Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

Greenbaum, Carla J.; Mandrup‐Poulsen, Thomas; McGee, Paula; Battelino, Tadej; Haastert, Burkhard; Ludvigsson, Johnny; Pozzilli, Paolo; Lachin, John M.; Kolb, Hubert

doi:10.2337/dc07-2451

Cited by 257 publications

(310 citation statements)

References 11 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%

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%

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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“…Patients underwent a standardised MMT by drinking a high-protein liquid formula (Boost HP; Mead Johnson Nutrition, Evansville, IN, USA) [20]. At −5, 0, 30, 90 and 120 min, blood samples were drawn for metabolic and immunological analyses.…”

Section: Methodsmentioning

confidence: 99%

“…The measurements of blood glucose, C-peptide and HbA 1c were performed at the central laboratory of the Steno Diabetes Center, Copenhagen, Denmark using fluoroimmunometric assay (AutoDELFIA; Perkin Elmer Wallac) as described elsewhere [20]. The interassay CV was <6% [20].…”

Section: Methodsmentioning

confidence: 99%

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

et al. 2013

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Aims/hypothesis Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and mealstimulated beta cell function in patients with longer term type 1 diabetes. Methods The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples A complete list of investigators is available in the electronic supplementary material (ESM).Electronic supplementary material The online version of this article

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“…We were concerned that excessive demands might cause patients to refuse to participate in the follow-up. We therefore decided to perform a mixed meal tolerance test (MMTT) in accordance with the European study on estimation of beta cell function [31] in only those 31 patients (21 in the GAD-alum group and 10 in the placebo-group) who at the 30 month follow-up had a maximal C-peptide response >0.20 nmol/l. This test includes ingestion of 6 ml Sustacal (Sustacal; Mead Johnson, Evansville, IN, USA)/kg of body weight, with a maximum of 360 ml, to be ingested within 5 min.…”

Section: Methodsmentioning

confidence: 99%

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

et al. 2010

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Aims/hypothesis The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD 65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Methods Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. Results One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GADalum group fasting C-peptide was 0.332±0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354± 0.039 and 0.184±0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GADalum group than in the placebo-treated group after 4 years.

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Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

Cited by 257 publications

References 11 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

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

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