Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3-6 months. If targets are not met, one diabetes technology-continuous subcutaneous insulin infusion or continuous glucose monitoring-should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.

Department of Diabetes and Clinical Nutrition Kyoto University Kyoto Japan

Department of Endocrinology and Diabetology University of Zurich Zurich Switzerland

Department of Medicine Division of Endocrinology Diabetes and Metabolism University of Pennsylvania Perelman School of Medicine Philadelphia PA

Department of Medicine Division of Endocrinology University of Alberta Edmonton Canada

Diabetes Center Institute for Clinical and Experimental Medicine Prague Czech Republic

Diabetes Clinic and Research Center Vrije Universiteit Brussel Brussels Belgium

Diabetes Research Group King's College London London U K

Diabetes Research Institute Scientific Institute Ospedale San Raffaele Milan Italy

Endocrinology and Metabolism Department INSERM U1190 European Genomics Institute for Diabetes Lille University Hospital Lille Cedex France

Immunology and Diabetes Unit St Vincent's Institute University of Melbourne Melbourne Australia

Schulze Diabetes Institute and Department of Surgery University of Minnesota Minneapolis MN

Komentář v

Diabetes Care. 38:968. PubMed

Komentář v

Diabetes Care. 38:971. PubMed

Komentář v

Diabetes Care. 38:979. PubMed

Komentář v

Diabetes Care. 38:989. PubMed

Komentář v

Diabetes Care. 38:997. PubMed

Komentář v

Diabetes Care. 38:1008. PubMed

Komentář v

Diabetes Care. 38:1030. PubMed

Komentář v

Diabetes Care. 38:1036. PubMed

Zobrazit více v PubMed

Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57:3169–3176 PubMed PMC

McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes. Diabetes 2010;59:2333–2339 PubMed PMC

Seaquist ER, Anderson J, Childs B, et al. . Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;36:1384–1395 PubMed PMC

Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol 2014;10:711–722 PubMed

Workgroup on Hypoglycemia, American Diabetes Association . Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005;28:1245–1249 PubMed

Pedersen-Bjergaard U, Pramming S, Heller SR, et al. . Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 2004;20:479–486 PubMed

UK Hypoglycaemia Study Group . Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007;50:1140–1147 PubMed

Gruden G, Barutta F, Chaturvedi N, et al. . Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 2012;35:1598–1604 PubMed PMC

Weinstock RS, Xing D, Maahs DM, et al. .; T1D Exchange Clinic Network . Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange clinic registry. J Clin Endocrinol Metab 2013;98:3411–3419 PubMed

Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 1995;18:517–522 PubMed

Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994;17:697–703 PubMed

Ryan EA, Shandro T, Green K, et al. . Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004;53:955–962 PubMed

Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013;369:362–372 PubMed

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

Choudhary P, Geddes J, Freeman JV, Emery CJ, Heller SR, Frier BM. Frequency of biochemical hypoglycaemia in adults with type 1 diabetes with and without impaired awareness of hypoglycaemia: no identifiable differences using continuous glucose monitoring. Diabet Med 2010;27:666–672 PubMed

Hopkins D, Lawrence I, Mansell P, et al. . Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience. Diabetes Care 2012;35:1638–1642 PubMed PMC

Frier BM. Morbidity of hypoglycemia in type 1 diabetes. Diabetes Res Clin Pract 2004;65(Suppl. 1):S47–S52 PubMed

Skrivarhaug T, Bangstad HJ, Stene LC, Sandvik L, Hanssen KF, Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49:298–305 PubMed

Feltbower RG, Bodansky HJ, Patterson CC, et al. . Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults. Diabetes Care 2008;31:922–926 PubMed

McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 2012;35:1897–1901 PubMed PMC

Sherr J, Tamborlane WV, Xing D, et al. .; Diabetes Research in Children Network (DirecNet) Study Group . Achievement of target A1C levels with negligible hypoglycemia and low glucose variability in youth with short-term type 1 diabetes and residual β-cell function. Diabetes Care 2012;35:817–820 PubMed PMC

Siegelaar SE, Holleman F, Hoekstra JB, DeVries JH. Glucose variability; does it matter? Endocr Rev 2010;31:171–182 PubMed

Vantyghem MC, Raverdy V, Balavoine AS, et al. . Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (β-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (β-score greater than 3). J Clin Endocrinol Metab 2012;97:E2078–E2083 PubMed PMC

Stuckey HL, Mullan-Jensen CB, Reach G, et al. . Personal accounts of the negative and adaptive psychosocial experiences of people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2) study. Diabetes Care 2014;37:2466–2474 PubMed

The Diabetes Control and Complications Trial Research Group . Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271–286 PubMed

Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 2006;49:261–270 PubMed

Nathan DM, Cleary PA, Backlund JY, et al. .; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group . Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653 PubMed PMC

