The honeymoon phase: Intersection of metabolism and immunology

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 16, Issue 4, 2009, Pages 286-292

  Aly, Hanan H ^a,c   Gottlieb, Peter ^b  

^a AIN SHAMS UNIVERSITY   (Egypt)

^b UNIVERSITY OF COLORADO   (United States)

^c UNIVERSITY OF COLORADO DENVER   (United States)

Author keywords

cell rest; C peptide; Clinical remission; Honeymoon; Residual cell function

Indexed keywords

GLUCOSE;

ADAPTIVE IMMUNITY; ANTIGEN SPECIFICITY; CYTOTOXIC T LYMPHOCYTE; DISEASE MARKER; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; INSULIN DEPENDENT DIABETES MELLITUS; METABOLIC REGULATION; METABOLISM; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; REMISSION; REVIEW;

ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 1; HUMANS; T-LYMPHOCYTES, CYTOTOXIC;

EID: 67651085715     PISSN: 1752296X     EISSN: None     Source Type: Journal    
DOI: 10.1097/MED.0b013e32832e0693     Document Type: Review

References (68)

1. Himsworth H. Diabetes mellitus: a differentiation into insulin-sensitive and insulin-insensitive types. Lancet 1936; 1:127-130.
2. Couper JJ, Donaghue KC. Phases of diabetes. ISPAD clinical practice consensus guidelines 2006/2007. Pediatr Diabetes 2007; 8:44-47.
3. Pörksen S, Kastaniegaard AK, Swift P, et al. A new definition of the partial remission phase in children and adolescents with type 1 diabetes. Results from the Hvidoere study group. Diabetes 2008; 57 (supplement 1): A494. The group puts forward a new definition of the honeymoon phase, which correlates better with the DCCT level of maximal stimulated C-peptide of responders.
4. Ludvigsson J. Immune intervention at diagnosis - should we treat children to preserve beta-cell function? A review article. Pediatr Diabetes 2007; 8 (Suppl 6):34-39. (Pubitemid 47323765)
5. Kordonouri O, Danne T. Insulin therapy in children and adolescents with type 1 diabetes. Diabetologe 2008; 4:499-505.
6. Chase HP, MacKenzie TA, Burdick J, et al. Redefining the clinical remission period in children with type 1 diabetes. Pediatr Diabetes 2004; 5:16-19. (Pubitemid 38489440)
7. Pozzilli P, Manfrini S, Buzzetti R, et al., the IMDIAB group. Glucose Evaluation Trial for Remission (GETREM) in type 1 diabetes: a European multicenter study. Diabetes Res Clin Pract 2005; 68:258-264.
8. Jackson RL, Boyd JD, Smith TE. Stabilization of the diabetic child. Am J Dis Child 1940; 59:332-341.
9. Unger RH, Grundy S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 1985; 28:119-121. (Pubitemid 15102179)
10. Rossetti L, Giaccari A, Defronzo RA. Glucose toxicity. Diabetes Care 1990; 13:610-630.
11. Kim WH, Lee JW, Suh YH, et al. Exposure to chronic high glucose induces β-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic β-cells. Diabetes 2005; 54:2602-2611.
12. Alemzadeh R, Holshouser S, Massey P, Koontz J. Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucher rats. Eur J Endocrinol 2002; 146:871-879. (Pubitemid 34705081)
13. Whiting PH, Kalansooriya A, Holbrook I, et al. The relationship between chronic hyperglycemic control and oxidative stress in type 2 diabetes. Br J Biomed Sci 2008; 65:71-74. (Pubitemid 351913978)
14. Bravi MC, Armiento A, Laurenti O, et al. Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus. Metabolism 2006; 55:691-695. (Pubitemid 44316511)
15. Shin CS, Moon BS, Park KS, et al. Serum 8-hydroxy-guanine levels are increased in diabetic patients. Diabetes Care 2001; 24:733-737. (Pubitemid 32888856)
16. Despa F. Dilation of the endoplasmic reticulum in beta cells due to molecular overcrowding? Kinetic simulations of extension limits and consequences on proinsulin synthesis. Biophys Chem 2009; 140:115-121. The study gives new details on proinsulin trafficking and effects of its accumulation on cell function and apoptosis.
17. Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic beta-cells and diabetes mellitus. Exp Biol Med (Maywood) 2003; 228:1213-1217. (Pubitemid 37413682)
18. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 2007; 9:2277-2293.
19. Kaneto H, Miyatsuka T, Kawamori D, et al. PDX-1 and MafA play a crucial role in pancreatic b-cell differentiation and maintenance of mature β-cell function. Endocr J 2008; 55:235-252. (Pubitemid 351670948)
20. Gleason CE, Gonzalez M, Harmon JS, Robertson RP. Determinants of glucose toxicity and its' reversibility in the pancreatic islet beta-cell line, HIT-T15. Am J Physiol Endocrinol Metab 2000; 279:E997-E1002. The article shows how persistent hyperglycemia will have irreversible effect on β-cells.
21. Meadler K, Donath MY. Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res 2004; 62 (suppl 3):67-73.
22. Bowden SA, Duck MM, Hoffman RP. Young children (<5 years) and adolescents (>12 years) with type 1 diabetes mellitus have low rate of partial remission: diabetic ketoacidosis is an important risk factor. Pediatr Diabetes 2008; 9 (part I):197-201.
23. Dost A, Herbst A, Kintzel K, et al. Shorter remission period in young versus older children with diabetes mellitus type 1. Exp Clin Endocrinol Diabetes 2007; 115:33-37. (Pubitemid 46293409)
24. Lombardo F, Valensize M, Wasniewska M, et al. Two-year prospective evaluation of the factors affecting honeymoon frequency and duration in children with insulin dependent diabetes mellitus: the key role of age at diagnosis. Diabetes Nutr Metab 2002; 15:246-251. (Pubitemid 35189809)
25. Bonfanti R, Bognetti E, Meschi F, et al. Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty. Acta Diabetol 1998; 35:91-95. (Pubitemid 28403239)
26. Bonfanti R, Bazzigaluppi E, Calori G, et al. Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with type 1 diabetes mellitus. Diabetic Med 1998; 15:844-850. (Pubitemid 28451954)
27. Mortensen HB, Hougaard P, Holl R, et al. Autoantibodies rather than HLA haplotypes predict poor residual beta-cell function during remission in children and adolescents with newly diagnosed type 1 diabetes. Data from the Hvidore study group on childhood diabetes. Diabetologia 2004; 47 (Suppl 1):A19.
28. Rosenbloom AR. The variable but inevitable loss of beta cells in overt type 1 diabetes. Pediatr Diabetes 2003; 4:1-3.
29. Von Herrath M, Sanda S, Herold K. Type 1 diabetes as a relapsing- remitting disease. Nat Rev Immunol 2007; 7:988-994. Authors put forward their view of T1D as a relapsing-remitting disease. (Pubitemid 350166057)
30. Tanchot C, Barber DL, Chiodetti L, Schwartz RH. Adaptive tolerance of CD4+ T cells in vivo: multiple thresholds in response to a constant level of antigen presentation. J Immunol 2001; 167:2030-2039. The article details the immune CD4+ T cell response to persistent antigen. (Pubitemid 32747510)
31. + T cell response.
32. Singh NJ, Schwartz RH. Primer: mechanisms of immunologic tolerance. Nat Clin Pract Rheumatol 2006; 2:44-52. The article reviews the different mechanisms of adaptive tolerance.
33. Schwartz RH. T cell anergy. Annu Rev Immunol 2003; 21:305-334. The article reviews anergy and adaptive tolerance and their molecular mechanisms.
34. Homann D, McGavern DB, Oldstone MB. Visualizing the viral burden: phenotypic and functional alterations of T cells and APC's during persistent infection. J Immunol 2004; 172:6239-6250. The researchers demonstrate a pattern of adaptive tolerance in a model of persistent viral infection. (Pubitemid 38621230)
35. Akirav E, Koshner JA, Herold KC. The beta-cell mass and type 1 diabetes: going, going and gone? Diabetes 2008; 57:2883-2888. This recent review looks into the dynamic process of β-cell regeneration versus immune destruction and the effect of that in exposing new antigenic targets.
36. Yu L, Rewers M, Gianani R, et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J Clin Endocrinol Metab 1996; 81:4264-4267. This prospective study was among the first to demonstrate how antigenic targets develop sequentially at different points of time along the course of type 1 diabetes. (Pubitemid 26412027)
