Skip to main content

Advertisement

Log in

Felix dies natalis, insulin… ceterum autem censeo “beta is better”

  • Review Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

One hundred years after its discovery, insulin remains the life-saving therapy for many patients with diabetes. It has been a 100-years-old success story thanks to the fact that insulin therapy has continuously integrated the knowledge developed over a century. In 1982, insulin becomes the first therapeutic protein to be produced using recombinant DNA technology. The first “mini” insulin pump and the first insulin pen become available in 1983 and 1985, respectively. In 1996, the first generation of insulin analogues were produced. In 1999, the first continuous glucose-monitoring device for reading interstitial glucose was approved by the FDA. In 2010s, the ultra-long action insulins were introduced. An equally exciting story developed in parallel. In 1966. Kelly et al. performed the first clinical pancreas transplant at the University of Minnesota, and now it is a well-established clinical option. First successful islet transplantations in humans were obtained in the late 1980s and 1990s. Their ability to consistently re-establish the endogenous insulin secretion was obtained in 2000s. More recently, the possibility to generate large numbers of functional human β cells from pluripotent stem cells was demonstrated, and the first clinical trial using stem cell-derived insulin producing cell was started in 2014. This year, the discovery of this life-saving hormone turns 100 years. This provides a unique opportunity not only to celebrate this extraordinary success story, but also to reflect on the limits of insulin therapy and renew the commitment of the scientific community to an insulin free world for our patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Joslin EP (1917) The treatment of diabetes mellitus: with observations upon the disease based upon thirteen hundred cases. Lea & Febiger, Philadelphia

    Google Scholar 

  2. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (1922) Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 12(3):141

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Porta M (2021) One hundred years ago: the dawning of the insulin era. Acta Diabetol 58(1):1–4. https://doi.org/10.1007/s00592-020-01642-1

    Article  CAS  PubMed  Google Scholar 

  4. Shah VN, DuBose SN, Li Z et al (2019) Continuous glucose monitoring profiles in healthy nondiabetic participants: a multicenter prospective study. J Clin Endocrinol Metab 104(10):4356–4364. https://doi.org/10.1210/jc.2018-027635479355

    Article  PubMed  PubMed Central  Google Scholar 

  5. Maahs DM, Buckingham BA, Castle JR et al (2016) Outcome measures for artificial pancreas clinical trials: a consensus report. Diabetes Care 39(7):1175–1179

    Article  PubMed  PubMed Central  Google Scholar 

  6. Danne T, Nimri R, Battelino T et al (2017) International consensus on use of continuous glucose monitoring. Diabetes Care 40(12):1631–1640

    Article  PubMed  PubMed Central  Google Scholar 

  7. Battelino T, Danne T, Bergenstal RM et al (2019) Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care 42(8):1593–1603. https://doi.org/10.2337/dci19-0028

    Article  PubMed  PubMed Central  Google Scholar 

  8. American Diabetes Association (2021) 6. Glycemic targets: standards of medical care in diabetes-2021. Diabetes Care 44(1):S73–S84. https://doi.org/10.2337/dc21-S006

    Article  Google Scholar 

  9. The Diabetes Control and Complications Trial Research Group (1996) The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 45(10):1289–1298

    Article  Google Scholar 

  10. Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258):405–412. https://doi.org/10.1136/bmj.321.7258.405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N (2004) Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 141(6):413–420. https://doi.org/10.7326/0003-4819-141-6-200409210-00006

    Article  CAS  PubMed  Google Scholar 

  12. The Diabetes Control and Complications Trial Research Group (1995) The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 44(8):968–983

    Article  Google Scholar 

  13. Benhalima K, Standl E, Mathieu C (2011) The importance of glycemic control: how low should we go with HbA1c? Start early, go safe, go low. J Diabetes Complic 25(3):202–207. https://doi.org/10.1016/j.jdiacomp.2010.03.002S1056-8727(10)00041-3

    Article  Google Scholar 

  14. Yang J, Zhou Y, Zhang T et al (2020) Fasting blood glucose and HbA1c correlate with severity of coronary artery disease in elective PCI patients with HbA1c 5.7% to 6.4%. Angiology 71(2):167–174

    Article  CAS  PubMed  Google Scholar 

  15. Verdoia M, Schaffer A, Cassetti E et al (2014) Glycosylated hemoglobin and coronary artery disease in patients without diabetes mellitus. Am J Prev Med 47(1):9–16

    Article  PubMed  Google Scholar 

  16. Xia J, Yin C (2019) Glucose variability and coronary artery disease. Heart Lung Circ 28(4):553–559

    Article  PubMed  Google Scholar 

  17. Ayhan SS, Tosun M, Ozturk S et al (2012) Glycated haemoglobin is correlated with the severity of coronary artery disease independently of traditional risk factors in young patients. Endokrynol Pol 63(5):367–371

    CAS  PubMed  Google Scholar 

  18. Dutta B, Neginhal M, Iqbal F (2016) Glycated hemoglobin (HbA1c) correlation with severity of coronary artery disease in non-diabetic patients—a hospital based Study from North-Eastern India. J Clin Diagn Res 10(9):20

    Google Scholar 

  19. Sarwar N, Aspelund T, Eiriksdottir G et al (2010) Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review. PLoS Med 7(5):e1000278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Garg N, Moorthy N, Kapoor A, et al. (2014) Hemoglobin A1c in nondiabetic patients: an independent predictor of coronary artery disease and its severity. In: Mayo Clinic proceedings, vol 89. Elsevier, pp 908–916

  21. Khaw K-T, Wareham N, Luben R et al (2001) Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ 322(7277):15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McKnight JA, Wild SH, Lamb MJ et al (2015) Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison. Diabet Med 32(8):1036–1050. https://doi.org/10.1111/dme.12676

    Article  CAS  PubMed  Google Scholar 

  23. Shah VN, Grimsmann JM, Foster NC et al (2020) Undertreatment of cardiovascular risk factors in the type 1 diabetes exchange clinic network (United States) and the prospective diabetes follow-up (Germany/Austria) registries. Diabetes Obes Metab 22(9):1577–1585. https://doi.org/10.1111/dom.14069

    Article  CAS  PubMed  Google Scholar 

  24. Foster NC, Beck RW, Miller KM et al (2019) State of type 1 diabetes management and outcomes from the T1D exchange in 2016–2018. Diabetes Technol Ther 21(2):66–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Phelan H, Clapin H, Bruns L et al (2017) The Australasian Diabetes Data Network: first national audit of children and adolescents with type 1 diabetes. Med J Aust 206(3):121–125

    Article  PubMed  Google Scholar 

  26. Carlsen S, Skrivarhaug T, Thue G et al (2017) Glycemic control and complications in patients with type 1 diabetes—a registry-based longitudinal study of adolescents and young adults. Pediatr Diabetes 18(3):188–195. https://doi.org/10.1111/pedi.12372

    Article  CAS  PubMed  Google Scholar 

  27. Gubitosi-Klug RA, Braffett BH, Hitt S et al (2021) Residual beta cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia. J Clin Invest. https://doi.org/10.1172/JCI143011

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nathan DM (2021) Realising the long-term promise of insulin therapy: the DCCT/EDIC study. Diabetologia. https://doi.org/10.1007/s00125-021-05397-4

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Beck R, Riddlesworth T, Ruedy K, Kollman C, Ahmann A, Bergenstal R (2017) Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol 5(9):700–708

