Skip to main content

05-13-2017 | Devices and technology | Review | Article

A Review of the Current Challenges Associated with the Development of an Artificial Pancreas by a Double Subcutaneous Approach

Journal: Diabetes Therapy

Authors: Sverre Christian Christiansen, Anders Lyngvi Fougner, Øyvind Stavdahl, Konstanze Kölle, Reinold Ellingsen, Sven Magnus Carlsen

Publisher: Springer Healthcare




Patients with diabetes type 1 (DM1) struggle daily to achieve good glucose control. The last decade has seen a rush of research groups working towards an artificial pancreas (AP) through the application of a double subcutaneous approach, i.e., subcutaneous (SC) continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion. Few have focused on the fundamental limitations of this approach, especially regarding outcome measures beyond time in range.


Based on insulin physiology, the limitations of CGM, SC insulin absorption, meal challenge, and physical activity in DM1 patients, we discuss the limitations of the double SC approach. Finally, we discuss safety measures and the achievements reported in some recent AP studies that have utilized the double SC approach.


Most studies show that a double SC AP increases the time in range compared to a sensor-augmented insulin pump and shortens the time in hypoglycemia. Despite these achievements, the proportion of time spent in hyperglycemia is still roughly 20–40%, and hypoglycemia is still present 1–4% of the time. The main factors limiting further progress are the latency of SC CGM (at least 5–10 min) and the slow pharmacokinetics of SC-delivered fast-acting insulin. The maximum blood insulin level is reached after 45 min and the maximum glucose-lowering effect is observed after 1.5–2 h, while the glucose-lowering effect lasts for at least 5 h.


