GUIDELINES FOR INTERVENTION TRIALS IN SUBJECTS WITH NEWLY-DIAGNOSED TYPE 1 DIABETES
Carla J. Greenbaum, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101 USA & Leonard C. Harrison, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital PO, Parkville 3050 Victoria, Australia
On behalf of the Immunology of Diabetes Society.The following individuals provided comment on these Guidelines: Desmond A. Schatz, George S. Eisenbarth, Jerry P. Palmer, Kevan C. Herold, Paolo Pozzilli, Edwin A. Gale, Hubert Kolb, Olov Rolandsson, Didac Mauricio, Peter G. Colman and Spiros Fourlanos
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Our purpose here is to highlight issues pertaining to trial variables and suggest ways of standardizing protocols for phase I and II intervention trials in newly-diagnosed patients. These issues will be discussed under three major headings: trial subjects, trial design and trial outcome measures.
Type 1 diabetes can have different clinical presentations that presumably reflect the nature of the underlying disease pathology, to which we have no direct access. Some patients present acutely with dehydration and ketoacidosis, whereas others have minimal or no symptoms. Natural history studies have indicated that these differences may correlate with the rate of loss of b-cell function and residual b-cell function, determined by genetic (45-47) and other (48-64) factors that modify disease pathology. However, the relationship between the nature of the clinical presentation and the effectiveness of intervention therapy is not known.
2. When should trial treatment be initiated in relation to time since diagnosis?
In general, time from diagnosis is inversely related to C-peptide secretion. However, data from the DCCT and other studies indicate that some subjects with type 1 diabetes continue to have residual C-peptide even 5 years after diagnosis (48,51,65-68). Time from diagnosis is therefore not necessarily an accurate index of residual b-cell function. Additionally, measurement of C-peptide secretion when diabetes is poorly controlled is unreliable (see below).
Two models of the disease have been proposed: in one, clinical onset occurs on a continuum of the immune assault, b-cell function finally being inadequate to maintain normoglycemia; in the other, the process of b-cell injury becomes abruptly destructive heralding clinical diagnosis (69,63,64). In the latter, initiation of treatment within a short time-window would be essential.
Document peak C-peptide of > 0.2 nM after liquid mixed meal stimulation (Sustacal/Boost).
3. Should age be an exclusion/inclusion criterion?
The natural history of pre- and post-clinical type 1 diabetes varies with age. The rate of b-cell destruction appears to be related inversely to age (48-51,56), directly to the presence of higher risk HLA class II (e.g. DR3,4;DQ2,8) and class I (e.g. A24) alleles (45-47,70) and directly to the number of islet autoantibodies (71-73). Therefore, it could be argued that the requirement for effective intervention treatment is likely to be more demanding in younger subjects, but may be less likely to accelerate the disease. On the other hand, a slower rate of b-cell destruction in older subjects may indicate a wider window of opportunity for intervention, although if the process was regulated it would be important that intervention treatment did not jeopardize this.
Though an upper age limit may delineate classic type 1 diabetes from slowly progressive type 1 diabetes or latent autoimmune diabetes of adults (LADA) (74-76), the combination of clinical type 2 diabetes and autoantibodies may still occur in children and younger adults (77).
Age is also an issue with respect to consent and recruitment.
Clearly define age and other parameters at diagnosis (see above).
People who have participated as subjects in control arms of pre-clinical intervention trials could in theory participate in subsequent trials involving newly-diagnosed subjects, but two objections have been raised. First, they may have been diagnosed when asymptomatic (78,79), which could influence both natural history and treatment effects. Second, further information about b-cell function post-diagnosis may be needed in these subjects. However, most people with newly-diagnosed diabetes will not have participated in prevention trials and this is not likely to be a major issue. If such a guideline was adopted, enrollees in prevention trials should be informed that their participation would exclude them from future trials.
Subjects who have participated in pre-clinical intervention trials may be included unless there are specific reasons for exclusion relating to entry criteria or therapy used. However, the number of these subjects participating should be reported and results should include subgroup analysis of this subset.