    Article  PubMed  Google Scholar 

  31. Karageorgiou V, Papaioannou TG, Bellos I et al (2019) Effectiveness of artificial pancreas in the non-adult population: a systematic review and network meta-analysis. Metabolism 90:20–30. https://doi.org/10.1016/j.metabol.2018.10.002

    Article  CAS  PubMed  Google Scholar 

  32. Weisman A, Bai J-W, Cardinez M, Kramer CK, Perkins BA (2017) Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials. Lancet Diabetes Endocrinol 5(7):501–512

    Article  CAS  PubMed  Google Scholar 

  33. Bekiari E, Kitsios K, Thabit H et al (2018) Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis. BMJ 361:k1310

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dai X, Luo Z-c, Zhai L, Zhao W-p, Huang F (2018) Artificial pancreas as an effective and safe alternative in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Therapy 9(3):1269–1277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tamburrini R, Odorico JS (2021) Pancreas transplant versus islet transplant versus insulin pump therapy: in which patients and when? Curr Opin Organ Transplant 26(2):176–183. https://doi.org/10.1097/MOT.000000000000085700075200-202104000-00012

    Article  CAS  PubMed  Google Scholar 

  36. Jacqueminet S, Masseboeuf N, Rolland M, Grimaldi A, Sachon C (2005) Limitations of the so-called intensified insulin therapy in type 1 diabetes mellitus. Diabetes Metab 31(4 Pt 2):4S45-44S50. https://doi.org/10.1016/s1262-3636(05)88267-9

    Article  CAS  PubMed  Google Scholar 

  37. Chase HP, Lockspeiser T, Peery B et al (2001) The impact of the diabetes control and complications trial and humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes. Diabetes Care 24(3):430–434. https://doi.org/10.2337/diacare.24.3.430

    Article  CAS  PubMed  Google Scholar 

  38. Nathan DM, Genuth S, Lachin J et al (1993) 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 329(14):977–986. https://doi.org/10.1056/NEJM199309303291401

    Article  CAS  PubMed  Google Scholar 

  39. Cooper MN, O’Connell SM, Davis EA, Jones TW (2013) A population-based study of risk factors for severe hypoglycaemia in a contemporary cohort of childhood-onset type 1 diabetes. Diabetologia 56(10):2164–2170. https://doi.org/10.1007/s00125-013-2982-1

    Article  PubMed  Google Scholar 

  40. Johnson SR, Cooper MN, Jones TW, Davis EA (2013) Long-term outcome of insulin pump therapy in children with type 1 diabetes assessed in a large population-based case-control study. Diabetologia 56(11):2392–2400. https://doi.org/10.1007/s00125-013-3007-9

    Article  CAS  PubMed  Google Scholar 

  41. Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW (2013) 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 310(12):1240–1247. https://doi.org/10.1001/jama.2013.2778181741822

    Article  CAS  PubMed  Google Scholar 

  42. Bohn B, Karges B, Vogel C et al (2016) 20 Years of pediatric benchmarking in Germany and Austria: age-dependent analysis of longitudinal follow-up in 63,967 children and adolescents with type 1 diabetes. PLoS ONE 11(8):e0160971. https://doi.org/10.1371/journal.pone.0160971PONE-D-16-20301

    Article  PubMed  PubMed Central  Google Scholar 

  43. Karges B, Rosenbauer J, Kapellen T et al (2014) Hemoglobin A1c Levels and risk of severe hypoglycemia in children and young adults with type 1 diabetes from Germany and Austria: a trend analysis in a cohort of 37,539 patients between 1995 and 2012. PLoS Med 11(10):e1001742. https://doi.org/10.1371/journal.pmed.1001742PMEDICINE-D-14-00497

    Article  PubMed  PubMed Central  Google Scholar 

  44. Miller KM, Foster NC, Beck RW et al (2015) Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry. Diabetes Care 38(6):971–978. https://doi.org/10.2337/dc15-007838/6/971

    Article  PubMed  Google Scholar 

  45. de Beaufort CE, Swift PG, Skinner CT et al (2007) Continuing stability of center differences in pediatric diabetes care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes. Diabetes Care 30(9):2245–2250. https://doi.org/10.2337/dc07-0475

    Article  PubMed  Google Scholar 

  46. Jarosinski MA, Dhayalan B, Rege N, Chatterjee D, Weiss MA (2021) “Smart” insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia. https://doi.org/10.1007/s00125-021-05422-6

    Article  PubMed  PubMed Central  Google Scholar 

  47. Thabit H, Hovorka R (2016) Coming of age: the artificial pancreas for type 1 diabetes. Diabetologia 59(9):1795–1805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nimri R, Battelino T, Laffel LM et al (2020) Insulin dose optimization using an automated artificial intelligence-based decision support system in youths with type 1 diabetes. Nat Med 26(9):1380–1384

    Article  CAS  PubMed  Google Scholar 

  49. Garg SK, Weinzimer SA, Tamborlane WV et al (2017) Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. Diabetes Technol Ther 19(3):155–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hanaire H, Franc S, Borot S et al (2020) Efficacy of the Diabeloop closed-loop system to improve glycaemic control in patients with type 1 diabetes exposed to gastronomic dinners or to sustained physical exercise. Diabetes Obes Metab 22(3):324–334

    Article  CAS  PubMed  Google Scholar 

  51. Breton M, Farret A, Bruttomesso D et al (2012) Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose control maintains near normoglycemia. Diabetes 61(9):2230–2237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Majdpour D, Yale J-F, Legault L et al (2020) 10-novel fully automated Fiasp-plus-pramlintide artificial pancreas for type 1 diabetes: randomized controlled trial. Can J Diabetes 44(7):S4–S5

    Article  Google Scholar 

  53. Jacobs PG, El Youssef J, Reddy R et al (2016) Randomized trial of a dual-hormone artificial pancreas with dosing adjustment during exercise compared with no adjustment and sensor-augmented pump therapy. Diabetes Obes Metab 18(11):1110–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Haidar A, Legault L, Messier V, Mitre TM, Leroux C, Rabasa-Lhoret R (2015) Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. Lancet Diabetes Endocrinol 3(1):17–26

    Article  CAS  PubMed  Google Scholar 

  55. Haidar A, Legault L, Matteau-Pelletier L et al (2015) Outpatient overnight glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or conventional insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, randomised controlled trial. Lancet Diabetes Endocrinol 3(8):595–604

    Article  CAS  PubMed  Google Scholar 

  56. Haidar A (2019) Insulin-and-glucagon artificial pancreas versus insulin-alone artificial pancreas: a short review. Diabetes Spectrum 32(3):215–221

    Article  PubMed  PubMed Central  Google Scholar 

  57. Castle JR, El Youssef J, Wilson LM et al (2018) Randomized outpatient trial of single-and dual-hormone closed-loop systems that adapt to exercise using wearable sensors. Diabetes Care 41(7):1471–1477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bertachi A, Ramkissoon CM, Bondia J, Vehi J (2018) Automated blood glucose control in type 1 diabetes: a review of progress and challenges. Endocrinol Diabetes Nutr 65(3):172–181. https://doi.org/10.1016/j.endinu.2017.10.011