37. Bonifacio E, Scirpoli M, Kredel K, et al. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J Immunol 1999; 163:525-532. Another prospective study that showed the sequence of development of antibodies along the course of type 1 diabetes. (Pubitemid 29295882)
38. Bonifacio E, Lampasona V, Bernasconi L, Ziegler AG. Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes. Diabetes 2000; 49:202-208. The article demonstrates the sequential spreading of a humoral antibody response to different epitopes on the GAD antigen during prediabetes. (Pubitemid 30070998)
39. Naserke HE, Ziegler AG, Lampasona V, Bonifacio E. Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes. J Immunol 1998; 161:6963-6969. The study looks into the epitope spreading along the course of type 1 diabetes. (Pubitemid 28562244)
40. Pozzilli P. The DPT-1 trial: a negative result with lessons for future type 1 diabetes prevention. Diabetes Metab Res Rev 2002; 18:257-259. The article reviews results of oral and subcutaneous insulin as forms of antigen-specific therapy in type 1 diabetes.
41. Barker JM, Mcfann KK, Orban T, on behalf of the DPT-1 study group. Effect of oral insulin on insulin autoantibody levels in the Diabetes Prevention Trial Type 1 Oral Insulin study. Diabetologia 2007; 50:1603-1606. The article gives an update on the results of oral insulin trial for prevention of T1D.
42. Achenbach P, Barker J, Bonifacio E. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Curr Diabetes Rep 2008; 8:87-93. The article outlines a new trial of mucosal insulin immunization and gives updated information about results of the oral insulin trial in the various age groups.
43. Berghaeuser MA, Kapellen T, Heidetmann B, et al. for the DPV-Science-Initiative and the German working gr*oup for insulin pump treatment in pediatric patients. Continuous subcutaneous insulin infusion in toddlers starting at diagnosis of type 1 diabetes mellitus. A multicenter analysis of 104 patients from 63 centres in Germany and Austria. Pediatr Diabetes 2008; 9:590-595. The article outlines the results of one of the trials using CSII starting at disease onset on C-peptide in T1D.
44. Edelmann E, Walter H, Biermann E, et al. Sustained normoglycemia and remission phase in newly diagnosed type 1 diabetic subjects. Comparison between continuous subcutaneous insulin infusion and conventional therapy during a one year follow-up. Horm Metab Res 1987; 19:419-421. Another study using SCII at onset to maintain C-peptide levels in type 1 diabetes.
45. Singh NJ, Chen C, Schwartz RH. The impact of T cell intrinsic antigen adaptation on peripheral immune tolerance. PLoS Biol 2006; 4:1957-1969. The article offers argument as to whether extrinsic regulation by suppressor cells is needed in adaptive tolerance models to self-antigen. (Pubitemid 44760012)
46. Homann D, Von Herrath M. Short analytical review: regulatory T cells and type 1 diabetes. Clin Immunol 2004; 112:202-209.
47. Jaeckel E, Mpofu N, Saal N, Maans MP. Role of regulatory T cells for the treatment of type 1 diabetes mellitus. Horm Metab Res 2008; 40:126-136.
48. Nikolova M, Lelievre J, Carriere M, et al. Regulatory T cells modulate differentially the maturation and apoptosis of human CD8 T cell subsets. Blood 2009; 113:4556-4565.
49. Sgouroudis E, Piccirillo CA. Control of type 1 diabetes by CD4+Foxp3+ regulatory T cells: lessons from the mouse models and implications for human disease. Diabetes Metab Res Rev 2009; 25:208-218.
50. hiCD25+ phenotype controls T cell-dependent inflammatory responses. Immunity 2008; 28:639-650.
51. Fillatreau S, Gray D, Anderton SM. Not always the bad guys: B cells as regulators of autoimmune pathology. Nat Rev Immunol 2008; 8:391-397. (Pubitemid 351595221)