Although using a double SC AP leads to significant improvements in glucose control, the SC approach has severe limitations that hamper further progress towards a robust AP.
Sovik O, Thordarson H. Dead-in-bed syndrome in young diabetic patients. Diabetes Care. 1999;22(Suppl 2):B40–2. PubMed
Basu A, Close CF, Jenkins D, et al. Persisting mortality in diabetic ketoacidosis. Diabet Med. 1993;10:282–4. CrossRefPubMed
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86. CrossRef
Skyler JS. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am. 1996;25:243–54. CrossRefPubMed
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9. CrossRefPubMedCentral
Le Floch JP, Kessler L. Glucose variability: comparison of different indices during continuous glucose monitoring in diabetic patients. J Diabetes Sci Technol. 2016;10:885–91. CrossRefPubMedPubMedCentral
Kohnert KD, Freyse EJ, Salzsieder E. Glycemic variability and pancreatic beta-cell dysfunction. Curr Diabetes Rev. 2012;8:345–54. CrossRefPubMed
Wandell PE. Quality of life of patients with diabetes mellitus. An overview of research in primary health care in the Nordic countries. Scand J Prim Health Care. 2005;23:68–74. CrossRefPubMed
Goldney RD, Phillips PJ, Fisher LJ, et al. Diabetes, depression, and quality of life: a population study. Diabetes Care. 2004;27:1066–70. CrossRefPubMed
Davis RE, Morrissey M, Peters JR, et al. Impact of hypoglycemia on quality of life and productivity in type 1 and type 2 diabetes. Curr Med Res Opin. 2005;21:1477–83. CrossRefPubMed
Barendse S, Singh H, Frier BM, et al. The impact of hypoglycemia on quality of life and related patient-reported outcomes in type 2 diabetes: a narrative review. Diabetes Med. 2012;29:293–302.
Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–8. CrossRefPubMed
Battelino T, Phillip M, Bratina N, et al. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011;34:795–800. CrossRefPubMedPubMedCentral
Rodbard D. Continuous glucose monitoring: a review of successes, challenges, and opportunities. Diabetes Technol Ther. 2016;18(Suppl 2):S23–213. CrossRef
Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369:224–32. CrossRefPubMed
Ly TT, Nicholas JA, Retterath A, et al. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA. 2013;310:1240–7. CrossRefPubMed
Marliss EB, Murray FT, Stokes EF, et al. Normalization of glycemia in diabetics during meals with insulin and glucagon delivery by the artificial pancreas. Diabetes. 1977;26:663–72. CrossRefPubMed
Mirouze J, Selam JL, Pham TC, et al. Evaluation of exogenous insulin homoeostasis by the artificial pancreas in insulin-dependent diabetes. Diabetologia. 1977;13:273–8. CrossRefPubMed
Albisser AM, Leibel BS, Ewart TG, et al. Clinical control of diabetes by the artificial pancreas. Diabetes. 1974;23:397–404. CrossRefPubMed
Gross TM, Bode BW, Einhorn D, et al. Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use. Diabetes Technol Ther. 2000;2:49–56. CrossRefPubMed
Nimri R, Muller I, Atlas E, et al. MD-Logic overnight control for 6 weeks of home use in patients with type 1 diabetes: randomized crossover trial. Diabetes Care. 2014;37:3025–32. CrossRefPubMed
van Bon AC, Luijf YM, Koebrugge R, et al. Feasibility of a portable bihormonal closed-loop system to control glucose excursions at home under free-living conditions for 48 hours. Diabetes Technol Ther. 2014;16:131–6. CrossRefPubMedPubMedCentral
Del Favero S, Place J, Kropff J, et al. Multicenter outpatient dinner/overnight reduction of hypoglycemia and increased time of glucose in target with a wearable artificial pancreas using modular model predictive control in adults with type 1 diabetes. Diabetes Obes Metab. 2015;17:468–76. CrossRefPubMed
Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control with an artificial pancreas at a diabetes camp. N Engl J Med. 2013;368:824–33. CrossRefPubMed
Reddy M, Herrero P, El Sharkawy M, et al. Feasibility study of a bio-inspired artificial pancreas in adults with type 1 diabetes. Diabetes Technol Ther. 2014;16:550–7. CrossRefPubMedPubMedCentral
Capel I, Rigla M, Garcia-Saez G, et al. Artificial pancreas using a personalized rule-based controller achieves overnight normoglycemia in patients with type 1 diabetes. Diabetes Technol Ther. 2014;16:172–9. CrossRefPubMedPubMedCentral
Schmidt S, Boiroux D, Duun-Henriksen AK, et al. Model-based closed-loop glucose control in type 1 diabetes: the DiaCon experience. J Diabetes Sci Technol. 2013;7:1255–64. CrossRefPubMedPubMedCentral