    Article  Google Scholar 

  59. Kovatchev BP, Patek SD, Ortiz EA, Breton MD (2015) Assessing sensor accuracy for non-adjunct use of continuous glucose monitoring. Diabetes Technol Ther 17(3):177–186. https://doi.org/10.1089/dia.2014.0272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cobelli C, Schiavon M, Dalla Man C, Basu A, Basu R (2016) 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 18(8):505–511. https://doi.org/10.1089/dia.2016.0112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nijhoff MF, de Koning EJP (2018) Artificial pancreas or novel beta-cell replacement therapies: a race for optimal glycemic control? Curr Diab Rep 18(11):110. https://doi.org/10.1007/s11892-018-1073-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Edridge CL, Dunkley AJ, Bodicoat DH et al (2015) Prevalence and incidence of hypoglycaemia in 532,542 people with type 2 diabetes on oral therapies and insulin: a systematic review and meta-analysis of population based studies. PLoS ONE 10(6):e0126427. https://doi.org/10.1371/journal.pone.0126427PONE-D-15-00548

    Article  PubMed  PubMed Central  Google Scholar 

  63. Alwafi H, Alsharif AA, Wei L et al (2020) Incidence and prevalence of hypoglycaemia in type 1 and type 2 diabetes individuals: a systematic review and meta-analysis. Diabetes Res Clin Pract 170:108522. https://doi.org/10.1016/j.diabres.2020.108522

    Article  PubMed  Google Scholar 

  64. Pedersen-Bjergaard U, Thorsteinsson B (2017) Reporting severe hypoglycemia in type 1 diabetes: facts and pitfalls. Curr DiabRep 17(12):131. https://doi.org/10.1007/s11892-017-0965-1

    Article  Google Scholar 

  65. Seaquist ER, Anderson J, Childs B et al (2013) Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab 98(5):1845–1859. https://doi.org/10.1210/jc.2012-4127

    Article  CAS  PubMed  Google Scholar 

  66. Khunti K, Alsifri S, Aronson R et al (2017) Impact of hypoglycaemia on patient-reported outcomes from a global, 24-country study of 27,585 people with type 1 and insulin-treated type 2 diabetes. Diabetes Res Clin Pract 130:121–129

    Article  CAS  PubMed  Google Scholar 

  67. Elliott L, Fidler C, Ditchfield A, Stissing T (2016) Hypoglycemia event rates: a comparison between real-world data and randomized controlled trial populations in insulin-treated diabetes. Diabetes Ther 7(1):45–60. https://doi.org/10.1007/s13300-016-0157-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pedersen-Bjergaard U, Thorsteinsson B (2017) Reporting severe hypoglycemia in type 1 diabetes: facts and pitfalls. Curr Diab Rep 17(12):131. https://doi.org/10.1007/s11892-017-0965-1

    Article  PubMed  Google Scholar 

  69. Agesen RM, Kristensen PL, Beck-Nielsen H et al (2018) Effect of insulin analogs on frequency of non-severe hypoglycemia in patients with type 1 diabetes prone to severe hypoglycemia: much higher rates detected by continuous glucose monitoring than by self-monitoring of blood glucose-the HypoAna trial. Diabetes Technol Ther 20(3):247–256. https://doi.org/10.1089/dia.2017.0372

    Article  CAS  PubMed  Google Scholar 

  70. Heinemann L, Freckmann G, Ehrmann D et al (2018) Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE): a multicentre, randomised controlled trial. Lancet 391(10128):1367–1377. https://doi.org/10.1016/S0140-6736(18)30297-6

    Article  CAS  PubMed  Google Scholar 

  71. Forlenza GP, Li Z, Buckingham BA et al (2018) Predictive low-glucose suspend reduces hypoglycemia in adults, adolescents, and children with type 1 diabetes in an at-home randomized crossover study: results of the PROLOG trial. Diabetes Care 41(10):2155–2161. https://doi.org/10.2337/dc18-0771

    Article  CAS  PubMed  Google Scholar 

  72. Riddlesworth T, Price D, Cohen N, Beck RW (2017) Hypoglycemic event frequency and the effect of continuous glucose monitoring in adults with type 1 diabetes using multiple daily insulin injections. Diabetes Ther 8(4):947–951. https://doi.org/10.1007/s13300-017-0281-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu J, Bispham J, Fan L et al (2020) Factors associated with fear of hypoglycaemia among the T1D Exchange Glu population in a cross-sectional online survey. BMJ Open 10(9):e038462. https://doi.org/10.1136/bmjopen-2020-038462

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ratzki-Leewing A, Harris SB, Mequanint S et al (2018) Real-world crude incidence of hypoglycemia in adults with diabetes: results of the InHypo-DM Study, Canada. BMJ Open Diabetes Res Care 6(1):e000503. https://doi.org/10.1136/bmjdrc-2017-000503

    Article  PubMed  PubMed Central  Google Scholar 

  75. Pettus JH, Zhou FL, Shepherd L et al (2019) Incidences of severe hypoglycemia and diabetic ketoacidosis and prevalence of microvascular complications stratified by age and glycemic control in U.S. adult patients with type 1 diabetes: a real-world study. Diabetes Care 42(12):2220–2227. https://doi.org/10.2337/dc19-0830

    Article  PubMed  Google Scholar 

  76. Cherubini V, Pintaudi B, Rossi M et al (2014) Severe hypoglycemia and ketoacidosis over one year in Italian pediatric population with type 1 diabetes mellitus: a multicenter retrospective observational study. Nutr Metab Cardiovasc Dis 24(5):538–546

    Article  CAS  PubMed  Google Scholar 

  77. Geddes J, Schopman JE, Zammitt NN, Frier BM (2008) Prevalence of impaired awareness of hypoglycaemia in adults with type 1 diabetes. Diabet Med 25(4):501–504

    Article  CAS  PubMed  Google Scholar 

  78. Wohland T, Holstein J, Patzer O et al (2017) New risk and protective factors for severe hypoglycaemia in people with type 1 diabetes. Nutr Metab Cardiovasc Dis 27(5):407–414

    Article  CAS  PubMed  Google Scholar 

  79. Olsen S, Åsvold B, Frier B, Aune S, Hansen L, Bjørgaas M (2014) Hypoglycaemia symptoms and impaired awareness of hypoglycaemia in adults with type 1 diabetes: the association with diabetes duration. Diabet Med 31(10):1210–1217

    Article  CAS  PubMed  Google Scholar 

  80. Schopman JE, Geddes J, Frier BM (2010) Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes. Diabetes Res Clin Pract 87(1):64–68

    Article  CAS  PubMed  Google Scholar 

  81. van Meijel LA, de Vegt F, Abbink EJ et al (2020) High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: the Dutch Diabetes Pearl Cohort. BMJ Open Diabetes Res Care 8(1):e000935. https://doi.org/10.1136/bmjdrc-2019-000935

    Article  PubMed  PubMed Central  Google Scholar 

  82. Heller SR, Peyrot M, Oates SK, Taylor AD (2020) Hypoglycemia in patient with type 2 diabetes treated with insulin: it can happen. BMJ Open Diabetes Res Care 8(1):e001194. https://doi.org/10.1136/bmjdrc-2020-001194

    Article  PubMed  PubMed Central  Google Scholar 

  83. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV (2009) Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301(15):1565–1572. https://doi.org/10.1001/jama.2009.460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lin CH, Sheu WH (2013) Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med 273(1):102–110. https://doi.org/10.1111/joim.12000

    Article  PubMed  Google Scholar 

  85. Yaffe K, Falvey CM, Hamilton N et al (2013) Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med 173(14):1300–1306. https://doi.org/10.1001/jamainternmed.2013.6176

    Article  PubMed  PubMed Central  Google Scholar 

  86. Nilsson M, Jensen N, Gejl M et al (2019) Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial. Diabetologia 62(10):1948–1958

