Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes

Keymeulen, Bart; Vandemeulebroucke, Evy; Ziegler, Anette G.; Mathieu, Chantal; Kaufman, Leonard; Hale, Geoff; Gorus, Frans; Goldman, Michel; Walter, Melanie; Candon, Sophie; Schandené, Liliane; Crenier, Laurent; Block, Christophe De; Seigneurin, Jean‐Marie; Pauw, Pieter De; Piérard, Denis; Weets, Ilse; Rebello, P; Bird, P.; Berrie, Eleanor; Frewin, Mark R.; Waldmann, Herman; Bach, J F; Pipeleers, Daniël; Chatenoud, Lucienne

doi:10.1056/nejmoa043980

Cited by 999 publications

(859 citation statements)

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“…A strength of the study is that it has allowed comparison of the abilities of hormone release during the hyperglycaemic clamp and during OGTT to discriminate between progressors and non-progressors to diabetes in a group of well-characterised FDRs with close metabolic follow-up. An advantage of the clamp test is that-unlike acute beta cell stimulation tests-it also allows study of second-phase and glucagon-stimulated hormone release after diagnosis of diabetes and thus it is possible to monitor beta cell function, if necessary, over a longer period [3,8,9]. Acute stimulation tests such as IVGTT or mixed-meal tolerance tests (MMTT) measure only hormonal release from the beta cell subpopulation that can be rapidly activated and some (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…A limitation of our study is that all relatives received prophylactic insulin injections after the initial clamp test, but this intervention did not affect clinical outcome [9] nor the ability of clamp variables to predict it. The hyperglycaemic clamp is more laborious to perform than acute stimulation tests that have been widely used in diabetes prediction and prevention studies [20,[24][25][26][27][28], but compliance of relatives or patients was high in our hands [3,8,9]. The glucagon injection is the most burdening part of the test and does not seem to provide much additional information: one may therefore consider omitting it.…”

Section: Discussionmentioning

confidence: 99%

“…A short treatment with humanised monoclonal anti-CD3 antibodies preserves beta cell function in recent-onset type 1 diabetes [2,3], particularly in individuals with residual beta cell function ≥25% of controls [3]. This opens perspectives for immunomodulatory interventions in the late preclinical phase where beta cell function is likely to be even better preserved [4] and where anti-CD3 antibodies have also shown efficacy in animal models [5].…”

Section: Introductionmentioning

confidence: 99%

“…An advantage of the clamp is that insulin release is not limited to the first phase, but is also quantified after prolonged glycaemic stimulation followed by a glucagon bolus. It was already instrumental in monitoring residual beta cell function in recent-onset type 1 diabetic patients and in recipients of a beta cell graft [3,8].…”

Section: Introductionmentioning

confidence: 99%

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Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Vandemeulebroucke

Keymeulen²,

Decochez

et al. 2009

Diabetologia

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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 firstphase 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.Trial registration: ClinicalTrials.gov NCT00654121 Funding: The insulin trial was financially supported by Novo Nordisk Pharma nv.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Vandemeulebroucke

Keymeulen²,

Decochez

et al. 2009

Diabetologia

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“…It is noteworthy that promoting beta cell replication was not required in any of these studies. There has also been some initial success in preserving insulin secretion in patients with recent-onset type 1 diabetes treated with CD3 antibodies [31].…”

Section: Discussionmentioning

confidence: 99%

Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes

Meier¹,

Lin

Butler³

et al. 2006

Diabetologia

169

113

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Aims/hypothesis We investigated whether there was evidence of attempted beta cell regeneration in the pancreas obtained from a patient with recent-onset type 1 diabetes, and if so by what mechanism this occurred. Subjects, materials and methods We examined pancreas tissue from a lean 89-year-old patient (BMI 18.0 kg/m 2 ) with recent-onset type 1 diabetes who had had a distal pancreatectomy to remove a low-grade pancreatic intraepithelial neoplasia. Results In the tumour-free tissue, the fractional beta cell area was 0.54±0.2% of pancreas area (about one-third of that in non-diabetic humans). CD3-positive T lymphocytes and macrophages had infiltrated the majority of the islets. Subclassification of the T cell population revealed a predominance of CD8-positive cells over CD4-positive cells. Beta cell apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling [TUNEL] staining) was greatly increased, consistent with ongoing immune-mediated beta cell destruction. There was also a marked increase (more than ∼100-fold) in the frequency of beta cell replication (0.69±0.15% Ki67-positive beta cells) in all blocks examined. Conclusions/interpretationThe present report provides direct evidence of attempted beta cell regeneration through the mechanism of beta cell replication in a case of newly diagnosed type 1 diabetes, and affirms that beta cell apoptosis is an important mechanism for beta cell loss in type 1 diabetes.

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Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus—Reply

Voltarelli¹

2009

JAMA

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YPE 1 DIABETES MELLITUS (DM) results from a cell-mediated autoimmune attack against pancreatic beta cells. 1 The course of autodestruction is subclinical until the amount of beta-cell mass is insufficient to maintain glucose homeostasis. Thus, at the time of clinical diagnosis, approximately 60% to 80% of the beta-cell mass has been destroyed. 2 Type 1 DM comprises only 5% to 10% of all diabetic etiologies but is associated with a high frequency of vascular complications and compromises quality and expectancy of life. 3,4 Patients with type 1 DM depend on exogenous insulin administration for survival and for control of long-term complications. The best-established treatment is tight control of blood glucose achieved by frequent daily injections or continuous subcutaneous in-For editorial comment see p 1599.

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Insulin Needs after CD3-Antibody Therapy in New-Onset Type 1 Diabetes

Abstract: Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

Cited by 999 publications

References 32 publications

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus—Reply

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