Dassau E, Brown SA, Basu A, et al. Adjustment of open-loop settings to improve closed-loop results in type 1 diabetes: a multicenter randomized trial. J Clin Endocrinol Metab. 2015;100:3878–86. CrossRefPubMedPubMedCentral
Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. N Engl J Med. 2014;371:313–25. CrossRefPubMedPubMedCentral
Thabit H, Tauschmann M, Allen JM, et al. Home use of an artificial beta cell in type 1 diabetes. N Engl J Med. 2015;373:2129–40. CrossRefPubMedPubMedCentral
Renard E, Farret A, Kropff J, et al. Day-and-night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: results of a single-arm 1-month experience compared with a previously reported feasibility study of evening and night at home. Diabetes Care. 2016;39:1151–60. CrossRefPubMed
Hovorka R, Elleri D, Thabit H, et al. Overnight closed-loop insulin delivery in young people with type 1 diabetes: a free-living, randomized clinical trial. Diabetes Care. 2014;37:1204–11. CrossRefPubMedPubMedCentral
Thabit H, Lubina-Solomon A, Stadler M, et al. Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study. Lancet Diabetes Endocrinol. 2014;2:701–9. CrossRefPubMedPubMedCentral
Kropff J, Del Favero S, Place J, et al. 2 month evening and night closed-loop glucose control in patients with type 1 diabetes under free-living conditions: a randomised crossover trial. Lancet Diabetes Endocrinol. 2015;3:939–47. CrossRefPubMed
Leelarathna L, Dellweg S, Mader JK, et al. Day and night home closed-loop insulin delivery in adults with type 1 diabetes: three-center randomized crossover study. Diabetes Care. 2014;37:1931–7. CrossRefPubMed
Ly TT, Roy A, Grosman B, et al. Day and night closed-loop control using the integrated Medtronic hybrid closed-loop system in type 1 diabetes at diabetes camp. Diabetes Care. 2015;38:1205–11. CrossRefPubMed
de Bock MI, Roy A, Cooper MN, et al. Feasibility of outpatient 24-hour closed-loop insulin delivery. Diabetes Care. 2015;38:e186–7. CrossRefPubMedPubMedCentral
Peyser T, Dassau E, Breton M, et al. The artificial pancreas: current status and future prospects in the management of diabetes. Ann N Y Acad Sci. 2014;1311:102–23. CrossRefPubMed
Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA. 2016;316:1407–8. CrossRefPubMed
de Bock M, Dart J, Roy A et al. Exploration of the performance of a hybrid closed loop insulin delivery algorithm that includes insulin delivery limits designed to protect against hypoglycemia. J Diabetes Sci Technol. 2017;11:68–73.
Grosman B, Ilany J, Roy A, et al. Hybrid closed-loop insulin delivery in type 1 diabetes during supervised outpatient conditions. J Diabetes Sci Technol. 2016;10:708–13. CrossRefPubMedPubMedCentral
Åstrøm KJ, Murray RM. Feedback systems: an introduction for scientists and engineers. Princeton: Princeton University Press; 2014.
Chee F, Fernando T. Closed-loop control of blood glucose. Berlin: Springer; 2007.
Kruszynska YT, Home PD, Hanning I, et al. Basal and 24-h C-peptide and insulin secretion rate in normal man. Diabetologia. 1987;30:16–21. CrossRefPubMed
Caumo A, Luzi L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab. 2004;287:E371–85. CrossRefPubMed
Grodsky GM. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest. 1972;51:2047–59.
Sorenson RL, Lindell DV, Elde RP. Glucose stimulation of somatostatin and insulin release from the isolated, perfused rat pancreas. Diabetes. 1980;29:747–51. CrossRefPubMed
Porksen N, Munn S, Steers J, et al. Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am J Physiol. 1995;269:E478–88. PubMed
Porksen N, Nyholm B, Veldhuis JD, et al. In humans at least 75% of insulin secretion arises from punctuated insulin secretory bursts. Am J Physiol. 1997;273:E908–14. PubMed
Paolisso G, Scheen AJ, Giugliano D, et al. Pulsatile insulin delivery has greater metabolic effects than continuous hormone administration in man: importance of pulse frequency. J Clin Endocrinol Metab. 1991;72:607–15. CrossRefPubMed
Matthews DR, Naylor BA, Jones RG, et al. Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes. 1983;32:617–21. CrossRefPubMed
Polonsky KS, Given BD, Van CE. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81:442–8. CrossRefPubMedPubMedCentral
Navalesi R, Pilo A, Ferrannini E. Insulin kinetics after portal and peripheral injection of [125I] insulin: II. Experiments in the intact dog. Am J Physiol. 1976;230:1630–6. PubMed
