Recent advances in the prevention of hypoglycemia in type 1 diabetes

Diabetes Technology and Therapeutics

Volumn 13, Issue 12, 2011, Pages 1177-1186

  Realsen, Jaime M ^a   Chase, H Peter ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

C PEPTIDE; HUMAN INSULIN; INSULIN; INSULIN ASPART; INSULIN DETEMIR; INSULIN GLARGINE; INSULIN LISPRO; RITUXIMAB;

BLOOD GLUCOSE MONITORING; CONTINUOUS INFUSION; DISEASE SEVERITY; DOSAGE SCHEDULE COMPARISON; DRUG WITHDRAWAL; EXERCISE; GLYCEMIC CONTROL; HEALTH CARE MANAGEMENT; HEALTH CARE PRACTICE; HUMAN; HYPOGLYCEMIA; INSULIN DEPENDENT DIABETES MELLITUS; PATIENT EDUCATION; PREVALENCE; PRIMARY PREVENTION; PRIORITY JOURNAL; PROTEIN SYNTHESIS; RECOMMENDED DRUG DOSE; REVIEW; SELF CONCEPT; SELF MONITORING;

BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 1; HUMANS; HYPOGLYCEMIA; INSULIN;

EID: 82455204663     PISSN: 15209156     EISSN: 15578593     Source Type: Journal    
DOI: 10.1089/dia.2011.0150     Document Type: Review

References (90)