5. What is the effect of concurrent treatment on trial outcomes?
Chronic ingestion of certain drugs, e.g. glucocorticoids, may affect glucose metabolism.
Exclude subjects taking chronic glucocorticoid treatment, but not necessarily periodic oral, inhaled or topical glucocorticoid treatment.
1. What factors may influence outcome measures?
2. Can trials stratify subjects to control for important variables?
Phase I and II studies are often not large enough to stratify subjects according to important variables
Collect standardized raw data on all subjects, for later combined analysis. Document age, gender, pubertal status, family history of diabetes, time from diagnosis, nature of clinical presentation (see above), HLA, baseline immune marker and C-peptide status.
3. What is the appropriate trial period?
It is assumed that mixed meal- or glucagon-stimulated C-peptide falls after diagnosis and power calculations may be predicated on intervention reducing the rate of fall. However, data from control arms of trials in recently-diagnosed adults indicate there may be little or no fall in C-peptide over the first year (22,42). Therefore, evaluation out to one year after either diagnosis or treatment initiation may fail to accurately reflect outcome, particularly in adults in whom there may only be a minimal fall in C-peptide over this period (22,42). Evaluation at this time may, however, provide short-term safety data.
Evaluate treatment for at least two years, particularly in adults; one year may be appropriate for safety.
TRIAL OUTCOME MEASURES
1. What metabolic tests can be used to determine the effects of intervention therapy?
Several tests can be used to evaluate b-cell function. C-peptide in healthy subjects can be stimulated by IV, IM or SC glucagon, IV sulfonylurea, IV glucagon-like peptide (GLP)-1, IV or oral amino acids, IV or oral glucose, or a mixed meal (86-90). During intervention with cyclosporin, subjects with type 1 diabetes had C-peptide responses to an oral mixed meal (Sustacal/Boost) at a time when IV glucose and glucagon responses were absent (91). Most studies have only evaluated the response over 2 hours, though it is suggested that a 4 hour test may provide additional useful information. There is considerable variability in both tests, which may be related to intestinal absorption. Use of IV glucose or arginine may reduce this variation (92), but this has not been studied. Alternatively, IV glucagon-stimulated C-peptide has been used in new-onset trials. However, there is limited information regarding the relationship between mixed meal test and glucagon test results (93,94).
2. What immune markers can be used to monitor the effects of intervention therapy?
Antibodies (titer, isotypes, IgG subclasses, epitope specificity) and T-cell responses (proliferation, activation markers, cytokine production) may change in response to intervention therapy and therefore provide important mechanistic surrogate marker information. However, the relationship between changes in these markers and therapeutic benefit remains unknown. Islet antibody levels did not correlate with benefit in the cyclosporin trials (100), although remission of autoantibody-mediated diseases, e.g. Graves' hyperthyroidism, has been associated with a decrease in autoantibody levels (101,102).
The place of markers such as IgG autoantibody subclasses (103,104), and islet antigen-reactive T-cell responses (105-107) is not yet clear. Assays for these cells are being evaluated by Immunology of Diabetes Society Workshops (108). T-cell assays require substantial improvement so that reproducible, quantitative and qualitative responses can be measured.
Measure islet autoantibodies and freeze sera/plasma for future studies. Continue to explore the feasibility of T-cell studies. Consider freezing blood mononuclear cells for future, e.g. genetic analysis.
3. What are the primary and secondary outcomes?
Studies have reported changes in fasting, peak and area-under-curve (AUC) C-peptide values over time. It remains unclear which is most useful. In addition, it is not known whether C-peptide expressed as a function of the blood glucose is more reliable. There are pre-pubertal vs. post-pubertal/age differences in C-peptide which are often not taken into account.
These Immunology of Diabetes Society guidelines have been developed in order to facilitate comparison of intervention therapies. Development and validation of novel assay technologies as well as new data on alternative outcome measures will undoubtedly require modifications to these recommendations in the future, but the principal that standardization of clinical intervention trials will benefit patients, families, and investigators will continue to underlie these efforts.