Meier JJ, Veldhuis JD, Butler PC. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes. 2005;54:1649–56. CrossRefPubMed
De Vos P, De Haan BJ, Vegter D, et al. Insulin levels after portal and systemic insulin infusion differ in a dose-dependent fashion. Horm Metab Res. 1998;30:721–5. CrossRefPubMed
Eaton RP, Allen RC, Schade DS. Hepatic removal of insulin in normal man: dose response to endogenous insulin secretion. J Clin Endocrinol Metab. 1983;56:1294–300. CrossRefPubMed
Porksen N, Munn SR, Steers JL, et al. Effects of somatostatin on pulsatile insulin secretion: elective inhibition of insulin burst mass. Am J Physiol. 1996;270:E1043–9. PubMed
Geidenstam N, Spegel P, Mulder H, et al. Metabolite profile deviations in an oral glucose tolerance test—a comparison between lean and obese individuals. Obesity (Silver Spring). 2014;22:2388–95.
Gerich JE, Langlois M, Noacco C, et al. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973;182:171–3. CrossRefPubMed
Boden G, Reichard GA Jr, Hoeldtke RD, et al. Severe insulin-induced hypoglycemia associated with deficiencies in the release of counterregulatory hormones. N Engl J Med. 1981;305:1200–5. CrossRefPubMed
Ferri S, Kojima K, Sode K. Review of glucose oxidases and glucose dehydrogenases: a bird’s eye view of glucose sensing enzymes. J Diabetes Sci Technol. 2011;5:1068–76. CrossRefPubMedPubMedCentral
Vaddiraju S, Burgess DJ, Tomazos I, et al. Technologies for continuous glucose monitoring: current problems and future promises. J Diabetes Sci Technol. 2010;4:1540–62. CrossRefPubMedPubMedCentral
Burnett DR, Huyett LM, Zisser HC, et al. Glucose sensing in the peritoneal space offers faster kinetics than sensing in the subcutaneous space. Diabetes. 2014;63:2498–505. CrossRefPubMedPubMedCentral
Basu A, Dube S, Veettil S, et al. Time lag of glucose from intravascular to interstitial compartment in type 1 diabetes. J Diabetes Sci Technol. 2015;9:63–8. CrossRefPubMed
Basu A, Dube S, Slama M, et al. Time lag of glucose from intravascular to interstitial compartment in humans. Diabetes. 2013;62:4083–7. CrossRefPubMedPubMedCentral
Stavdahl Ø, Fougner AL, Kölle K, et al. The artificial pancreas: a dynamic challenge. IFAC-PapersOnLine. 2016;49:765–72. doi: 10.​1016/​j.​ifacol.​2016.​07.​280. CrossRef
Blevins TC, Bode BW, Garg SK, et al. Statement by the American Association of Clinical Endocrinologists Consensus Panel on Continuous Glucose Monitoring. Endocr Pract. 2010;16:730–45.
Facchinetti A, Sparacino G, Guerra S, et al. Real-time improvement of continuous glucose monitoring accuracy: the smart sensor concept. Diabetes Care. 2013;36:793–800. CrossRefPubMedPubMedCentral
Cobelli C, Schiavon M, Dalla MC, et al. Interstitial fluid glucose is not just a shifted-in-time but a distorted mirror of blood glucose: insight from an in silico study. Diabetes Technol Ther. 2016;18:505–11. CrossRefPubMedPubMedCentral
Schmelzeisen-Redeker G, Schoemaker M, Kirchsteiger H, et al. Time delay of CGM sensors: relevance, causes, and countermeasures. J Diabetes Sci Technol. 2015;9:1006–15. CrossRefPubMedPubMedCentral
Bailey T, Bode BW, Christiansen MP, et al. The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes Technol Ther. 2015;17:787–94. CrossRefPubMedPubMedCentral
Damiano ER, McKeon K, El-Khatib FH, et al. A comparative effectiveness analysis of three continuous glucose monitors: the Navigator, G4 Platinum, and Enlite. J Diabetes Sci Technol. 2014;8:699–708.
Helton KL, Ratner BD, Wisniewski NA. Biomechanics of the sensor–tissue interface—effects of motion, pressure, and design on sensor performance and foreign body response—part II: examples and application. J Diabetes Sci Technol. 2011;5:647–56.
Lodwig V, Kulzer B, Schnell O, et al. What are the next steps in continuous glucose monitoring? J Diabetes Sci Technol. 2014;8:397–402. CrossRefPubMedPubMedCentral
Basu A, Veettil S, Dyer R, et al. Direct evidence of acetaminophen interference with subcutaneous glucose sensing in humans: a pilot study. Diabetes Technol Ther. 2016;18(Suppl 2):S243–7. CrossRefPubMed
Maahs DM, DeSalvo D, Pyle L, et al. Effect of acetaminophen on CGM glucose in an outpatient setting. Diabetes Care. 2015;38:e158–9. CrossRefPubMedPubMedCentral
Slama M, Veettil S, Norby B et al. Medication interference with continuous glucose monitoring devices: implications for the artificial endocrine pancreas (abstract for poster 907-P-2016). In: American Diabetes Association, editor. American Diabetes Association 76th Scientific Sessions; 2016 June 10–14; New Orleans, LA, USA. Rochester: ADA; 2016. p. 907. https://​ada.​scientificposter​s.​com/​epsAbstractADA.​cfm?​id=​1.