    Article  CAS  PubMed  Google Scholar 

  87. McCrimmon RJ (2021) Consequences of recurrent hypoglycaemia on brain function in diabetes. Diabetologia. https://doi.org/10.1007/s00125-020-05369-0

    Article  PubMed  PubMed Central  Google Scholar 

  88. Goto A, Arah OA, Goto M, Terauchi Y, Noda M (2013) Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. Brit Med Jo 347:f4533. https://doi.org/10.1136/bmj.f4533

    Article  Google Scholar 

  89. Bedenis R, Price AH, Robertson CM et al (2014) Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study. Diabetes Care 37(12):3301–3308. https://doi.org/10.2337/dc14-0908

    Article  PubMed  Google Scholar 

  90. Giménez M, Gilabert R, Monteagudo J et al (2011) Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes. Diabetes Care 34(1):198–203. https://doi.org/10.2337/dc10-1371

    Article  CAS  PubMed  Google Scholar 

  91. Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK (2015) Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care 38(2):316–322. https://doi.org/10.2337/dc14-0920

    Article  PubMed  Google Scholar 

  92. Hendrieckx C, Halliday J, Bowden J et al (2014) Severe hypoglycaemia and its association with psychological well-being in Australian adults with type 1 diabetes attending specialist tertiary clinics. Diabetes Res Clin Pract 103(3):430–436

    Article  CAS  PubMed  Google Scholar 

  93. Evans M, Khunti K, Mamdani M et al (2013) Health-related quality of life associated with daytime and nocturnal hypoglycaemic events: a time trade-off survey in five countries. Health Qual Life Outcomes 11(1):1–9

    Article  Google Scholar 

  94. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA (2012) Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 35(9):1897–1901. https://doi.org/10.2337/dc11-2054

    Article  PubMed  PubMed Central  Google Scholar 

  95. Gruden G, Barutta F, Chaturvedi N et al (2012) Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 35(7):1598–1604. https://doi.org/10.2337/dc11-1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gimenez M, Lopez JJ, Castell C, Conget I (2012) Hypoglycaemia and cardiovascular disease in Type 1 Diabetes. Results from the Catalan National Public Health registry on insulin pump therapy. Diabetes Res Clin Pract 96(2):e23-25. https://doi.org/10.1016/j.diabres.2012.01.014S0168-8227(12)00035-6

    Article  PubMed  Google Scholar 

  97. Lu CL, Shen HN, Hu SC, Wang JD, Li CY (2016) A population-based study of all-cause mortality and cardiovascular disease in association with prior history of hypoglycemia among patients with type 1 diabetes. Diabetes Care 39(9):1571–1578. https://doi.org/10.2337/dc15-2418

    Article  PubMed  Google Scholar 

  98. Amiel SA, Aschner P, Childs B et al (2019) Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 7(5):385–396

    Article  Google Scholar 

  99. Cameron F (2019) Type 1 diabetes: new and fellow travellers. Lancet Child Adolescent Health 3(1):4–6. https://doi.org/10.1016/S2352-4642(18)30337-7

    Article  PubMed  Google Scholar 

  100. Dabelea D, Stafford JM, Mayer-Davis EJ et al (2017) Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA 317(8):825–835

    Article  PubMed  PubMed Central  Google Scholar 

  101. Sauder KA, Stafford JM, Mayer-Davis EJ et al (2019) Co-occurrence of early diabetes-related complications in adolescents and young adults with type 1 diabetes: an observational cohort study. Lancet Child Adolescent Health 3(1):35–43

    Article  PubMed  Google Scholar 

  102. Cameron FJ, Wherrett DK (2015) Care of diabetes in children and adolescents: controversies, changes, and consensus. Lancet 385(9982):2096–2106

    Article  PubMed  Google Scholar 

  103. Marcovecchio ML, Dalton RN, Daneman D et al (2019) A new strategy for vascular complications in young people with type 1 diabetes mellitus. Nat Rev Endocrinol 15(7):429–435. https://doi.org/10.1038/s41574-019-0198-2

    Article  PubMed  Google Scholar 

  104. Gylfadottir SS, Weeracharoenkul D, Andersen ST, Niruthisard S, Suwanwalaikorn S, Jensen TS (2019) Painful and non-painful diabetic polyneuropathy: clinical characteristics and diagnostic issues. J Diabetes Invest 10(5):1148–1157

    Article  Google Scholar 

  105. Umanath K, Lewis JB (2018) Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 71(6):884–895

    Article  PubMed  Google Scholar 

  106. Yau JWY, Rogers SL, Kawasaki R et al (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35(3):556–564. https://doi.org/10.2337/dc11-1909

    Article  PubMed  PubMed Central  Google Scholar 

  107. Wong TY, Cheung CMG, Larsen M, Sharma S, Simó R (2016) Diabetic retinopathy. Nat Rev Dis Primers 2(1):16012. https://doi.org/10.1038/nrdp.2016.12

    Article  PubMed  Google Scholar 

  108. Libby P, Nathan DM, Abraham K et al (2005) Report of the national heart, lung, and blood institute-national institute of diabetes and digestive and kidney diseases working group on cardiovascular complications of type 1 diabetes mellitus. Circulation 111(25):3489–3493

    Article  PubMed  Google Scholar 

  109. Huo L, Shaw JE, Wong E, Harding JL, Peeters A, Magliano DJ (2016) Burden of diabetes in Australia: life expectancy and disability-free life expectancy in adults with diabetes. Diabetologia 59(7):1437–1445

    Article  PubMed  Google Scholar 

  110. Livingstone SJ, Levin D, Looker HC et al (2015) Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA 313(1):37–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Petrie D, Lung TW, Rawshani A et al (2016) Recent trends in life expectancy for people with type 1 diabetes in Sweden. Diabetologia 59(6):1167–1176

    Article  PubMed  Google Scholar 

  112. Lind M, Svensson A-M, Kosiborod M et al (2014) Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 371(21):1972–1982

    Article  PubMed  CAS  Google Scholar 

  113. Orchard TJ, Nathan DM, Zinman B et al (2015) Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 313(1):45–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gonzalez JS, Hood KK, Esbitt SA et al (2018) Psychiatric and psychosocial issues among individuals living with diabetes. In: Cowie CC, Casagrande SS, Menke A et al (eds) Diabetes in America, 3rd edn. National Institute of Diabetes and Digestive and Kidney Diseases (US), Bethesda (MD), CHAPTER 33. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567974/

  115. Garrett CJ, Ismail K, Fonagy P (2021) Understanding developmental psychopathology in Type 1 diabetes through attachment, mentalisation and diabetes distress. Clin Child Psychol Psychiatry. https://doi.org/10.1177/1359104521994640

    Article  PubMed  Google Scholar 

  116. Kalra S, Verma K, Balhara Y (2018) Diabetes distress. J Soc Health Diabetes 6(1):4–7

    Article  Google Scholar 

  117. Sturt J, Dennick K, Due-Christensen M, McCarthy K (2015) The detection and management of diabetes distress in people with type 1 diabetes. Curr DiabRep 15(11):101. https://doi.org/10.1007/s11892-015-0660-z

    Article  CAS  Google Scholar 

  118. Duffus SH, Ta’ani ZA, Slaughter JC, Niswender KD, Gregory JM (2020) Increased proportion of time in hybrid closed-loop “Auto Mode” is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump. Diabetes Obes Metab 22(4):688–693