3. Bonifacio E, Dawkins R, Lernmark A: Immunology and Diabetes Workshops: Report of the 2nd International Workshop on the standardization of cytoplasmic islet cell antibodies. Diabetologia 30:273, 1987.
4. Boitard C, Bonifacio E, Bottazzo G, Gleichmann H, Molenaar J: Immunology and Diabetes Workshop: Report on the Third International Workshop on the standardization of cytoplasmic islet cell antibodies. Diabetologia 31: 1988.
5. Wilkin T, Palmer J, Kurta A, Bonifacio E, Diaz J-L: The second international workshop on the standardization of insulin autoantibody (IAA) measurement. Diabetologia 31:449-450, 1988.
6. Bonifacio E, Bointard C, Gleichmann H, Shattock MA, Molenaar JL, Bottazzo GF: Assessment of precision, concordance, specificity, and sensitivity of islet cell antibody measurement in 41 assays. Diabetologia 33: 1990.
7. Lernmark A, Molenaar JL, van Beers WA, Yamaguchi Y, Nagataki S, Ludvigsson J, Maclaren NK: The Fourth International Serum Exchange Workshop to standardize cytoplasmic islet cell antibodies. The Immunology and Diabetes Workshops and Participating Laboratories. Diabetologia 34:534-535, 1991.
8. Greenbaum C, Palmer J, Nagataki S, Yamaguchi Y, Molenaar J, VanBeers W, Maclaren N, Lernmark A: Improved Specificity of ICA Assays in the Fourth International Immunology of Diabetes Serum Exchange Workshop. Diabetes 41:1570-1574, 1992.
9. Greenbaum CJ, Palmer JP, Kuglin B, Kolb H, laboratories: Insulin autoantibodies measured by radioimmunoassay methodology are more related to insulin-dependent diabetes mellitus that those measured by enzyme-linked immunosorbent assay: results of the Fourth International Workshop on the standardization of insulin autoantibody measurement. J Clin Endocrinol Metab 74:1040-44, 1992.
10. Greenbaum C, Wilkin T, Palmer J: Fifth international serum exchange workshop for insulin autoantibody (IAA) standardization. Diabetologia 35:798-800, 1992.
11. Schmidli RS, Colman PG, Bonifacio E, Bottazzo GF, Harrison LC: High level of concordance between assays for glutamic acid decarboxylase antibodies. The First International Glutamic Acid Decarboxylase Antibody Workshop. Diabetes 43:1005-1009, 1994.
12. Bingley P: Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives. The ICARUS data set. Diabetes 45:1720-1728, 1996.
13. Verge CF, Stenger D, Bonifacio E, Colman PG, Pilcher C, Bingley PJ, Eisenbarth GS: Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop. Diabetes 47:1857-66, 1998.
15. Koschmann M, Alford FP, Ward GM, Walters J, Clolman PG, Harrison LC: Reproducibility of estimating first phase insulin responses to intravenous glucose. Diab Nutr Merab 5:73-79.
16. Bingley PJ, Colman P, Eisenbarth GS, Jackson RA, McCulloch DK, Riley WJ, Gale EA: Standardisation of IVGTT to predict IDDM. Diabetes Care 15:1313-1316, 1992.
17. McCulloch D, Bingley P, Colman P, Jackson R, Gale E: Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. Diabetes Care 16:911-915, 1993.
18. McNair PD, Colman PG, Alford A, Harrison LC. Reproducibility of the first phase insulin response to intravenous glucose is not improved by retrograde cannulation and arterialisation or the use of a lower glucose dose. Diabetes Care 18:1168-1173, 1995.
20. Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S: Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. New Engl J Med 319:599-604, 1988.
21. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 year of cyclosporin treatment with enhanced insulin secretion. The Canadian-European Randomised Trial Group. Diabetes 37:1574-1582, 1988.