52. Knoechel B, Lohr J, Kahn E, et al. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 2005; 202:1375-1386. Perhaps the only study on the sequence of development of CD25+Foxp3+regula+regulatory cell response in relation to effector cell response in response to a self-autoantigen. (Pubitemid 41668740)
53. Barron L, Knoechel B, Lohr J, Abbas Abul K. Cutting the edge: contributions of apoptosis and anergy to systemic antigen tolerance. J Immunol 2008; 180:2762-2766. Results of this recent study show also the contribution of anergy versus extrinsic regulation in the development of tolerance to a self-antigen.
54. Battaglia M, Stabilini A, Draghici E, et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 2006; 55:1571-1580. (Pubitemid 44324109)
55. Zheng Y, Collins SL, Lutz MA, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 2007; 178:2163-2170. (Pubitemid 46233414)
56. Li S, Gowans EJ, Chougnet C, et al. Minireview: natural regulatory T cells and persistent viral infection. J Virol 2008; 82:21-30. (Pubitemid 350309119)
57. Tree TIM, Roep BO, Peakman M. A mini meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes: report of the Immunology of Diabetes Society T cell workshop. Ann N Y Acad Sci 2006; 1079: 9-18. The article offers a meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes. (Pubitemid 44968695)
58. Palmer JP. C-peptide in the natural history of type 1 diabetes. Diabetes Metab Res Rev 2009; 25:325-328.
59. Karges I, Durinovic-Bello I, Heinze E, et al. Immunological mechanisms associated with long-term remission of human type 1 diabetes. Diabetes Metab Res Rev 2006; 22:184-189. This is one of the very few studies on specifically a type 1 diabetes patient during clinical remission. (Pubitemid 43805398)
60. Alizadeh BZ, Hanifi-Moghaddam P, Eerligh P, et al. Association of interferon-γ and interleukin 10 genotypes and serum levels with partial clinical remission in type 1 diabetes. Clin Exp Immunol 2006; 145:480-484. Another study (multicentric) aiming to study immune markers in the honeymoon phase. (Pubitemid 44252491)
61. Schloot NC, Hanifi-Moghaddam P, Aerbenus-Andersent N, et al. Association of immune mediators at diagnosis of type 1 diabetes with later clinical remission. Diabetic Med 2007; 24:512-520. Another study (multicentric) on some of the immune mediators in the honeymoon phase. (Pubitemid 46669316)
62. Sanda S, Roep BO, Von Herrath M. Islet antigen specific IL-10+ immune responses but not CD4+CD25+foxp3+ cells at diagnosis predict glycemic control in type 1 diabetes. Clin Immunol 2007; 127:138-143. Another of the few studies on the honeymoon phase looking into the IL-10 response and a subtype of regulatory cells.
63. Pfleger C, Kaas A, Hansen L, et al., on behalf of the HvidØre study group on childhood diabetes. Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes. Clin Immunol 2008; 128:57-65. A study (multicentric) of chemokines during the honeymoon phase in T1D.
64. Pfleger C, Mortensen HB, Hansen L, et al., on behalf of the HvidØre study group on childhood diabetes. Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes. Diabetes 2008; 57:929-937. Another study by the HvidØre group looking into some other immune mediators during the honeymoon phase of T1D.
65. +T cell role in T1D and the interplay between the ambient glucose level and its function.
66. Maclver N, Jacobs SR, Wieman HL, et al. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol 2008; 84:949-957. A study outlining new concepts in T-cell metabolism, function and survival in relation to glucose level.
67. Brown RJ, Rother KI. Effects of beta-cell rest on beta-cell function: a reviewof clinical and preclinical data. Pediatr Diabetes 2008; 9 (Part II):14-22. The article outlines concepts in β-cell rest and relation to antigenicity.
68. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual β-cell function in patients with type 1 diabetes in the diabetes control and complications trial. Ann Intern Med 1998; 128:517-523.