothly, it is estimated that the MiniMed 670G/Enlite 3 should be available to T1D people within one year. 

Narrative

 The main feature of Type 1 Diabetes (T1D) is the inability of the body to produce insulin, a protein hormone that helps certain body cells, such as those of the muscles and adipose tissue, to take up blood glucose which is then used to produce energy to sustain life. Insulin is produced and released by the β-cells housed within the islets of Langheran (footnote i) of the pancreas in response to blood glucose elevation; moreover, the islets of Langheran also contain α-cells that release the hormone glucagon into the blood stream when sugar gets low, e.g., when a person skips a meal and/or performs physical exercise. The release of glucagon by the pancreas stimulates the production of glucose by the liver to restore normoglycemia (Figure 1).

In T1D the β-cells are attacked and silenced and/or killed by a dysfunctional immune system and fail to supply the needed insulin. Without insulin the level of glucose rises to dangerous levels and failure to bring it back within a normal range causes health complications and can be fatal. In fact, T1D was a fatal disease until insulin’s discovery in 1921 by Banting, Best, McLeod, and Collip, at the University of Toronto. Since its discovery, insulin has become the mainstay of T1D and various chemical/biochemical modifications along with continuous improvements in glucose monitoring technology (critical to verify if therapy works) over the span of nearly 95 years, have transformed a once deadly disease into a manageable one. Insulin therapy has raised the bar so high that any other approach studied thus far to treat T1D has fallen short of becoming a therapy with the exception of pancreas and islets transplant procedures. These pancreas and islet transplants have brought benefits to a relatively small percentage of patients mainly due to shortage of pancreases. Moreover, these are not permanent cures as they are only effective for a few years and suffer serious drawbacks as both require immune-suppressant drugs that are rather toxic.

Managing the disease properly to avoid, or at least delay, long-term health complications, is a demanding task requiring a combination of daily insulin injections, good diet, exercise, and a careful monitoring of glucose levels. Therefore, a cure for the already affected people (estimated between 1.5 to 3.0 million in the USA alone) is needed. Throughout this blog we have already extensively described the intense research undertaken worldwide to find a permanent cure based on both replacement of the dysfunctional β-cells and restoration of the faulty immune system to make it not attack β-cells. However, we also recognized that these are daunting tasks and may take many years to come to fruition.  

A more modest, yet very important, therapeutic goal is to improve current exogenous insulin therapy by means of a complete automated system which would be able to deliver the correct amount of insulin matched to daily lifestyle. This system, also referred to as the “artificial pancreas”, is already in an advanced phase clinical trial and will soon be on the market. It is composed of a continuous glucose (CG) monitor that sends real-time glucose concentrations’ data to an algorithm center (AC) which instructs a pump for subcutaneous insulin delivery. There are also systems in development designed to deliver glucagon when the blood sugar gets too low.  Such systems should be able to deliver accurate amounts of insulin to match the carbohydrate content and the size of the meal, or glucagon, and keep body glucose levels within a fixed range while largely avoiding hypo- and hyper-glycemia (Figure 2).

The diaTribe Foundation has compiled a list of organizations at the forefront in “Artificial Pancreas” research and development. They include plans for key studies and FDA submission for the product; their article was updated on May 27, 2016: http://diatribe.org/artificialpancreas.

Moreover, Dr. Hood Thabit and Dr. Roman Hovorka of the University of Cambridge, UK just published a comprehensive review reporting on “the progress being made in the development and evaluation of closed-loop systems in outpatient settings” (Reference 1, 10.1007/s00125-016-4022-4 ).