22. Cook JJ, Hudson I, Harrison LC, Dean B, Colman PG, Werther GA, Warne GL, Court JM: Double-blind controlled trial of azathioprine in children with newly diagnosed type 1 diabetes. Diabetes 38:779-83, 1989.
23. Mendola G, Casamitjana R, Gomis R: Effect of nicotinamide therapy upon B-cell function in newly diagnosed Type I(insulin-dependent) diabetic patients. Diabetologia 32:160-162, 1989.
25. Vague P, Picq R, Bernal M, Lassman-Vague V, Vialettes B: Effect of nicotinamide treatment on the residual insulin secretion in Type 1 (insulin-dependent) diabetic patients. Diabetologia 32:316-321, 1989.
26. Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D: A trial of nicotinamide in newly diagnosed patients with Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33:444-446, 1990.
27. Giordano C, Panto F, Amato MP, Sapienza N, Pugliese A, Galluzzo A: Early administration of an immunomodulator and induction of remission in insulin-dependent diabetes mellitus. J Autoimmun 3:611-617, 1990.
28. Secchi A, Pastore MR, Sergi A, Pontiroli AE, Pozza G: Prednisone administration in recent onset type 1 diabetes. J Autoimmun 3:593-600, 1990.
29. Skyler JS, Rabinovitch A: Cyclosporine in recent onset type 1 diabetes mellitus. Effects on islet beta cell function. Miami Cyclosporine Diabetes Study Group. J Diabetes Complications 6:77-88, 1992.
30. Goday A, Pujol-Borrell R, Fernandez J, Casamitjana R, Rios M, Vilardell E, Gomis R: Effects of a short prednisone regime at clinical onset of type 1 diabetes. Diabetes Res Clin Pract 20:39-46, 1993.
31. Muir A, Schatz D, Maclaren N: Antigen-specific immunotherapy: oral tolerance and subcutaneous immunization in the treatment of insulin-dependent diabetes. Diabetes Metab Rev 9:279-87, 1993.
32. Skyler JS, Lorenz TJ, Schwartz S, Eisenbarth GS, Einhorn D, Palmer JP, Marks JB, Greenbaum C, Saria EA, Byers V: Effects of an anti-CD5 immunoconjugate (CD5-plus) in recent onset type 1 diabetes mellitus: a preliminaryinvestigation. The CD5 Diabetes Project Team. J Diabetes Complications 7:224-32, 1993.
33. Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, Boccuni ML, Fava D, Gragnoli C, Andreani D: Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 38:848-852, 1995.
34. Bjork E, Berne C, Kampe O, Wibell L, Oskarsson P, Karlsson FA: Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes. Diabetes 45:1427-30, 1996.
35. Kohnert KD, Hehmke B, Keilacker H, Ziegler M, Emmrich F, Laube F, Michaelis D: Antibody response to islet antigens in anti-CD4/prednisolone immune intervention of type 1 diabetes. Int J Clin Lab Res 26:55-59, 1996.
36. Linn T, Ortac K, Laube H, Federlin K: Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism 45:1508-1513, 1996.
37. Schnell O, Eisfelder B, Standl E, Ziegler AG: High-dose intravenous insulin infusion versus intensive insulin treatment in newly diagnosed IDDM. Diabetes 46:1607-1611, 1997.
38. Coutant R, Landais P, Rosilio M, Johnsen C, Lahlou N, Chatelain P, Carel JC, Ludvigsson J, Boitard C, Bougneres PF: Low dose linomide in Type 1 juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial. Diabetologia 41:1040-6, 1998.
39. Elliott JF, Marlin KL, Couch RM: Effect of Bacillus Calmette-Guerin vaccination on C-peptide secretion in children newly diagnosed with IDDM. Diabetes Care 21:1691-1693, 1998.
40. Allen HF, Klingensmith GJ, Jensen P, Simoes E, Hayward A, Chase HP: Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study. Diabetes Care 22:1703-1707, 1999.