Orchard TJ, Nathan DM, Zinman B, et al. .; Writing Group for the DCCT/EDIC Research Group . Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313:45–53 PubMed PMC

Stadler M, Peric S, Strohner-Kaestenbauer H, et al. . Mortality and incidence of renal replacement therapy in people with type 1 diabetes mellitus—a three decade long prospective observational study in the Lainz T1DM cohort. J Clin Endocrinol Metab 2014;99:4523–4530 PubMed

Lind M, Svensson AM, Kosiborod M, et al. . Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2014;371:1972–1982 PubMed

Schoenaker DA, Simon D, Chaturvedi N, Fuller JH, Soedamah-Muthu SS; EURODIAB Prospective Complications Study Group . Glycemic control and all-cause mortality risk in type 1 diabetes patients: the EURODIAB prospective complications study. J Clin Endocrinol Metab 2014;99:800–807 PubMed

Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes 2014;63:2188–2195 PubMed

Mühlhauser I, Bruckner I, Berger M, et al. . Evaluation of an intensified insulin treatment and teaching programme as routine management of type 1 (insulin-dependent) diabetes. The Bucharest-Düsseldorf Study. Diabetologia 1987;30:681–690 PubMed

Sämann A, Mühlhauser I, Bender R, Kloos Ch, Müller UA. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia 2005;48:1965–1970 PubMed

Sämann A, Mühlhauser I, Bender R, Hunger-Dathe W, Kloos C, Müller UA. Flexible intensive insulin therapy in adults with type 1 diabetes and high risk for severe hypoglycemia and diabetic ketoacidosis. Diabetes Care 2006;29:2196–2199 PubMed

Cox D, Gonder-Frederick L, Polonsky W, Schlundt D, Julian D, Clarke W. A multicenter evaluation of blood glucose awareness training-II. Diabetes Care 1995;18:523–528 PubMed

Broers S, van Vliet KP, le Cessie S, Spinhoven P, van der Ven NC, Radder JK. Blood glucose awareness training in Dutch type 1 diabetes patients: one-year follow-up. Neth J Med 2005;63:164–169 PubMed

Schachinger H, Hegar K, Hermanns N, et al. . Randomized controlled clinical trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany. J Behav Med 2005;28:587–594 PubMed

Fanelli CG, Epifano L, Rambotti AM, et al. . Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993;42:1683–1689 PubMed

Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 1994;344:283–287 PubMed

Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994;43:1426–1434 PubMed

Fanelli C, Pampanelli S, Epifano L, et al. . Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM (published correction appears in Diabetolgia 1995;38:254). Diabetologia 1994;37:1265–1276 PubMed

Cox DJ, Kovatchev B, Koev D, et al. . Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus. Int J Behav Med 2004;11:212–218 PubMed

Hermanns N, Kulzer B, Krichbaum M, Kubiak T, Haak T. Long-term effect of an education program (HyPOS) on the incidence of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 2010;33:e36. PubMed PMC

Rankin D, Elliott J, Heller S, et al. . Experiences of hypoglycaemia unawareness amongst people with Type 1 diabetes: a qualitative investigation. Chronic Illn 2013;10:180–191 PubMed

Rogers HA, de Zoysa N, Amiel SA. Patient experience of hypoglycaemia unawareness in type 1 diabetes: are patients appropriately concerned? Diabet Med 2012;29:321–327 PubMed

de Zoysa N, Rogers H, Stadler M, et al. . A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care 2014;37:863–866 PubMed

Little SA, Leelarathna L, Walkinshaw E, et al. . Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 × 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes Care 2014;37:2114–2122 PubMed

Little S, Shaw J, Home P. Hypoglycemia rates with basal insulin analogs. Diabetes Technol Ther 2011;13(Suppl. 1):S53–S64 PubMed

Holleman F, Gale EA. Nice insulins, pity about the evidence. Diabetologia 2007;50:1783–1790 PubMed

Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 2009;180:385–397 PubMed PMC

Heise T, Nosek L, Rønn BB, et al. . Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004;53:1614–1620 PubMed

Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis. Diabetes Obes Metab 2009;11:372–378 PubMed

Tricco AC, Antony J, Khan PA, et al. . Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis. BMJ Open 2014;4:e005752. PubMed PMC

Heller S, Buse J, Fisher M, et al. .; BEGIN Basal-Bolus Type 1 Trial Investigators . Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012;379:1489–1497 PubMed

Pedersen-Bjergaard U, Kristensen PL, Beck-Nielsen H, et al. . Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. Lancet Diabetes Endocrinol 2014;2:553–561 PubMed

Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008;25:765–774 PubMed

Giménez M, Lara M, Conget I. Sustained efficacy of continuous subcutaneous insulin infusion in type 1 diabetes subjects with recurrent non-severe and severe hypoglycemia and hypoglycemia unawareness: a pilot study. Diabetes Technol Ther 2010;12:517–521 PubMed

Chetty VT, Almulla A, Odueyungbo A, Thabane L. The effect of continuous subcutaneous glucose monitoring (CGMS) versus intermittent whole blood finger-stick glucose monitoring (SBGM) on hemoglobin A1c (HbA1c) levels in type I diabetic patients: a systematic review. Diabetes Res Clin Pract 2008;81:79–87 PubMed

Szypowska A, Ramotowska A, Dzygalo K, Golicki D. Beneficial effect of real-time continuous glucose monitoring system on glycemic control in type 1 diabetic patients: systematic review and meta-analysis of randomized trials. Eur J Endocrinol 2012;166:567–574 PubMed

Leelarathna L, Little SA, Walkinshaw E, et al. . Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial. Diabetes Care 2013;36:4063–4070 PubMed PMC

Bergenstal RM, Tamborlane WV, Ahmann A, et al. .; STAR 3 Study Group . Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med 2010;363:311–320 PubMed

Buckingham B, Block J, Burdick J, et al. .; Diabetes Research in Children Network . Response to nocturnal alarms using a real-time glucose sensor. Diabetes Technol Ther 2005;7:440–447 PubMed PMC

Bergenstal RM, Klonoff DC, Garg SK, et al. .; ASPIRE In-Home Study Group . Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013;369:224–232 PubMed

Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW. 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;310:1240–1247 PubMed

Choudhary P, Ramasamy S, Green L, et al. . Real-time continuous glucose monitoring significantly reduces severe hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes. Diabetes Care 2013;36:4160–4162 PubMed PMC

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;371:313–325 PubMed PMC

Hovorka R, Kumareswaran K, Harris J, et al. Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies. BMJ 2011;342:d1855 PubMed PMC

Haidar A, Legault L, Messier V, Mitre TM, Leroux C, Rabasa-Lhoret R. 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 2015;3:17–26 PubMed

Gruessner RW, Gruessner AC. The current state of pancreas transplantation. Nat Rev Endocrinol 2013;9:555–562 PubMed

Barton FB, Rickels MR, Alejandro R, et al. . Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012;35:1436–1445 PubMed PMC

Niclauss N, Morel P, Berney T. Has the gap between pancreas and islet transplantation closed? Transplantation 2014;98:593–599 PubMed

Bassi R, Fiorina P. Impact of islet transplantation on diabetes complications and quality of life. Curr Diab Rep 2011;11:355–363 PubMed

Thompson DM, Meloche M, Ao Z, et al. . Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91:373–378 PubMed

Robertson RP. Islet transplantation for type 1 diabetes, 2015: what have we learned from alloislet and autoislet successes? Diabetes Care 2015;38:1030–1035 PubMed PMC

Kendall DM, Rooney DP, Smets YF, Salazar Bolding L, Robertson RP. Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 1997;46:249–257 PubMed

Rickels MR, Fuller C, Dalton-Bakes C, et al. . Restoration of glucose counterregulation by islet transplantation in long-standing type 1 diabetes. Diabetes 2015;64:1713–1718 PubMed PMC

Rickels MR, Mueller R, Teff KL, Naji A. β-Cell secretory capacity and demand in recipients of islet, pancreas, and kidney transplants. J Clin Endocrinol Metab 2010;95:1238–1246 PubMed PMC

Rickels MR, Liu C, Shlansky-Goldberg RD, et al. . Improvement in β-cell secretory capacity after human islet transplantation according to the CIT07 protocol. Diabetes 2013;62:2890–2897 PubMed PMC

Paty BW, Lanz K, Kendall DM, Sutherland DE, Robertson RP. Restored hypoglycemic counterregulation is stable in successful pancreas transplant recipients for up to 19 years after transplantation. Transplantation 2001;72:1103–1107 PubMed

Barrou Z, Seaquist ER, Robertson RP. Pancreas transplantation in diabetic humans normalizes hepatic glucose production during hypoglycemia. Diabetes 1994;43:661–666 PubMed

Matsumoto I, Sawada T, Nakano M, et al. . Improvement in islet yield from obese donors for human islet transplants. Transplantation 2004;78:880–885 PubMed

Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant 2012;17:100–105 PubMed

Sollinger HW, Odorico JS, Becker YT, D’Alessandro AM, Pirsch JD. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg 2009;250:618–630 PubMed

Lehmann R, Graziano J, Brockmann J, et al. . Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: a prospective 13-year follow-up. Diabetes Care 2015;38:752–759 PubMed