1. Cryer PE: Hypoglycemia in Diabetes. Pathophysiology, Prevalence and Prevention. Alexandria, VA: American Diabetes Association, 2009.
2. Feltbower RG, Bodansky HJ, Patterson CC, Parslow RC, Stephenson CR, Reynolds C, McKinney PA: Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes. Diabetes Care 2008;31:922-926.
3. 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. (Pubitemid 43185398)
4. Tanenberg RJ, Newton CA, Drake AJ: Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 2010;16:244-248.
5. Barnard K, Thomas S, Royle P, Noyes K, Waugh N: Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC Pediatr 2010;10:1-8.
6. American Diabetes Association Workgroup on Hypoglycemia: Defining and reporting hypoglycemia in diabetes. Diabetes Care 2005;28:1245-1249.
7. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: Variation of interstitial glucose measurements assessed by continuous glucose monitors in healthy, nondiabetic individuals. Diabetes Care 2010;33: 1297-1299.
8. Chase HP, Maahs DM: Understanding Diabetes, 12th ed. Denver, CO: Children's Diabetes Foundation, 2011.
9. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. J Pediatr 1994; 125:177-188.
10. Rewers A, Chase HP, Mackenzie T, Walravens P, Roback M, Rewers M, Hamman RF, Klingensmith G: Predictors of acute complications in children with type 1 diabetes. JAMA 2002; 287:2511-2518. (Pubitemid 34517196)
11. Davis EA, Keating B, Byrne GC, Russell M, Jones TW: Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. Diabetes Care 1997;20:22-25. (Pubitemid 27020036)
12. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes. Diabetes Care 2010;33:1004-1008.
13. Cryer PE: The barrier of hypoglycemia in diabetes. Diabetes 2008;57:3169-3176.
14. Wasserman DH, Zinman B: Exercise in individuals with IDDM. Diabetes Care 1994;17:924-937. (Pubitemid 24235521)
15. Camacho RC, Pencek RR, Lacy DB, James FD, Wasserman DH: Suppression of endogenous glucose production by mild hyperinsulinemia during exercise is determined predominately by portal venous insulin. Diabetes 2004;53:285-293. (Pubitemid 38174542)
16. Jones TW, Porter P, Sherwin RS, Davis EA, O'Leary P, Frazer F, Byrne G, Stick S, Tamborlane WV: Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med 1998; 338:1657-1662. (Pubitemid 28267910)
17. Siler SQ, Neese RA, Christiansen MP, Hellerstein MK: The inhibition of gluconeogenesis following alcohol in humans. Am J Physiol Endocrinol Metab 1998;275:E897-E907.
18. Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes. Diabetes Care 2003;26:1902-1912. (Pubitemid 36929141)
19. Dagogo-Jack SE, Craft S, Cryer PE: Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. J Clin Invest 1993;91:819-828.
20. Bhatia V, Wolfsdorf JI: Severe hypoglycemia in youth with insulin-dependent diabetes mellitus: frequency and causative factors. Pediatrics 1991;88:1187-1193.
21. 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.
22. Burdick PL, Gage VL, Dignan GW, Cobry E, Chase HP: Hypoglycemia unawareness (HUN) in youth with type 1 diabetes (T1D) [abstract]. Diabetes 2007;56(Suppl 1):1918-P.
23. Ly TT, Davis EA, Gallego PH, Jones TW: Impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes. Diabetes Care 2009;32:1802-1806.
24. Janssen MM, Snoek FJ, de Jongh RT, Casteleijn S, Deville W, Heine RJ: Biological and behavioral determinants of the frequency of mild, biochemical hypoglycaemia in patients with type 1 diabetes on multiple insulin injection therapy. Metab Res Rev 2000;16:157-163. (Pubitemid 30410270)
25. Diabetes Research in Children Network (DirecNet) Study Group: Blunted counterregulatory hormone responses to hypoglycemia in young children and adolescents with wellcontrolled type 1 diabetes. Diabetes Care 2009;32:1954-1959.
26. Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Di Vincenzo A, Modarelli F, Ciofetta M, Lepore M, Annibale B, Torlone E, Perriello G, De Feo P, Santuesanio F, Brunetti P, Bolli GB: Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia following institution of rational intensive insulin therapy in IDDM. Diabetologia 1994;37:1265-1276. (Pubitemid 24356767)
27. 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. (Pubitemid 24230294)
28. Dagogo-Jack S, Rattarasarn C, Cryer PE: Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994;43:1426-1434.
29. Fanelli C, Pampanelli S, Lalli C, Del Sindaco P, Ciofetta M, Lepore M, Porcellati F, Bottini P, Di Vincenzo A, Brunetti P, Bolli GB: Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. Diabetes 1997;46:1172-1181. (Pubitemid 27271079)
30. American Diabetes Association: Standards of medical care in diabetes-2010. Diabetes Care 2010;33(Suppl 1):S11-S61.
31. American Diabetes Association: Self-monitoring of blood glucose. Diabetes Care 1994;17:81-86.
32. Shekelle P, Munjas B, Romanova M, Towfigh A, Weinreb J, Zhou A, Suttorp M: Self-Monitoring of Blood Glucose in Patients with Type 2 Diabetes Mellitus: Meta Analysis of Effectiveness. Washington, DC: Department of Veteran Affairs, 2007.
33. Hansen MV, Pedersen-Bjergaard U, Heller SR, Wallace TM, Rasmussen AK, Jorgensen HV, Pramming S, Thorsteinsson B: Frequency and motives of blood glucose self-monitoring in type 1 diabetes. Diabetes Res Clin Pract 2009;85:183-188.
34. Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R; DPV-Wiss-Initiative: Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes 2011; 12:11-17.