41. Buckingham BA, Sandborg CI: A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus. Clin.Immunol 96:86-90, 2000.
42. Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C, Bouhanick B, Mogenet A, Nicolino M, Carel JC, Lecomte P, Marechaud R, Bougneres P, Charbonnel B, Sai P: Oral insulin administration and residual beta-cell function in recent- onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 356:545-549, 2000.
43. Pozzilli P, Pitocco D, Visalli N, Cavallo MG, Buzzetti R, Crino A, Spera S, Suraci C, Multari G, Cervoni M, Manca Bitti ML, Matteoli MC, Marietti G, Ferrazzoli F, Cassone Faldetta MR, Giordano C, Sbriglia M, Sarugeri E, Ghirlanda G.: No effect of oral insulin on residual b-cell function in recent-onset type 1 diabetes (the IMDIAB VII).IMDIAB Group. Diabetologia 43:1000-1004, 2000.
44. Vidal J, Fernandez-Balsells M, Sesmilo G, Aguilera E, Casamitjana R, Gomis R, Conget I: Effects of nicotinamide and intravenous insulin therapy in newly diagnosed type 1 diabetes. Diabetes Care 23:360-364, 2000.
45. Caillat-Zucman S, Garchon HJ, Timsit J, Assan R, Boitard C, Djilali-Saiah I, Bougneres P, Bach JF: Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest 90:2242-50, 1992.
46. Tait BD, Harrison LC, Drummond BP, Stewart V, Varney MD, Honeyman MC: HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus. Hum.Immunol 42:116-122, 1995.
47. Honeyman MC, Harrison LC, Drummond B, Colman PG, Tait BD: Analysis of families at risk for insulin-dependent diabetes reveals that HLA antigens influence progression to preclinical disease. Mol Med 1:576-582, 1995.
48. Madsbad S, Faber O, Binder C, McNair P, Christiansen C, Transbol I: Prevalence of residual beta-cell function in insulin-dependent diabetics in relation to age at onset and duration of diabetes. Diabetes 27 S1:262-4, 1978.
49. Bonora E, Coscelli C, Butturini U: Residual B-cell function in type 1 (insulin-dependent) diabetes mellitus: its relation to clinical and metabolic features. Acta Diabetol Lat 21:375-83, 1984.
50. Sochett EB, Daneman D, Clarson C, Ehrlich RM: Factors affecting and patterns of residual insulin secretion during the first year of type 1 (insulin-dependent) diabetes mellitus in children. Diabetologia 30:453-459, 1987.
51. Diabetes Control and Complications Trial Research Group. Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual b-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J Clin Endocrinol Metab, 65:30-36, 1987.
52. Schiffrin A, Suissa S, Poussier P, Guttmann R, Weitzner G: Prospective study of predictors of beta-cell survival in type 1 diabetes. Diabetes 37:920-925, 1988.
53. Ludvigsson J, Binder C, Mandrup-Poulsen T: Insulin autoantibodies are associated with islet cell antibodies; their relation to insulin antibodies and b-cell function in diabetic children. Diabetologia 647-651, 1988.
54. Peig M, Gomis R, Ercilla G, Casamitjana R, Bottazzo GF, Pujol-Borrell R: Correlation between residual beta-cell function and islet cell antibodies in newly diagnosed type I diabetes. Follow-up study. Diabetes 38:1396-1401, 1989.
55. Couper JJ, Hudson I, Werther GA, Warne GL, Court JM, Harrison LC. Factors predicting residual beta-cell function in the first year after diagnosis of childhood type 1 diabetes. Diabetes Res Clin Pract. 11:9-16, 1991.
56. Montanya E, Fernandez-Castaner M, Rosel P, Gomez J, Soler J: Age, sex and ICA influence on beta-cell secretion during the first year after the diagnosis of type 1 diabetes mellitus. Diabet Metab 17:460-468, 1991.
57. Schiffrin A, Suissa S, Weitzner G, Poussier P, Lalla D: Factors predicting course of beta-cell function in IDDM. Diabetes Care 15:997-1001, 1992.