Gruessner RW, Dunn DL, Gruessner AC, Matas AJ, Najarian JS, Sutherland DE. Recipient risk factors have an impact on technical failure and patient and graft survival rates in bladder-drained pancreas transplants. Transplantation 1994;57:1598–1606 PubMed

Kandaswamy R, Sutherland DE. Pancreas versus islet transplantation in diabetes mellitus: how to allocate deceased donor pancreata? Transplant Proc 2006;38:365–367 PubMed

Senior PA, Bellin MD, Alejandro R, et al. . Consistency of quantitative scores of hypoglycemia severity and glycemic lability and comparision with continuous glucose monitoring system measures in long-standing type 1 diabetes. Diabetes Technol Ther 2015;17:235–242 PubMed PMC

Bellin MD, Barton FB, Heitman A, et al. . Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 2012;12:1576–1583 PubMed PMC

Qi M, Kinzer K, Danielson KK, et al. . Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol 2014;51:833–843 PubMed PMC

Clinical Islet Transplantation Consortium. Available from http://www.isletstudy.org. Accessed 2 February 2015

O’Connell PJ, Holmes-Walker DJ, Goodman D, et al. .; Australian Islet Transplant Consortium . Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant 2013;13:1850–1858 PubMed

Brooks AM, Walker N, Aldibbiat A, et al. . Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations. Am J Transplant 2013;13:3236–3243 PubMed

Ang M, Meyer C, Brendel MD, Bretzel RG, Linn T. Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes. Diabetologia 2014;57:623–632 PubMed

Paty BW, Senior PA, Lakey JR, Shapiro AM, Ryan EA. Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects. Diabetes Technol Ther 2006;8:165–173 PubMed

Gorn L, Faradji RN, Messinger S, et al. . Impact of islet transplantation on glycemic control as evidenced by a continuous glucose monitoring system. J Diabetes Sci Tech 2008;2:221–228 PubMed PMC

Brooks AM, Oram R, Home P, Steen N, Shaw JA. Demonstration of an intrinsic relationship between endogenous C-peptide concentration and determinants of glycemic control in type 1 diabetes following islet transplantation. Diabetes Care 2015;38:105–112 PubMed

Cryer PE. Hypoglycemia begets hypoglycemia in IDDM. Diabetes 1993;42:1691–1693 PubMed

Gerber PA, Pavlicek V, Demartines N, et al. . Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5 year single centre follow-up. Diabetologia 2008;51:110–119 PubMed

Östenson CG, Geelhoed-Duijvestijn P, Lahtela J, Weitgasser R, Markert Jensen M, Pedersen-Bjergaard U. Self-reported non-severe hypoglycaemic events in Europe. Diabet Med 2014;31:92–101 PubMed PMC

Kovatchev BP, Cox DJ, Gonder-Frederick LA, Young-Hyman D, Schlundt D, Clarke W. Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the low blood glucose index. Diabetes Care 1998;21:1870–1875 PubMed

Kovatchev BP, Otto E, Cox D, Gonder-Frederick L, Clarke W. Evaluation of a new measure of blood glucose variability in diabetes. Diabetes Care 2006;29:2433–2438 PubMed

Bode BW, Buse JB, Fisher M, et al. .; BEGIN® Basal-Bolus Type 1 Trial Investigators . Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN(®) Basal-Bolus Type 1): 2-year results of a randomized clinical trial. Diabet Med 2013;30:1293–1297 PubMed PMC

Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ 2011;343:d3805. PubMed PMC

Wiseman AC. Pancreas transplant options for patients with type 1 diabetes mellitus and chronic kidney disease: simultaneous pancreas kidney or pancreas after kidney? Curr Opin Organ Transplant 2012;17:80–86 PubMed

Maffi P, Bertuzzi F, De Taddeo F, et al. . Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy. Diabetes Care 2007;30:1150–1155 PubMed

Ojo AO, Held PJ, Port FK, et al. . Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931–940 PubMed

Klein AS, Messersmith EE, Ratner LE, Kochik R, Baliga PK, Ojo AO. Organ donation and utilization in the United States, 1999-2008. Am J Transplant 2010;10:973–986 PubMed

Matesanz R, Domínguez-Gil B, Coll E, de la Rosa G, Marazuela R. Spanish experience as a leading country: what kind of measures were taken? Transpl Int 2011;24:333–343 PubMed

Byrne ML, Hopkins D, Littlejohn W, et al. . Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service. Horm Metab Res 2015;47:9–15 PubMed

Decellularized Pancreatic Tail as Matrix for Pancreatic Islet Transplantation into the Greater Omentum in Rats

Transplant Options for Patients With Diabetes and Advanced Kidney Disease: A Review

Benefits of Islet Transplantation as an Alternative to Pancreas Transplantation: Retrospective Study of More Than 10 Ten Years of Experience in a Single Center