Autoantibodies/*blood C-Peptide/blood; C-Peptide/blood MH - Diabetes Mellitus/*epidemiology/genetics MH - Diabetes Mellitus, Type 1/genetics/immunology MH - MH - Risk Assessment; Reference Values; Medical History Taking; Insulin/blood; Hyperglycemia; Humans; HLA-DQ Antigens/genetics; Glucose Clamp Technique; diabtes mellitus Type 1/genetics/immunology
Abstract :
[en] AIMS/HYPOTHESIS: The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients.
METHODS: Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT.
RESULTS: Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp.
CONCLUSIONS/INTERPRETATION: Clamp-derived functional variables stratify risk of diabetes in IA-2A(+) FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Vandemeulebroucke, E.
Keymeulen, B.
Decochez, K.
Weets, I.
De Block, C.
Féry, F.
Van de Velde, U.
Vermeulen, I.
De Pauw, P.
Mathieu, C.
Pipeleers, D. G.
Paquot, Nicolas ; Université de Liège - ULiège > Services généraux (Faculté de médecine) > Relations académiques et scientifiques (Médecine)
MW Steffes S Sibley M Jackson W Thomas 2003 Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial Diabetes Care 26 832 836 10.2337/diacare.26.3.832 12610045 (Pubitemid 36929351)
KC Herold W Hagopian JA Auger, et al. 2002 Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus N Engl J Med 346 1692 1698 10.1056/NEJMoa012864 1:CAS:528:DC%2BD38XktVansLY%3D 12037148 (Pubitemid 34547482)
B Keymeulen E Vandemeulebroucke AG Ziegler, et al. 2005 Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes N Engl J Med 352 2598 2608 10.1056/NEJMoa043980 1:CAS:528:DC%2BD2MXls1Wqu7k%3D 15972866 (Pubitemid 41007846)
JM Sosenko JP Palmer CJ Greenbaum, et al. 2006 Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1 Diabetes Care 29 643 649 10.2337/diacare.29.03.06.dc05-1006 16505520
L Chatenoud J Primo JF Bach 1997 CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice J Immunol 158 2947 2954 1:CAS:528:DyaK2sXhvVOltro%3D 9058834
RA DeFronzo JD Tobin R Andres 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance Am J Physiol 237 E214 E223 1:CAS:528:DyaE1MXlslWhs70%3D 382871
D Elahi 1996 In praise of the hyperglycemic clamp. A method for assessment of beta-cell sensitivity and insulin resistance Diabetes Care 19 278 286 10.2337/diacare.19.3.278 1:STN:280:DyaK28zktF2lug%3D%3D 8742583
B Keymeulen P Gillard C Mathieu, et al. 2006 Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft Proc Natl Acad Sci USA 103 17444 17449 10.1073/pnas.0608141103 1:CAS:528:DC%2BD28Xht1KqtLvP 17090674 (Pubitemid 44788988)
E Vandemeulebroucke FK Gorus K Decochez, et al. 2009 Insulin treatment in IA-2A positive relatives of type 1 diabetic patients. Belgian Diabetes Registry Diabetes Metab 35 319 327 10.1016/j.diabet.2009.02.005 1:CAS:528: DC%2BD1MXhtlOrsrbN 19647467
FK Gorus P Goubert C Semakula, et al. 1997 IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. Belgian Diabetes Registry Diabetologia 40 95 99 10.1007/s001250050648 1:CAS:528:DyaK2sXmvFamug%3D%3D 9028724 (Pubitemid 27035716)
K Decochez I De Leeuw B Keymeulen, et al. 2002 IA-2 autoantibodies predict impending type I diabetes in siblings of patients. Belgian Diabetes Registry Diabetologia 45 1658 1666 10.1007/s00125-002-0949-8 1:CAS:528:DC%2BD38XpsFOmsL4%3D 12488955 (Pubitemid 35478135)
P Achenbach K Warncke J Reiter, et al. 2004 Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics Diabetes 53 384 392 10.2337/diabetes.53.2.384 1:CAS:528:DC%2BD2cXhtlWhu74%3D 14747289 (Pubitemid 38174554)
K Savola E Bonifacio E Sabbah, et al. 1998 IA-2 antibodies-a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group Diabetologia 41 424 429 10.1007/s001250050925 1:CAS:528:DyaK1cXitVaqtL8%3D 9562346 (Pubitemid 28157413)
B Van der Auwera F Schuit I Lyaruu, et al. 1995 Genetic susceptibility for insulin-dependent diabetes mellitus in Caucasians revisited: the importance of diabetes registries in disclosing interactions between HLA-DQ- and insulin gene-linked risk. Belgian Diabetes Registry J Clin Endocrinol Metab 80 2567 2573 10.1210/jc.80.9.2567 7673396
American Diabetes Association 2008 Diagnosis and classification of diabetes mellitus Diabetes Care 31 Suppl 1 S55 S60 10.2337/dc08-S055
I Truyen P De Pauw PN Jorgensen, et al. 2005 Proinsulin levels and the proinsulin: C-peptide ratio complement autoantibody measurement for predicting type 1 diabetes. Belgian Diabetes Registry Diabetologia 48 2322 2329 10.1007/s00125-005-1959-0 1:CAS:528:DC%2BD2MXht1Skt7vE 16211374 (Pubitemid 41618924)