58. Hramiak IM, Dupre J, Finegood DT: Determinants of clinical remission in recent-onset IDDM. Diabetes Care 16:125-32, 1993.
59. Yokota I, Shirakawa N, Shima K, Matsuda J, Naito E, Ito M, Kuroda Y: Relationship between GAD antibody and residual beta-cell function in children after overt onset of IDDM. Diabetes Care 19:74-5, 1996.
60. Bonfanti R, Bazzigaluppi E, Calori G, Riva MC, Viscardi M, Bognetti E, Meschi F, Bosi E, Chiumello G, Bonifacio E: Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with Type 1 diabetes mellitus. Diabet Med 15:844-850, 1998.
61. Sabbah E, Savola K, Kulmala P, Veijola R, Vahasalo P, Karjalainen J, Akerblom HK, Knip M: Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. J Clin Endocrinol Metab 84:1534-1539, 1999.
62. Torn C, Landin-Olsson M, Lernmark A, Palmern JP, Arnqvist HJ, Blohme G, Lithner F, Littorin B, Nystrom L, Schersten B, Sundkvist G, Wibell L, Ostman J: Prognostic factors for the course of beta cell function in autoimmune diabetes. J Clin Endocrinol Metab 85:4619-4623, 2000.
63. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. New Engl J Med 342:301-7, 2000.
66. Faber O: Beta-cell function and diabetic control in insulin dependent diabetes mellitus. Acta Endocrinol Suppl (Copenh) 272:73-7, 1985.
67. Faber OK, Binder C: C-peptide: an index of insulin secretion. Diabetes Metab Rev. 2:331-345, 1986.
68. Diabetes Control and Complications Trial Research Group: Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 128:517-523, 1998.
70. Hoogwerf BJ, Rich SS, Barbosa JJ: Meal-stimulated C-peptide and insulin antibodies in type I diabetic subjects and their nondiabetic siblings characterized by HLA-DR antigens. Diabetes 34:440-445, 1985.
71. Bingley P: Interactions of age, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+ relatives. The ICARUS data set. Islet Cell Antibody Register Users Study. Diabetes 45:1720-1728, 1996.
72. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS: Prediction of type 1 diabetes in first-degree relatives using a combination of insulin, GAD and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926-933, 1996.
73. Torn C, Landin-Olsson M, Lernmark A, Schersten B, Ostman J, Arnqvist HJ, Bjork E, Blohme G, Bolinder J, Eriksson J, Littorin B, Nystrom L, Sundkvist G: Combinations of beta-cell-specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage. Autoimmunity 33:115-120, 2001.
74. Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang DA: Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11:299-303, 1994.
75. Zimmet P, Turner R, McCarty D, Rowley M, Mackay I: Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes. Diabetes Care 22 S2:59-64, 1999.
76. Carlsson A, Sundkvist G, Groop L, Tuomi T: Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J Clin Endocrinol Metab 85:76-80, 2000.
78. Rjasanowski I, Michaelis D, Besch W, Keilacker H, Ziegler B, Hildmann W: Glucose tolerance behaviour before the onset of type I (insulin- dependent) diabetes in young people as a predictor of the further course of the disease: a retrospective analysis of 33 cases. Diabetes Res Clin Pract. 11:107-115, 1991.
79. Greenbaum CJ, Cuthbertson D, Krischer JP and the DPT-1 Study Group: Type 1 diabetes manifested solely by 2 hour OGTT criteria. Diabetes 50:470-476, 2001.
80. Kobayashi T, Nakanishi K, Murase T, Kosaka K: Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45:622-626, 1996.
81. Montanya E, Fernandez-Castaner M, Soler J: Improved metabolic control preserved beta-cell function two years after diagnosis of insulin-dependent diabetes mellitus. Diabetes Metab 23:314-319, 1997.
82. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 329:977-986, 1993.
83. The Canadian-European Randomized Control Trial Group: Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 37:1574-1582, 1988.
84. Feutren G, Papoz L, Assan R, Vialettes B, Karsenty G, Vexiau P, Du RH, Rodier M, Sirmai J, Lallemand A: Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double- blind trial. Lancet 2:119-124, 1986.
