Correlation between β cell mass and glycemic control in type 1 diabetic recipients of islet cell graft

Keymeulen, Bart; Gillard, Pieter; Mathieu, Chantal; Moeini, Babak; Maleux, Geert; Delvaux, Georges; Ysebaert, Dirk; Roep, Bart O.; Vandemeulebroucke, Evy; Marichal, Miriam; Veld, Pieter In 'T; Bogdani, Marika; Hendrieckx, Christel; Gorus, Frans; Ling, Zhidong; Rood, JJ van; Pipeleers, Daniël

doi:10.1073/pnas.0608141103

Cited by 160 publications

(213 citation statements)

References 38 publications

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“…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 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%

“…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%

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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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“…Since those in the younger age group had the most pronounced antibody-induced preservation of beta cell function, we used a post hoc analysis to examine whether this effect was associated with better glucose control as reflected by a greater number of patients with HbA 1c levels <6.5% [13], with fasting blood glucose (FBG) <7.2 mmol/l [14] and with CV for FBG of <20% [15]. Table 2 shows data at start of the study and at month 48, together with the number of patients that injected <0.5 U kg −1 day −1 insulin at these time points; data are also shown for the older age group.…”

Section: Effect Of Chaglycd3 On Insulin Requirements Over 48 Monthsmentioning

confidence: 99%

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

et al. 2010

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Aims/hypothesis The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. Methods Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg −1 day −1 ) over 48 months was chosen as primary endpoint and compared in 31 placeboand 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. Results Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg −1 day −1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA 1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. Conclusions/interpretation A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.

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“…The estimated islet replacement level is about 10% after each transplantation procedure. (5) If the procedure is repeated (dotted line) once or twice (arrows) (6) the total beta cell mass reaches a level at which insulin can be withdrawn [2,3], although most recipients show impaired glucose metabolism (postprandial hyperglycaemia) equivalent (IEQ), with an average diameter of 150 μm, generally becomes entrapped in a relatively large branch of the portal vein. These branches have a complete vessel wall with its various layers, making it even more unlikely that a proper revascularisation process will be induced.…”

Section: Revascularisation Of Intraportally Transplanted Isletsmentioning

confidence: 99%

Optimising islet engraftment is critical for successful clinical islet transplantation

et al. 2007

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Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although 'proof-of-principle' has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

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Correlation between β cell mass and glycemic control in type 1 diabetic recipients of islet cell graft

Abstract: Islet grafts can induce insulin independence in type 1 diabetic patients, but their function is variable with only 10% insulin indepence after 5 years. We investigated whether cultured grafts with defined ␤ cell number help standardize metabolic outcome.

Cited by 160 publications

References 38 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

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Optimising islet engraftment is critical for successful clinical islet transplantation

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