35. Chase HP, Lockspeiser T, Peery B, Shepherd M, MacKenzie T, Anderson J, Garg SK: The impact of the Diabetes Control and Complications Trial and Humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes. Diabetes Care 2001;24:430-434. (Pubitemid 32198408)
36. Heller SR, Colagiuri S, Vaaler S, Wolffenbuttel BH, Koelendorf K, Friberg HH, Windfeld K, Lindholm A: Hypoglycaemia with insulin aspart: a double-blind, randomized, crossover trial in subjects with type 1 diabetes. Diabet Med 2004;21:769-775. (Pubitemid 38916224)
37. Dixon B, Chase HP, Burdick J, Fiallo-Scharer R, Walravens P, Klingensmith G, Rewers M, Garg SK: Use of insulin glargine in children under age 6 with type 1 diabetes. Pediatr Diabetes 2005;6:150-154. (Pubitemid 41223240)
38. American Diabetes Association: Continuous subcutaneous insulin infusion. Diabetes Care 2004;27(Suppl 1):S110.
39. National Institute for Health and Clinical Excellence: Continuous Subcutaneous Insulin Infusion for the Treatment of Diabetes Mellitus: Review of Technology Appraisal Guidance
40. NICE Technology Appraisal Guidance 151. London: National Institute for Health and Clinical Excellence, 2008.
41. 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.
42. Scrimgeour L, Cobry E, McFann K, Burdick P, Weimer C, Slover R, Chase HP: Improved glycemic control after longterm insulin pump use in pediatric patients with type 1 diabetes. Diabetes Technol Ther 2007;9:421-428. (Pubitemid 47585352)
43. Shalitin S, Gil M, Nimri R, De Vries L, Gavan MY, Phillip M: Predictors of glycaemic control in patients with Type 1 diabetes commencing continuous subcutaneous insulin infusion therapy. Diabet Med 2010;27:339-347.
44. Gimenez 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 awareness: a pilot study. Diabetes Technol Ther 2010;12:517-521.
45. DirecNet: Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr 2005; 147:528-534.
46. DirecNet: Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care 2006;29:2200-2204.
47. Taplin CE, Cobry E, Messer L, McFann K, Chase HP, Fiallo-Scharer R: Preventing post-exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr 2010;157:784-788.
48. Admon G, Weinstein Y, Falk B, Weintrob N, Benzaquen H, Ofan R, Fayman G, Zigel L, Constantini N, Phillip M: Exercise with and without an insulin pump among children and adolescents with type 1 diabetes mellitus. Pediatrics 2005;116:e348-e355. (Pubitemid 44336648)
49. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
50. Garg S, Zisser H, Schwartz S, Bailey T, Kaplan R, Ellis S, Jovanovic L: Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor. Diabetes Care 2006;29:44-50. (Pubitemid 44033429)
51. Garg SK, Kelly WC, Voelmle MK, Ritchie PJ, Gottlieb PA, McFann KK, Ellis SL: Continuous home monitoring of glucose: improved glycemic control with real-life use of continuous glucose sensors in adult subjects with type 1 diabetes. Diabetes Care 2007;30:3023-3025. (Pubitemid 350255236)
52. DiessD, Bosi E, Bolinder J, Tubiana-Rufi N, Riveline JP,KerrD, Battelino T, Phillip M: Improved glycemic control in poorly controlled patients with type 1 diabetes using real-time continuous glucose monitoring. Diabetes Care 2006;29:2730-2732. (Pubitemid 44912209)
53. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008;359:1464-1476.
54. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care 2009;32:1378-1383.
55. Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kaufman FR, Mastrototaro J, Parkin CG, Wolpert HA, Buckingham BA: Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Technol Ther 2008;10:377-383.
56. Raccah D, Renard E, Sulmont V, Hanaire H, Reznik Y, Jeandidier N, Guerci B, Nicolino M: Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes. Diabetes Care 2009;32:2245-2250.
57. Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA: Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med 2010;363:311-320.
58. Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J: Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care 2011;34: 795-800.
59. Buckingham B, Block J, Burdick J, Kalajian A, Kollman C, Choy M, Wilson DM, Chase HP; Diabetes Research in Children Network (DirecNet): Response to nocturnal alarms using a real-time glucose sensor. Diabetes Technol Ther 2005;7:440-447. (Pubitemid 40847806)
60. Ly TT, Lim EM, Hewitt J, Davis EA, Davey RJ, Jones TW: Improving epinephrine responses in hypoglycemia unawareness with real-time continuous glucose monitoring in adolescents with type 1 diabetes. Diabetes Care 2011;34:50-52.
61. Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-238. (Pubitemid 30490390)
62. Zucchini S, Scipione M, Balsamo C, Maltoni G, Rollo A, Molinari E, Mangoni L, Cicognani A: Comparison between sensor-augmented insulin therapy with continuous subcutaneous insulin infusion or multiple daily injections in everyday life: 3-day analysis of glucose patterns and sensor accuracy in children. Diabetes Technol Ther 2011; 13:1187-1193.
63. Sato T, Seiki O, Hagino K, Asakura Y, Kikkawa Y, Kojima J, Watanabe T, Maekawa Y, Isobe K, Koike R, Nakajima H, Asano K: Measurement of glucose area under the curve using minimally invasive interstitial fluid extraction technology: evaluation of glucose monitoring concepts without blood sampling. Diabetes Technol Ther 2011;13:1194-1200.
64. Keenan DB, Cartaya R, Mastrototaro JJ: The pathway to the closed-loop artificial pancreas: research and commercial perspectives. Pediatr Endocrinol Rev 2010;7:445-451.
65. Buckingham B, Cobry E, Clinton P, Gage V, Caswell K, Kunselman E, Cameron F, Chase HP: Preventing hypoglycemia using predictive alarm algorithms and insulin pump suspension. Diabetes Technol Ther 2009;11:93-97.