    Article  CAS  PubMed  Google Scholar 

  119. Messer LH, Berget C, Vigers T et al (2020) Real world hybrid closed-loop discontinuation: predictors and perceptions of youth discontinuing the 670G system in the first 6 months. Pediatr Diabetes 21(2):319–327

    Article  PubMed  PubMed Central  Google Scholar 

  120. Lal RA, Basina M, Maahs DM, Hood K, Buckingham B, Wilson DM (2019) One year clinical experience of the first commercial hybrid closed-loop system. Diabetes Care 42(12):2190–2196

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lung TW, Hayes AJ, Herman WH, Si L, Palmer AJ, Clarke PM (2014) A meta-analysis of the relative risk of mortality for type 1 diabetes patients compared to the general population: exploring temporal changes in relative mortality. PLoS ONE 9(11):e113635. https://doi.org/10.1371/journal.pone.0113635PONE-D-14-37400

    Article  PubMed  PubMed Central  Google Scholar 

  122. Centers for Disease Control and Prevention (2012) Diabetes death rates among youths aged </= 19 years–United States, 1968–2009. MMWR Morb Mortal Wkly Rep 61(43): 869–872

    Google Scholar 

  123. Control D, Trial C (2016) Mortality in type 1 diabetes in the DCCT/EDIC versus the general population. Diabetes Care 39(8):1378–1383

    Article  Google Scholar 

  124. Secrest AM, Becker DJ, Kelsey SF, LaPorte RE, Orchard TJ (2010) All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care 33(12):2573–2579

    Article  PubMed  PubMed Central  Google Scholar 

  125. Soedamah-Muthu S, Fuller J, Mulnier H, Raleigh V, Lawrenson R, Colhoun H (2006) All-cause mortality rates in patients with type 1 diabetes mellitus compared with a non-diabetic population from the UK general practice research database, 1992–1999. Diabetologia 49(4):660–666

    Article  CAS  PubMed  Google Scholar 

  126. Jørgensen ME, Almdal TP, Carstensen B (2013) Time trends in mortality rates in type 1 diabetes from 2002 to 2011. Diabetologia 56(11):2401–2404

    Article  PubMed  CAS  Google Scholar 

  127. Huo L, Harding JL, Peeters A, Shaw JE, Magliano DJ (2016) Life expectancy of type 1 diabetic patients during 1997–2010: a national Australian registry-based cohort study. Diabetologia 59(6):1177–1185

    Article  PubMed  Google Scholar 

  128. Patterson CC, Dahlquist G, Harjutsalo V et al (2007) Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989. Diabetologia 50(12):2439–2442

    Article  CAS  PubMed  Google Scholar 

  129. Jarosinski MA, Dhayalan B, Rege N, Chatterjee D, Weiss MA (2021) “Smart” insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia 64(5):1016–1029. https://doi.org/10.1007/s00125-021-05422-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren P-O, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci 103(7):2334–2339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Abdulreda MH, Berggren PO (2021) The pancreatic islet: a micro-organ in control. Cell R4 Repair Replace Regen Reprogram 9:e3093. https://doi.org/10.32113/cellr4_20213_3093

    Article  Google Scholar 

  132. Weir GC, Bonner-Weir S (2021) Why pancreatic islets should be regarded and regulated like organs. CellR4 Repair Replace Regen Reprogram 9:e3083. https://doi.org/10.32113/cellr4_20213_3083

    Article  Google Scholar 

  133. Lawlor N, Stitzel ML (2019) (Epi)genomic heterogeneity of pancreatic islet function and failure in type 2 diabetes. Mol Metab 27S:S15–S24. https://doi.org/10.1016/j.molmet.2019.06.002

    Article  CAS  PubMed  Google Scholar 

  134. Benninger RKP, Dorrell C, Hodson DJ, Rutter GA (2018) The impact of pancreatic beta cell heterogeneity on type 1 diabetes pathogenesis. Curr Diab Rep 18(11):112. https://doi.org/10.1007/s11892-018-1085-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Pipeleers D, De Mesmaeker I, Robert T, Van Hulle F (2017) Heterogeneity in the beta-cell population: a guided search into its significance in pancreas and in implants. Curr Diab Rep 17(10):86. https://doi.org/10.1007/s11892-017-0925-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mundinger TO, Mei Q, Foulis AK, Fligner CL, Hull RL, Taborsky GJ (2016) Human type 1 diabetes is characterized by an early, marked, sustained, and islet-selective loss of sympathetic nerves. Diabetes 65(8):2322–2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jansson L, Barbu A, Bodin B et al (2016) Pancreatic islet blood flow and its measurement. Ups J Med Sci 121(2):81–95. https://doi.org/10.3109/03009734.2016.1164769

    Article  PubMed  PubMed Central  Google Scholar 

  138. Herold KC, Gitelman SE, Willi SM et al (2013) Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia 56(2):391–400. https://doi.org/10.1007/s00125-012-2753-4

    Article  CAS  PubMed  Google Scholar 

  139. Keymeulen B, Vandemeulebroucke E, Ziegler AG et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352(25):2598–2608. https://doi.org/10.1056/NEJMoa043980

    Article  CAS  PubMed  Google Scholar 

  140. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361(22):2143–2152. https://doi.org/10.1056/NEJMoa0904452361/22/2143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Orban T, Bundy B, Becker DJ et al (2011) Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378(9789):412–419. https://doi.org/10.1016/S0140-6736(11)60886-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Haller MJ, Long SA, Blanchfield JL et al (2019) Low-dose anti-thymocyte globulin preserves C-peptide, reduces HbA1c, and increases regulatory to conventional T-cell ratios in new-onset type 1 diabetes: two-year clinical trial data. Diabetes 68(6):1267–1276. https://doi.org/10.2337/db19-0057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Rigby MR, DiMeglio LA, Rendell MS et al (2013) Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol 1(4):284–294. https://doi.org/10.1016/S2213-8587(13)70111-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lord S, Greenbaum CJ (2020) Insulin is necessary but not sufficient: changing the therapeutic paradigm in type 1 diabetes. F1000Res 9:F1000. https://doi.org/10.12688/f1000research.21801.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Herold KC, Bundy BN, Long SA et al (2019) An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 381(7):603–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Piemonti L (2019) Islet transplantation. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J, Kalra S, Kaltsas G, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, McGee EA, McLachlan R, Morley JE, New M, Purnell J, Sahay R, Singer F, Stratakis CA, Trence DL, Wilson DP (eds). Endotext [Internet], South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905200

  147. Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L (2016) The state of the art of islet transplantation and cell therapy in type 1 diabetes. Acta Diabetol 53(5):683–691. https://doi.org/10.1007/s00592-016-0847-z

    Article  CAS  PubMed  Google Scholar 

  148. Piemonti L, Pileggi A (2013) 25 Years of the ricordi automated method for islet isolation. Cell R4 Repair Replace Regen Reprogram 1(1):e128

    Google Scholar 

  149. Pellegrini S, Piemonti L, Sordi V (2018) Pluripotent stem cell replacement approaches to treat type 1 diabetes. Curr Opin Pharmacol 43:20–26. https://doi.org/10.1016/j.coph.2018.07.007

    Article  CAS  PubMed  Google Scholar 

  150. Choudhary P, Rickels MR, Senior PA et al (2015) Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 38(6):1016–1029. https://doi.org/10.2337/dc15-009038/6/1016

    Article  PubMed  PubMed Central  Google Scholar 

  151. Rickels MR, Stock PG, de Koning EJP et al (2018) Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transp Int 31(4):343–352. https://doi.org/10.1111/tri.13138

