Development and in silico validation of the PID-algorithm for the artificial pancreas with intraperitoneal insulin delivery

Background: The efficacy of the treatment of type 1 diabetes can be markedly improved using artificial pancreas (AP), which is a technology to automatically control blood glucose levels.

Aim: In this paper, we propose the construction of a controller for controlling the automated delivery of insulin in AP based on a proportional–integral–derivative (PID) algorithm using intraperitoneal (IP) insulin delivery.

Methods: The project used rapid-acting insulin in the IP space when setting up a PID controller with feedback to ensure the safe and efficient delivery of insulin. The controller was configured to satisfy feedback insulin present in blood. Controller check was performed In Silico using the metabolic simulator UVA|Padova T1DMS on 10 virtual patients.

Results: The proposed controller design has time to reach 83% within the glycaemic range of 70–140 mg/dl (3.9–7.8 mmol/l), without time spent in hypoglycaemia.

Conclusions: In a future study we plan to test this controller in vivo to evaluate its performance in vivo.

аrtificial pancreas, intraperitoneal insulin infusion, in silico, control algorithm, insulin pump, preclinical studies

1. Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care. 2002;25(3):593-598.

2. Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363(4):311-320. doi: 10.1056/NEJMoa1002853

3. Doyle FJ, 3rd, Huyett LM, Lee JB, et al. Closed-loop artificial pancreas systems: engineering the algorithms. Diabetes Care. 2014;37(5):1191-1197. doi: 10.2337/dc13-2108

4. Renard E, Place J, Cantwell M, et al. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas. Diabetes Care. 2010;33(1):121-127. doi: 10.2337/dc09-1080

5. Dassau E, Renard E, Place J, et al. Intraperitoneal insulin delivery provides superior glycaemic regulation to subcutaneous insulin delivery in model predictive control-based fully-automated artificial pancreas in patients with type 1 diabetes: a pilot study. Diabetes, Obesity and Metabolism. 2017;19(12):1698-1705. doi: 10.1111/dom.12999

6. Карпельев В.А., Федорова Е.А., Филиппов Ю.И., и др. Интраперитонеальная инфузия инсулина при сахарном диабете: на пути к искусственной поджелудочной железе // Сахарный диабет. – 2015. – Т. 18. – №3. – C. 32-45. [ Karpel'ev VA, Fedorova EAe, Philippov YI, et al. Intraperitoneal insulin infusion: on the way to the artificial pancreas. Diabetes mellitus. 2015;18(3):32-45.] doi: 10.14341/dm2015332-45

7. Botz CK, Leibel BS, Zingg W, et al. Comparison of peripheral and portal routes of insulin infusion by a computer-controlled insulin infusion system (artificial endocrine pancreas). Diabetes. 1976;25(8):691-700.

8. Homko C, Deluzio A, Jimenez C, et al. Comparison of insulin aspart and lispro: pharmacokinetic and metabolic effects. Diabetes Care. 2003;26(7):2027-2031.

9. Schaepelynck Belicar P, Vague P, Lassmann-Vague V. Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes Metab. 2003;29(4 Pt 1):344-348.

10. Grosman B, Dassau E, Zisser HC, et al. Zone model predictive control: a strategy to minimize hyper- and hypoglycemic events. J Diabetes Sci Technol. 2010;4(4):961-975. doi: 10.1177/193229681000400428

11. Steil GM, Panteleon AE, Rebrin K. Closed-loop insulin delivery-the path to physiological glucose control. Adv Drug Deliv Rev. 2004;56(2):125-144.

12. Huyett LM, Dassau E, Zisser HC, Doyle FJ, 3rd. Design and Evaluation of a Robust PID Controller for a Fully Implantable Artificial Pancreas. Ind Eng Chem Res. 2015;54(42):10311-10321. doi: 10.1021/acs.iecr.5b01237

13. Argoud GM, Schade DS, Eaton RP. Insulin suppresses its own secretion in vivo. Diabetes. 1987;36(8):959-962.

14. Steil GM, Palerm CC, Kurtz N, et al. The effect of insulin feedback on closed loop glucose control. J Clin Endocrinol Metab. 2011;96(5):1402-1408. doi: 10.1210/jc.2010-2578

15. Palerm CC. Physiologic insulin delivery with insulin feedback: a control systems perspective. Comput Methods Programs Biomed. 2011;102(2):130-137. doi: 10.1016/j.cmpb.2010.06.007

16. Steil GM, Rebrin K, Darwin C, et al. Feasibility of automating insulin delivery for the treatment of type 1 diabetes. Diabetes. 2006;55(12):3344-3350. doi: 10.2337/db06-0419

17. Nathan DM, Dunn FL, Bruch J, et al. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am J Med. 1996;100(4):412-417. doi: 10.1016/S0002-9343(97)89516-2

18. Patek SD, Bequette BW, Breton M, et al. In silico preclinical trials: methodology and engineering guide to closed-loop control in type 1 diabetes mellitus. J Diabetes Sci Technol. 2009;3(2):269-282. doi: 10.1177/193229680900300207

19. Kovatchev BP, Breton M, Man CD, Cobelli C. In silico preclinical trials: a proof of concept in closed-loop control of type 1 diabetes. J Diabetes Sci Technol. 2009;3(1):44-55. doi: 10.1177/193229680900300106

20. Man CD, Micheletto F, Lv D, et al. The UVA/PADOVA Type 1 Diabetes Simulator: New Features. J Diabetes Sci Technol. 2014;8(1):26-34. doi: 10.1177/1932296813514502

21. Lee JJ, Dassau E, Zisser H, Doyle FJ, 3rd. Design and in silico evaluation of an intraperitoneal-subcutaneous (IP-SC) artificial pancreas. Comput Chem Eng. 2014;70:180-188. doi: 10.1016/j.compchemeng.2014.02.024

22. Liebl A, Hoogma R, Renard E, et al. A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion. Diabetes Obes Metab. 2009;11(11):1001-1008. doi: 10.1111/j.1463-1326.2009.01059.x