The medical devices company Medtronic has now completed a US key clinical trial of its MiniMed 670G/Enlite 3 hybrid closed loop system involving 124 patients; the description and results of the trial were presented to the American Diabetes Association's (ADA) 76th Annual Scientific Sessions. Important aspects of the trial and the MiniMed 670G/Enlite 3 features are detailed by the diaTribe Foundation at http://diatribe.org/drugdevice-name/medtronic-minimed-670g . Here are some highlights put together by using the diaTribe Foundation narrative as basis: 

The baseline of the study was a two-week “open-loop” period during which 94 adults and 30 adolescents participating in the study wore the MiniMed 670G insulin pump plus Enlite 3 CGM, but the two devices were not connected for automatic insulin delivery. After this preliminary phase, all participants were switched to a “hybrid closed loop” phase where the two devices were connected for automatic insulin delivery. This latter phase lasted three months and the participants were left unsupervised to their normal daily lives.   

Relevant RESULTS: patients started the trials with an average A1C of 7.0 and at trial’s end A1C was 6.9 (a 0.5% decrease), with 58% of the patients hitting their goal. The times spent with low blood glucose (under 70mg/dl) and dangerous hypoglycemia  (under 50 mg/dl) were reduced by 44% and 40%, respectively. There was also an 8% increase in the time spent in-the-range (71-180 mg/dl) and an 11% drop in the time spent over 180 mg/dl.

These patients were already managing their diabetes reasonably well, and improving it by the use of this system was an important accomplishment. It is remarkable that more than 100 participants/124 requested to continue access to the MiniMed 670G/Enlite 3, a fact that underlines the favorable opinion for this system by a high percentage of participants.

MiniMed 670G/Enlite 3 is somewhat different from the idealized system depicted in Figure 2: (1) it carries the insulin pump (monohormone system); of course, being able to control blood sugar properly without the use of glucagon would be a big plus as glucagon is a relatively unstable protein requiring daily reconstitution and is expensive. (2) The 670G algorithm has the nice feature of being fully integrated with the pump allowing a patient to wear the Enlite 3 CGM sensor and the MiniMed 670G pump without the need to carry a separate CGM receiver or phone; (3) The MiniMed 670G measures blood glucose every 5 minutes and needs recalibration every 12 hours against the glucose values determined by finger sticks; the glucose sensor is replaced weekly. (4) The insulin reservoir has to be refilled every 3 days. (5) The system delivers basal insulin only; this is a significant limitation as the patient needs to count carbohydrates and give himself/herself meal boluses. However, automatic correction boluses will be a part of the next generation systems.

Medtronic has applied to the Food and Drug Administration (FDA) for approval of this system. If the approval procedure goes smoothly, it can be estimated that the first system should be available to T1D people in 2017.

In conclusion, the “artificial pancreas” expectation is to keep body glucose levels within a fixed range while minimizing hypo- and hyper-glycemia and providing relief to the patient. However, to be widely accepted, this multifunctional device incorporating such a high level technology needs to be both easily wearable and operable by the patient, and needs to demonstrate ability to carry out its multiple tasks in an efficient, seamless, and SAFE way. Moreover, it should be affordable and/or acceptable to insurance agencies for expense reimbursements. It is expected that the first “artificial pancreas” on the market (most likely the MiniMed 670G/Enlite 3 hybrid closed loop system) will be quickly followed by continuously improved systems in terms of varieties of tasks they can perform, efficiency, precision, size, and patient’s operability to become used by a sizable number of people with T1D.

References

  1. Hood Thabit and Roman Hovorka. Coming of age: the artificial pancreas for type 1 diabetes. Diabetologia,  published on line June 2016 DOI: 10.1007/s00125-016-4022-4

     

    Footnotes

  1. The islets of the Langheran are small (about 0.2 mm diameter) clusters of cells disseminated across the pancreas constituting 1-2% of its mass. They contain glycemic regulatory hormones producing cell species such as: (I) β-cells that produce insulin and amylin (each islet contains approximately 1,000 β-cells, i.e., they constitute the majority of the cells of the islet); amylin, co-secreted with insulin, is involved in preventing spikes in blood glucose after meals by slowing down gastric emptying and fostering satiety; and (II) α-cells that produce glucagon that raises the glucose concentration in the blood, thus opposing the insulin glucose-lowering activity.

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