    Article  CAS  Google Scholar 

  152. Rickels MR, Stock PG, de Koning EJP et al (2018) Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transplantation 102(9):1479-1486. https://doi.org/10.1097/TP.0000000000002158

    Article  PubMed  PubMed Central  Google Scholar 

  153. Barton FB, Rickels MR, Alejandro R et al (2012) Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 35(7):1436–1445. https://doi.org/10.2337/dc12-006335/7/1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Alejandro R, Barton FB, Hering BJ, Wease S (2008) 2008 update from the Collaborative Islet Transplant Registry. Transplantation 86(12):1783–1788. https://doi.org/10.1097/TP.0b013e3181913f6a00007890-200812270-00029

    Article  PubMed  Google Scholar 

  155. Hering BJ, Clarke WR, Bridges ND et al (2016) Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39(7):1230–1240. https://doi.org/10.2337/dc15-1988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Markmann JF, Rickels MR, Eggerman TL et al (2021) Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Am J Transplant 21(4):1477–1492. https://doi.org/10.1111/ajt.16174

    Article  CAS  PubMed  Google Scholar 

  157. Lablanche S, Vantyghem MC, Kessler L et al (2018) Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol 6(7):527–537. https://doi.org/10.1016/S2213-8587(18)30078-0

    Article  CAS  PubMed  Google Scholar 

  158. Maffi P, Lundgren T, Tufveson G et al (2020) Targeting CXCR1/2 does not improve insulin secretion after pancreatic islet transplantation: a phase 3, double-blind, randomized, placebo-controlled trial in type 1 diabetes. Diabetes Care 43(4):710–718. https://doi.org/10.2337/dc19-1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Pileggi A, Ricordi C, Kenyon NS, et al. (2004) Twenty years of clinical islet transplantation at the Diabetes Research Institute—University of Miami. Clin Transpl 177–204

  160. Johnson JA, Kotovych M, Ryan EA, Shapiro AM (2004) Reduced fear of hypoglycemia in successful islet transplantation. Diabetes Care 27(2):624–625

    Article  PubMed  Google Scholar 

  161. Poggioli R, Faradji RN, Ponte G et al (2006) Quality of life after islet transplantation. Am J Transplant 6(2):371–378. https://doi.org/10.1111/j.1600-6143.2005.01174.x

    Article  CAS  PubMed  Google Scholar 

  162. Toso C, Shapiro AM, Bowker S et al (2007) Quality of life after islet transplant: impact of the number of islet infusions and metabolic outcome. Transplantation 84(5):664–666. https://doi.org/10.1097/01.tp.0000280550.01028.8900007890-200709150-00017

    Article  PubMed  Google Scholar 

  163. Leitao CB, Tharavanij T, Cure P et al (2008) Restoration of hypoglycemia awareness after islet transplantation. Diabetes Care 31(11):2113–2115. https://doi.org/10.2337/dc08-0741

    Article  PubMed  PubMed Central  Google Scholar 

  164. Tharavanij T, Betancourt A, Messinger S et al (2008) Improved long-term health-related quality of life after islet transplantation. Transplantation 86(9):1161–1167. https://doi.org/10.1097/TP.0b013e31818a7f4500007890-200811150-00002

    Article  PubMed  PubMed Central  Google Scholar 

  165. Radosevich DM, Jevne R, Bellin M, Kandaswamy R, Sutherland DE, Hering BJ (2013) Comprehensive health assessment and five-yr follow-up of allogeneic islet transplant recipients. Clin Transplant 27(6):E715-724. https://doi.org/10.1111/ctr.12265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Benhamou PY, Milliat-Guittard L, Wojtusciszyn A et al (2009) Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials. Diabet Med 26(6):617–621. https://doi.org/10.1111/j.1464-5491.2009.02731.xDME2731

    Article  CAS  PubMed  Google Scholar 

  167. Cure P, Pileggi A, Froud T et al (2008) Improved metabolic control and quality of life in seven patients with type 1 diabetes following islet after kidney transplantation. Transplantation 85(6):801–812. https://doi.org/10.1097/TP.0b013e318166a27b00007890-200803270-00005

    Article  CAS  PubMed  Google Scholar 

  168. Barshes NR, Vanatta JM, Mote A et al (2005) Health-related quality of life after pancreatic islet transplantation: a longitudinal study. Transplantation 79(12):1727–1730

    Article  PubMed  Google Scholar 

  169. Vantyghem MC, de Koning EJP, Pattou F, Rickels MR (2019) Advances in beta-cell replacement therapy for the treatment of type 1 diabetes. Lancet 394(10205):1274–1285. https://doi.org/10.1016/S0140-6736(19)31334-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Vantyghem M-C, Chetboun M, Gmyr V et al (2019) Ten-year outcome of islet alone or islet after kidney transplantation in type 1 diabetes: a prospective parallel-arm cohort study. Diabetes Care 42(11):2042–2049

    Article  PubMed  Google Scholar 

  171. Vantyghem MC, Raverdy V, Balavoine AS et al (2012) Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (beta-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (beta-score greater than 3). J Clin Endocrinol Metab 97(11):E2078-2083. https://doi.org/10.1210/jc.2012-2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Reid L, Baxter F, Forbes S (2021) Effects of islet transplantation on microvascular and macrovascular complications in type 1 diabetes. Diabet Med. https://doi.org/10.1111/dme.14570

    Article  PubMed  Google Scholar 

  173. Gerber PA, Pavlicek V, Demartines N et al (2008) Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5 year single centre follow-up. Diabetologia 51(1):110–119. https://doi.org/10.1007/s00125-007-0860-4

    Article  CAS  PubMed  Google Scholar 

  174. Thompson DM, Meloche M, Ao Z et al (2011) Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 91(3):373–378. https://doi.org/10.1097/TP.0b013e31820437f3

    Article  PubMed  Google Scholar 

  175. Toso C, Baertschiger R, Morel P et al (2006) Sequential kidney/islet transplantation: efficacy and safety assessment of a steroid-free immunosuppression protocol. Am J Transplant 6(5 Pt 1):1049–1058. https://doi.org/10.1111/j.1600-6143.2006.01303.x

    Article  CAS  PubMed  Google Scholar 

  176. Fiorina P, Folli F, Zerbini G et al (2003) Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants. J Am Soc Nephrol 14(8):2150–2158

    Article  PubMed  Google Scholar 

  177. Fiorina P, Venturini M, Folli F et al (2005) Natural history of kidney graft survival, hypertrophy, and vascular function in end-stage renal disease type 1 diabetic kidney-transplanted patients: beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care 28(6):1303–1310

    Article  PubMed  Google Scholar 

  178. Maffi P, Bertuzzi F, De Taddeo F et al (2007) Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care 30(5):1150–1155. https://doi.org/10.2337/dc06-1794

    Article  CAS  PubMed  Google Scholar 

  179. Senior PA, Zeman M, Paty BW, Ryan EA, Shapiro AM (2007) Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant 7(1):91–98. https://doi.org/10.1111/j.1600-6143.2006.01573.x

    Article  CAS  PubMed  Google Scholar 

  180. Gillard P, Rustandi M, Efendi A et al (2014) Early alteration of kidney function in nonuremic type 1 diabetic islet transplant recipients under tacrolimus-mycophenolate therapy. Transplantation. https://doi.org/10.1097/TP.0000000000000086