66. Buckingham B, Chase HP, Dassau E, Cobry E, Clinton P, Gage V, Caswell K, Wilkinson J, Cameron F, Lee H, Bequette BW, Doyle FJ: Prevention of nocturnal hypoglycemia using predictive alarm algorithms and insulin pump suspension. Diabetes Care 2010;33:1013-1017.
67. Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, Wysocki T, Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy KJ: Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr 2005;147:528-534. (Pubitemid 41446549)
68. Orsini-Federici M, Akwi JA, Canonico V, Celleno R, Ferolla P, Pippi R, Tassi C, Timi A, Benedetti MM: Early detection of insulin deprivation in continuous subcutaneous insulin infusion-treated patients with type 1 diabetes. Diabetes Technol Ther 2006;8:67-75.
69. Boyne MS, Silver DM, Kaplan J, Saudek CD: Timing of changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes 2003;52:2790-2794. (Pubitemid 37339709)
70. Castillo MJ, Scheen AJ, Lefebvre PJ: The degree/rapidity of the metabolic deterioration following interruption of a continuous subcutaneous insulin infusion is influenced by the prevailing blood glucose Level. J Clin Endocrinol Metab1996; 81:1975-1978.
71. Elleri D, Allen JM, Nodale M, Wilinska ME, Acerini CL, Dunger DB, Hovorka R: Suspended insulin infusion during overnight closed-loop glucose control in children and adolescents with type 1 diabetes. Diabet Med 2010;27:480-484.
72. Cengiz E, Swan KL, Tamborlane WV, Steil GM, Steffen AT, Weinzimer SA: Is an automatic pump suspension feature safe for children with type 1 diabetes? An exploratory analysis with a closed-loop system. Diabetes Technol Ther 2009;11:207-210.
73. O'Connell R, Oroszlan G, Hamer G, Yusi J, Kaufman F, Welsh J, Mihalakis M, Lee S: Efficacy of low glucose suspend and low predictive alert: data analysis using the Medtronic Carelink-Therapy Management Software Database [abstract P-128]. 4th International Conference on Advanced Technologies & Treatments for Diabetes. Diabetes Technol Ther 2011;13:244.
74. Steil GM, Rebrin K, Darwin C, Hariri F, Saad MF: Feasibility of automating insulin delivery for the treatment of type 1 diabetes. Diabetes 2006;55:3344-3350. (Pubitemid 44923591)
75. Magni L, Raimondo DM, Bossi L, Man CD, De Nicolau G, Kovatchev B, Cobelli C: Model predictive control of type 1 diabetes: anin silico trial. JDiabetes SciTechnol 2007;1:804-812.
76. Hovorka R, Canonico V, Chassin LJ, Haueter U, Massi-Benedetti M, Orsini Federici M, Piever TR, Schaller HC, Schaupp L, Vering T, Wilinska ME: Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes. Physiol Meas 2004;25:905-920. (Pubitemid 39121173)
77. Grosman B, Dassau E, Zisser HC, Jovanovic L, Doyle FJ III: Zone model predictive control: a strategy to minimize hyperand hypoglycemic events. J Diabetes Sci Technol 2010;4: 961-975.
78. Clarke WL, Anderson S, Breton M, Patek S, Kashmer L, Kovatchev B: Closed-loop artificial pancreas using subcutaneous glucose sensing and insulin delivery and a model predictive control algorithm: the Virginia experience. J Diabetes Sci Technol 2009;3:1031-1038.
79. Kovatchev B, Cobelli C, Renard E, Anderson S, Breton M, Patek S, Clarke W,Bruttomesso D, Maran A, Costa S, Avogaro A, Dalla Man C, Facchinetti A, Magni L, De Nicolao G, Place J, Farret A: Multinational study of subcutaneous modelpredictive closed-loop control in type 1 diabetes: summary of results. J Diabetes Sci Technol 2010;4:1374-1381.
80. El-Khatib FH, Russell SJ, Nathan DM, Sutherlin RG, Damiano ER: A bihormonal closed-loop artificial pancreas for type 1 diabetes. Sci Transl Med 2010;2:27ra27.
81. Castle JR, Engle JM, El Youssef J, Massoud RG, Yuen KCJ, Kagan R, Ward WK: Novel use of glucagon in a closed-loop system for prevention of hypoglycemia in type 1 diabetes. Diabetes Care 2010;33:1282-1287.
82. Russell SJ, El-Khatib FH, Nathan DM, Damiano ER: Efficacy determinants of subcutaneous microdose glucagon during closed-loop control. J Diabetes Sci Technol 2010;4:1288-1304.
83. Steffes MW, Jackson M, Sibley S, Thomas W: Beta-cell function and the development of diabetes-related complications in the Diabetes Control and Complications Trial. Diabetes Care 2003;26:832-836. (Pubitemid 36929351)
84. Shah SC, Malone J, Simpson NE: A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989;320:550-554. (Pubitemid 19070538)
85. Kordonouri O, Pankowska E, Rami B, Kapellen T, Coutant R, Hartmann R, Lange K, Knip M, Danne T: Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia 2010;53:2487-2495.
86. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA: Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692-1698. (Pubitemid 34547482)
87. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, Raskin P, Rodriguez H, Schatz DA, Wherrett D, Wilson DM, Lachin JM, Skyler JS: Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009;361:2143-2152.
88. Diabetes Prevention Trial-Type 1 Study Group: Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial-Type 1 Study Group. Diabetes Care 2005;28:1068-1076.
89. Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R: GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008;359:1909-1920.
90. Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Herold KC, Marks JB, Monzavi R, Moran A, Orban T, Palmer JP, Raskin P, Rodriguez H, Schatz D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes Trialnet GAD Study Group: Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomized double-blind trial. Lancet 2011;378:319-327.