85. Pozzilli P, Visalli N, Boccuni ML, Baroni MG, Buzzetti-R FE, Signore A, Cavallo MG, Andreani D, Lucentini L et al: Randomized trial comparing nicotinamide and nicotinamide plus cyclosporin in recent onset insulin-dependent diabetes (IMDIAB 1). The IMDIAB Study Group. Diabet Med 11:98-104, 1994.
87. Menchini M, Meschi F, Lambiase R, Puzzovio M, Del Guercio MJ, Chiumello G: C-peptide response to arginine stimulation in diabetic children. J Pediatr. 96:362-366, 1980.
88. Scheen AJ, Castillo MJ, Lefebvre PJ: Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications. Diabetes Metab 22:397-406, 1996.
89. Rakotoambinina B, Timsit J, Deschamps I, Laborde K, Gautier D, Jos J, Boitard C, Robert JJ: Insulin responses to intravenous glucose, intravenous arginine and a hyperglycaemic clamp in ICA-positive subjects with different degrees of glucose tolerance. Diabetes Metab 23:43-50, 1997.
90. Sjoberg S, Gunnarsson R, Ostman J. Residual C-peptide production in type I diabetes mellitus. A comparison of different methods of assessment and influence on glucose control. Acta Med Scand. 214:231-7, 1983.
91. Skyler JS, Rabinovitch A. Cyclosporine in recent onset type I diabetes mellitus. Effects on islet beta cell function. Miami Cyclosporine Diabetes Study Group. J Diabetes Complications 2:77-88, 1992.
94. Pasquali R, Buratti P, Biso P, Patrono D, Capelli M, Pasqui F, Melchionda N: Estimation of B-cell function by the urinary excretion rate of C- peptide in diabetic patients: comparison with C-peptide response to glucagon and to a mixed meal. Diabete Metab 13:44-51, 1987.
98. Madsbad S, Sauerbrey N, Moller-Jensen B, Krarup T, Kuhl C: Outcome of the glucagon test depends upon the prevailing blood glucose concentration in type I (insulin-dependent) diabetic patients. Acta Med Scand 222:71-74, 1987.
99. Gjessing HJ, Reinholdt B, Faber OK, Pedersen O: The effect of acute hyperglycemia on the plasma C-peptide response to intravenous glucagon or to a mixed meal in insulin-dependent diabetes mellitus. Acta Endocrinol (Copenh) 124:556-562, 1991.
100. Mandrup-Poulsen T, Molvig J, Andersen HU, Helqvist S, Spinas GA, Munck M: Lack of predictive value of islet cell antibodies, insulin antibodies, and HLA-DR phenotype for remission in cyclosporin-treated IDDM patients. The Canadian-European Randomized Control Trial Group. Diabetes 39:204-10, 1990
102. Kahaly G, Pitz S, Muller-Forell W, Hommel G: Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol 106:197-202, 1996.
103. Couper JJ, Harrison LC, Aldis JE, Colman PG, Honeyman MC, Ferrante A: IgG subclass antibodies to glutamic acid decarboxylase and risk for progression to clinical insulin-dependent diabetes. Human Immunol 59:493-499, 1998.
104. Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler, AG: Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J Immunol 163: 525-32, 1999.
106. Durinovic-Bellò I, Hummel M, Ziegler A: Cellular immune response to diverse islet cell antigens in IDDM. Diabetes 45:795-800, 1996.
107. Honeyman MC, Brusic V, Stone N, Harrison LC: Neural network-based prediction of candidate T-cell epitopes. Nature Biotech 16:966-970, 1998.
108. Roep BO, Atkinson MA, van Endert PM, Gottlieb PA, Wilson SB, Sachs JA: Autoreactive T cell Responses in Insulin-dependent (Type 1) Diabetes Mellitus. Report of the First International Workshop for Standardization of T cell assays. J Autoimmun 13:267-282, 1999