    Article  PubMed  Google Scholar 

  181. Fung MA, Warnock GL, Ao Z et al (2007) The effect of medical therapy and islet cell transplantation on diabetic nephropathy: an interim report. Transplantation 84(1):17–22. https://doi.org/10.1097/01.tp.0000265502.92321.ab00007890-200707150-00006

    Article  PubMed  Google Scholar 

  182. Leitao CB, Cure P, Messinger S et al (2009) Stable renal function after islet transplantation: importance of patient selection and aggressive clinical management. Transplantation 87(5):681–688. https://doi.org/10.1097/TP.0b013e31819279a800007890-200903150-00010

    Article  PubMed  PubMed Central  Google Scholar 

  183. Lee TC, Barshes NR, O’Mahony CA et al (2005) The effect of pancreatic islet transplantation on progression of diabetic retinopathy and neuropathy. Transplant Proc 37(5):2263–2265. https://doi.org/10.1016/j.transproceed.2005.03.011

    Article  CAS  PubMed  Google Scholar 

  184. Warnock GL, Thompson DM, Meloche RM et al (2008) A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes. Transplantation 86(12):1762–1766. https://doi.org/10.1097/TP.0b013e318190b05200007890-200812270-00025

    Article  PubMed  Google Scholar 

  185. Venturini M, Fiorina P, Maffi P et al (2006) Early increase of retinal arterial and venous blood flow velocities at color Doppler imaging in brittle type 1 diabetes after islet transplant alone. Transplantation 81(9):1274–1277. https://doi.org/10.1097/01.tp.0000208631.63235.6a00007890-200605150-00009

    Article  PubMed  Google Scholar 

  186. Del Carro U, Fiorina P, Amadio S et al (2007) Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care 30(12):3063–3069. https://doi.org/10.2337/dc07-0206

    Article  CAS  PubMed  Google Scholar 

  187. Vantyghem MC, Quintin D, Caiazzo R et al (2014) Improvement of electrophysiological neuropathy after islet transplantation for type 1 diabetes: a 5-year prospective study. Diabetes Care 37(6):e141–142. https://doi.org/10.2337/dc14-032037/6/e141

    Article  PubMed  Google Scholar 

  188. D’Addio F, Maffi P, Vezzulli P et al (2014) Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes. Diabetes Care 37(1):267–276. https://doi.org/10.2337/dc13-1663

    Article  CAS  PubMed  Google Scholar 

  189. Fiorina P, Folli F, Bertuzzi F et al (2003) Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. Diabetes Care 26(4):1129–1136

    Article  PubMed  Google Scholar 

  190. Fiorina P, Folli F, Maffi P et al (2003) Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: a comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 75(8):1296–1301

    Article  PubMed  Google Scholar 

  191. Fiorina P, Gremizzi C, Maffi P et al (2005) Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients. Diabetes Care 28(6):1358–1365

    Article  PubMed  Google Scholar 

  192. Danielson KK, Hatipoglu B, Kinzer K et al (2013) Reduction in carotid intima-media thickness after pancreatic islet transplantation in patients with type 1 diabetes. Diabetes Care 36(2):450–456. https://doi.org/10.2337/dc12-0679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zarinsefat A, Stock PG (2020) Chapter 34—Islet vs pancreas transplantation in nonuremic patients with type 1 diabetes. In: Orlando G, Piemonti L, Ricordi C, Stratta RJ, Gruessner RWG (eds) Transplantation, bioengineering, and regeneration of the endocrine pancreas. Academic Press, pp 417-423

  194. Gruessner AC, Gruessner RW (2018) Pancreas transplantation for patients with type 1 and type 2 diabetes mellitus in the United States: a registry report. Gastroenterol Clin 47(2):417–441

    Article  Google Scholar 

  195. Becker BN, Brazy PC, Becker YT et al (2000) Simultaneous pancreas-kidney transplantation reduces excess mortality in type 1 diabetic patients with end-stage renal disease. Kidney Int 57(5):2129–2135

    Article  CAS  PubMed  Google Scholar 

  196. Reddy KS, Stablein D, Taranto S et al (2003) Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis 41(2):464–470

    Article  PubMed  Google Scholar 

  197. Ojo AO, Meier-Kriesche H-U, Hanson JA et al (2001) The impact of simultaneous pancreas-kidney transplantation on long-term patient survival1. Transplantation 71(1):82–89

    Article  CAS  PubMed  Google Scholar 

  198. Boggi U, Rosati CM, Marchetti P (2013) Follow-up of secondary diabetic complications after pancreas transplantation. Curr Opin Organ Transplant 18(1):102–110

    Article  PubMed  Google Scholar 

  199. Gremizzi C, Vergani A, Paloschi V, Secchi A (2010) Impact of pancreas transplantation on type 1 diabetes-related complications. Curr Opin Organ Transplant 15(1):119–123

    Article  PubMed  Google Scholar 

  200. Jenssen T, Hartmann A, Birkeland KI (2017) Long-term diabetes complications after pancreas transplantation. Curr Opin Organ Transplant 22(4):382–388

    Article  PubMed  Google Scholar 

  201. Adler JT, Odorico JS (2020) Chapter 11—Pancreas after kidney transplantation. In: Orlando G, Piemonti L, Ricordi C, Stratta RJ, Gruessner RWG (eds) Transplantation, bioengineering, and regeneration of the endocrine pancreas. Academic Press, pp 125-132

  202. Stratta RJ, Gruessner AC, Gruessner RWG (2020) Chapter 31—Pancreas transplantation: current issues, unmet needs, and future perspectives. In: Orlando G, Piemonti L, Ricordi C, Stratta RJ, Gruessner RWG (eds) Transplantation, bioengineering, and regeneration of the endocrine pancreas. Academic Press, pp 375–386

  203. Al-Qaoud TM, Odorico JS, Redfield RR III (2018) Pancreas transplantation in type 2 diabetes: expanding the criteria. Curr Opin Organ Transplant 23(4):454–460

    Article  PubMed  Google Scholar 

  204. Scalea JR, Redfield RR III, Arpali E et al (2016) Pancreas transplantation in older patients is safe, but patient selection is paramount. Transpl Int 29(7):810–818

    Article  PubMed  Google Scholar 

  205. Stratta RJ, Fridell JA (2021) Pancreas transplantation alone: Radical or rationale? Transplantation online first

  206. Boggi U, Baronti W, Amorese G et al (2021) Treating type 1 diabetes by pancreas transplant alone: a cohort study on actual long-term (10 years) efficacy and safety. Transplantation online first

  207. Stratta RJ, Fridell JA, Gruessner AC, Odorico JS, Gruessner RWG (2016) Pancreas transplantation: a decade of decline. Curr Opin Organ Transplant 21(4):386–392. https://doi.org/10.1097/MOT.0000000000000319

    Article  PubMed  Google Scholar 

  208. Sharples E, Mittal S, Friend P (2016) Challenges in pancreas transplantation. Acta Diabetol 53(6):871–878

    Article  CAS  PubMed  Google Scholar 

  209. Iglesias-Lopez C, Obach M, Vallano A, Agustí A (2021) Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States. Cytotherapy 23(3):261–274

    Article  CAS  PubMed  Google Scholar 

  210. Odorico J, Markmann J, Melton D et al (2018) Report of the key opinion leaders meeting on stem cell-derived beta cells. Transplantation 102(8):1223–1229. https://doi.org/10.1097/TP.0000000000002217