LL Kjems ME Røder B Dinesen SG Hartling PN Jorgensen C Binder 1993 Highly sensitive enzyme immunoassay of proinsulin immunoreactivity with use of two monoclonal antibodies Clin Chem 39 2146 2150 1:CAS:528:DyaK2cXmvFc%3D 8403400
K Decochez J Tits JL Coolens, et al. 2000 High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. Belgian Diabetes Registry Diabetes Care 23 838 844 10.2337/diacare.23.6.838 1:STN:280:DC%2BD3cvjsF2gsQ%3D%3D 10841006
CP Smith AC Tarn JM Thomas, et al. 1988 Between and within subject variation of the first phase insulin response to intravenous glucose Diabetologia 31 123 125 10.1007/BF00395560 1:CAS:528:DyaL1cXhvVShtrk%3D 3282953
F Bacha N Gungor SA Arslanian 2008 Measures of beta-cell function during the oral glucose tolerance test, liquid mixed-meal test, and hyperglycemic clamp test J Pediatr 152 618 621 10.1016/j.jpeds.2007.11.044 1:CAS:528: DC%2BD1cXks1ars7o%3D 18410762
B Ahren G Pacini 2004 Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies Eur J Endocrinol 150 97 104 10.1530/eje.0.1500097 1:CAS:528:DC%2BD2cXitVWltLs%3D 14763905 (Pubitemid 38312800)
J Schirra M Katschinski C Weidmann, et al. 1996 Gastric emptying and release of incretin hormones after glucose ingestion in humans J Clin Invest 97 1 92 103 10.1172/JCI118411 1:CAS:528:DyaK28Xhtlajurc%3D 8550855
D Pipeleers M Chintinne B Denys G Martens B Keymeulen F Gorus 2008 Restoring a functional beta-cell mass in diabetes Diabetes Obes Metab 10 Suppl 4 54 62 10.1111/j.1463-1326.2008.00941.x 18834433
CJ Greenbaum D Cuthbertson JP Krischer 2001 Type I diabetes manifested solely by 2-h oral glucose tolerance test criteria Diabetes 50 470 476 10.2337/diabetes.50.2.470 1:CAS:528:DC%2BD3MXhtVOgsLY%3D 11272162
Diabetes Prevention Trial-Type 1 diabetes Study Group 2002 Effects of insulin in relatives of patients with type 1 diabetes mellitus N Engl J Med 346 1685 1691 10.1056/NEJMoa012350 (Pubitemid 34547481)
EA Gale PJ Bingley CL Emmett T Collier 2004 European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes Lancet 363 925 931 10.1016/S0140-6736(04)15786-3 1:STN:280:DC%2BD2c7ltFynsw%3D%3D 15043959 (Pubitemid 38388325)
S Mrena K Savola P Kulmala HK Akerblom M Knip 1999 Staging of preclinical type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group Pediatrics 104 925 930 10.1542/peds.104.4.925 1:STN:280: DyaK1Mvjs1ChsQ%3D%3D 10506236 (Pubitemid 29463562)
CJ Greenbaum T Mandrup-Poulsen PF McGee, et al. 2008 The mixed meal tolerance test versus the glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes Diabetes Care 31 1966 1971 10.2337/dc07-2451 18628574
I Truyen J De Grijse C Van Schravendijk, et al. 2007 Adiponectin levels do not predict clinical onset of type 1 diabetes in antibody-positve relatives Diabetologia 50 2143 2146 10.1007/s00125-007-0774-1 1:CAS:528: DC%2BD2sXpvF2ls7g%3D 17687539 (Pubitemid 47373856)
C Winkler S Marienfeld M Zwilling E Bonifacio AG Ziegler 2009 Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes? Diabetologia 10.1007/s00125-009-146-1
GM Steil J Murray RN Bergman TA Buchanan 1994 Repeatability of insulin sensitivity and glucose effectiveness from the minimal model. Implications for study design Diabetes 43 1365 1371 10.2337/diabetes.43.11.1365 1:CAS:528:DyaK2cXmvFaqsb4%3D 7926313
HJ Gjessing EM Damsgaard LE Matzen A Froland OK Faber 1987 Reproducibility of beta-cell function estimates in non-insulin-dependent diabetes mellitus Diabetes Care 10 558 562 10.2337/diacare.10.5.558 1:STN:280:DyaL1c%2FlsVChtg%3D%3D 3315512
A Gottsater M Landin-Olsson P Fernlund B Gullberg A Lernmark G Sundkvist 1992 Pancreatic beta-cell function evaluated by intravenous glucose and glucagon stimulation. A comparison between insulin and C-peptide to measure insulin secretion Scand J Clin Lab Invest 52 631 639 10.3109/00365519209115506 1:STN:280:DyaK3s%2Fosl2ktw%3D%3D 1455155
H Hedstrand J Boberg 1975 Statistical analysis of the reproducibility of the intravenous glucose tolerance test and the serum insulin response to this test in the middle-aged men Scand J Clin Lab Invest 35 331 337 10.3109/00365517509095749 1:CAS:528:DyaE2MXlsVeqtLg%3D 1103265
JP Palmer GA Fleming CJ Greenbaum, et al. 2004 C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001 Diabetes 53 250 264 10.2337/diabetes.53.1.250 1:CAS:528:DC%2BD2cXitlaltQ%3D%3D 14693724 (Pubitemid 38044724)
D Schatz D Cuthbertson M Atkinson, et al. 2004 Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus-a new surrogate measure of non-progression? Pediatr Diabetes 5 72 79 10.1111/j.1399-543X.2004.00047.x 15189492 (Pubitemid 38923633)