Pleus S, Schoemaker M, Morgenstern K, et al. Rate-of-change dependence of the performance of two CGM systems during induced glucose swings. J Diabetes Sci Technol. 2015;9:801–7. CrossRefPubMedPubMedCentral
Zijlstra E, Heise T, Nosek L, et al. Continuous glucose monitoring: quality of hypoglycaemia detection. Diabetes Obes Metab. 2013;15:130–5. CrossRefPubMed
Zschornack E, Schmid C, Pleus S, et al. Evaluation of the performance of a novel system for continuous glucose monitoring. J Diabetes Sci Technol. 2013;7:815–23. CrossRefPubMedPubMedCentral
Kropff J, Bruttomesso D, Doll W, et al. Accuracy of two continuous glucose monitoring systems: a head-to-head comparison under clinical research centre and daily life conditions. Diabetes Obes Metab. 2015;17:343–9. CrossRefPubMed
Mader JK, Hajnsek M, Aberer F et al. Standardized evaluation of three continuous glucose monitoring systems under routine clinical conditions (abstract for poster 870-P-2016). In: American Diabetes Association, editor. American Diabetes Association 76th Scientific Sessions; 2016 June 10–14; New Orleans, LA, USA. Rochester: ADA; 2016. p. 870. https://​ada.​scientificposter​s.​com/​epsAbstractADA.​cfm?​id=​1.
Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100. CrossRefPubMed
Pickup JC. Insulin-pump therapy for type 1 diabetes mellitus. N Engl J Med. 2012;366:1616–24. CrossRefPubMed
Heinemann L, Krinelke L. Insulin infusion set: the Achilles heel of continuous subcutaneous insulin infusion. J Diabetes Sci Technol. 2012;6:954–64. CrossRefPubMedPubMedCentral
Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metab. 2005;31:4S7–24. CrossRefPubMed
Heise T, Hovelmann U, Brondsted L, et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab. 2015;17:682–8. CrossRefPubMedPubMedCentral
De Vries JH, Snoek FJ, Kostense PJ, et al. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care. 2002;25:2074–80. CrossRef
Hildebrandt P, Sejrsen P, Nielsen SL, et al. Diffusion and polymerization determines the insulin absorption from subcutaneous tissue in diabetic patients. Scand J Clin Lab Invest. 1985;45:685–90.
Deiss D, Adolfsson P, Alkemade-van Zomeren M, et al. Insulin infusion set use: European perspectives and recommendations. Diabetes Technol Ther. 2016;18:517–24. CrossRefPubMedPubMedCentral
Zinman B, Ruderman N, Campaigne BN, et al. Physical activity/exercise and diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S73–7. PubMed
Shetty VB, Fournier PA, Davey RJ, et al. Effect of exercise intensity on glucose requirements to maintain euglycemia during exercise in type 1 diabetes. J Clin Endocrinol Metab. 2016;101:972–80. CrossRefPubMed
Tonoli C, Heyman E, Roelands B, et al. Effects of different types of acute and chronic (training) exercise on glycaemic control in type 1 diabetes mellitus: a meta-analysis. Sports Med. 2012;42:1059–80. CrossRefPubMed
Yardley JE, Kenny GP, Perkins BA, et al. Resistance versus aerobic exercise: acute effects on glycemia in type 1 diabetes. Diabetes Care. 2013;36:537–42. CrossRefPubMedPubMedCentral
Stenerson M, Cameron F, Wilson DM, et al. The impact of accelerometer and heart rate data on hypoglycemia mitigation in type 1 diabetes. J Diabetes Sci Technol. 2014;8:64–9. CrossRefPubMedPubMedCentral
Breton MD, Brown SA, Karvetski CH, et al. Adding heart rate signal to a control-to-range artificial pancreas system improves the protection against hypoglycemia during exercise in type 1 diabetes. Diabetes Technol Ther. 2014;16:506–11. CrossRefPubMedPubMedCentral
Turksoy K, Quinn LT, Littlejohn E, et al. An integrated multivariable artificial pancreas control system. J Diabetes Sci Technol. 2014;8:498–507. CrossRefPubMedPubMedCentral
Blauw H, van Bon AC, Koops R, et al. Performance and safety of an integrated bihormonal artificial pancreas for fully automated glucose control at home. Diabetes Obes Metab. 2016;18:671–7. CrossRefPubMedPubMedCentral
Fullerton B, Jeitler K, Seitz M, et al. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2014;2014:CD009122.
Wong JC, Neinstein AB, Spindler M, et al. A minority of patients with type 1 diabetes routinely downloads and retrospectively reviews device data. Diabetes Technol Ther. 2015;17:555–62. CrossRefPubMedPubMedCentral
Christiansen SC, Carlsen SM. Kunstig pankreas – drøm eller virkelighet? Indremedisineren. 2017;1:30–3.