    Article  PubMed  PubMed Central  Google Scholar 

  211. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987):41–46

    Article  CAS  PubMed  Google Scholar 

  212. Wang P, Alvarez-Perez J-C, Felsenfeld DP et al (2015) A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med 21(4):383–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Furuyama K, Chera S, Van Gurp L et al (2019) Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature 567(7746):43–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Zhong F, Jiang Y (2019) Endogenous pancreatic β cell regeneration: a potential strategy for the recovery of β cell deficiency in diabetes. Front Endocrinol. https://doi.org/10.3389/fendo.2019.00101

    Article  Google Scholar 

  215. D’Amour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24(11):1392–1401

    Article  CAS  PubMed  Google Scholar 

  216. Zhang D, Jiang W, Liu M et al (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19(4):429–438

    Article  CAS  PubMed  Google Scholar 

  217. Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y (2008) Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 283(46):31601–31607

    Article  CAS  PubMed  Google Scholar 

  218. Nostro MC, Sarangi F, Ogawa S et al (2011) Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138(5):861–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Hrvatin S, O’Donnell CW, Deng F et al (2014) Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci 111(8):3038–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Pagliuca FW, Millman JR, Gürtler M et al (2014) Generation of functional human pancreatic β cells in vitro. Cell 159(2):428–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Rezania A, Bruin JE, Arora P et al (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32(11):1121

    Article  CAS  PubMed  Google Scholar 

  222. Russ HA, Parent AV, Ringler JJ et al (2015) Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J 34(13):1759–1772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Sambathkumar R, Migliorini A, Nostro MC (2018) Pluripotent stem cell-derived pancreatic progenitors and β-like cells for type 1 diabetes treatment. Physiology 33(6):394–402

    Article  CAS  PubMed  Google Scholar 

  224. Pellegrini S, Chimienti R, Scotti GM et al (2021) Transcriptional dynamics of induced pluripotent stem cell differentiation into beta cells reveals full endodermal commitment and homology with human islets. Cytotherapy 23(4):311–319. https://doi.org/10.1016/j.jcyt.2020.10.004

    Article  CAS  PubMed  Google Scholar 

  225. Sebastiani G, Valentini M, Grieco GE et al (2017) MicroRNA expression profiles of human iPSCs differentiation into insulin-producing cells. Acta Diabetol 54(3):265–281. https://doi.org/10.1007/s00592-016-0955-9

    Article  CAS  PubMed  Google Scholar 

  226. Pellegrini S, Ungaro F, Mercalli A et al (2015) Human induced pluripotent stem cells differentiate into insulin-producing cells able to engraft in vivo. Acta Diabetol 52(6):1025–1035. https://doi.org/10.1007/s00592-015-0726-z

    Article  CAS  PubMed  Google Scholar 

  227. Veres A, Faust AL, Bushnell HL et al (2019) Charting cellular identity during human in vitro β-cell differentiation. Nature 569(7756):368–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Pullen LC (2018) Stem cell-derived pancreatic progenitor cells have now been transplanted into patients: report from IPITA 2018. Wiley Online Library

  229. Schulz TC, Young HY, Agulnick AD et al (2012) A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS ONE 7(5):e37004. https://doi.org/10.1371/journal.pone.0037004PONE-D-12-04537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26(4):443–452

    Article  CAS  PubMed  Google Scholar 

  231. Kelly OG, Chan MY, Martinson LA et al (2011) Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 29(8):750–756

    Article  CAS  PubMed  Google Scholar 

  232. Cooper-Jones B, Ford C (2017) Islet cell replacement therapy for insulin-dependent diabetes. CADTH Issues in Emerging Health Technologies

  233. Henry RR, Pettus J, Wilensky J, et al. (2018) Initial clinical evaluation of VC-01TM combination product—a stem cell–derived islet replacement for Type 1 Diabetes (T1D). Am Diabetes Assoc

  234. Shapiro A, Thompson D, Donner TW, et al. (2019) Insulin expression and glucose-responsive circulating C-peptide in type 1 diabetes patients implanted subcutaneously with pluripotent stem cell-derived pancreatic endoderm cells in a macro-device. (December 9, 2019). Available at SSRN: https://ssrn.com/abstract=3501034 or https://doi.org/10.2139/ssrn.3501034

  235. Vaithilingam V, Bal S, Tuch BE (2017) Encapsulated islet transplantation: where do we stand? Rev Diabet Stud 14(1):51–78. https://doi.org/10.1900/RDS.2017.14.51

    Article  PubMed  PubMed Central  Google Scholar 

  236. Sordi V, Pellegrini S, Piemonti L (2017) Immunological issues after stem cell-based beta cell replacement. Curr Diab Rep 17(9):68. https://doi.org/10.1007/s11892-017-0901-4

    Article  CAS  PubMed  Google Scholar 

  237. Barry J, Hyllner J, Stacey G, Taylor CJ, Turner M (2015) Setting up a haplobank: issues and solutions. Curr Stem Cell Rep 1(2):110–117

    Article  PubMed  PubMed Central  Google Scholar 

  238. Zheng D, Wang X, Xu RH (2016) Concise review: one stone for multiple birds: generating universally compatible human embryonic stem cells. Stem Cells 34(9):2269–2275

    Article  CAS  PubMed  Google Scholar 

  239. Senior P, Pettus J (2019) Stem cell therapies for Type 1 diabetes: current status and proposed road map to guide successful clinical trials. Diabet Med 36(3):297–307

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is grateful to his research coworkers Dr. ssa Valeria Sordi, Dr.ssa Silvia pellegrini and Dr. Antonio Citro for their long-term collaboration and numerous discussions on the science and technology of stem cell and tissue engineering. The author is highly grateful to his research coworkers Dr.ssa Marina Scavini for help in the preparation of this review and for helpful discussions. This work was supported by SOStegno 70 Insieme ai ragazzi diabetici Associazione Onlus (Project “Beta is better”). The author is indebted to Paola Macchieraldo, Antonio Mincione, Elena Riva, Antonio Civita, Luca Casaura, Patrizia Pappini, Giorgio Mario Oldrati, Andrea Marchesi and Michele Mainardi for their support to the fundraising campaign “Un brutto t1po”.

Funding

This work was supported by SOStegno 70 Insieme ai ragazzi diabetici Associazione Onlus (Project “Beta is better”). The author is indebted to Paola Macchieraldo, Antonio Mincione, Elena Riva, Antonio Civita, Luca Casaura, Patrizia Pappini, Giorgio Mario Oldrati, Andrea Marchesi and Michele Mainardi for their support to the fundraising campaign “Un brutto t1po”.

Author information

Authors and Affiliations

Authors

Contributions

LP contributed to the conception of the work, wrote the manuscript, researched data and contributed to the discussion. Professor LP is the guarantor of this work and, as such, had full access to all the data presented in the study and takes responsibility for the integrity of data and the accuracy of data analysis. The author is highly grateful to his research coworkers Dr. ssa MS for help in the preparation of this review and for helpful discussions.

Corresponding author

Correspondence to Lorenzo Piemonti.

Ethics declarations

Conflict of interest

The author has no conflict of interest to disclose in relation to the topic of this manuscript. The author declares that there are no relationships or activities that might bias, or be perceived to bias, his work.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Institutional and National) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent

Informed consent was obtained from all patients for being included in the study.

Additional information

Managed by Massimo Federici.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piemonti, L. Felix dies natalis, insulin… ceterum autem censeo “beta is better”. Acta Diabetol 58, 1287–1306 (2021). https://doi.org/10.1007/s00592-021-01737-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-021-01737-3

Keywords

Navigation