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New definition for the partial remission period in children and adolescents with type 1 diabetes.

Mortensen HB, Hougaard P, Swift P, Hansen L, Holl RW, Hoey H, Bjoerndalen H, de Beaufort C, Chiarelli F, Danne T, Schoenle EJ, Aman J, Hvidoere Study Group on Childhood Diabet - Diabetes Care (2009)

Bottom Line: The IDAA1C < or =9 had a significantly higher agreement (P < 0.001) with residual beta-cell function than use of a definition of A1C < or =7.5%.IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6 and 12 months.It reflects residual beta-cell function and has better stability compared with the conventional definitions.

View Article: PubMed Central - PubMed

Affiliation: 1Glostrup University Hospital, Department of Paediatrics, Glostrup, Denmark. hbmo@glo.regionh.dk

ABSTRACT
OBJECTIVE To find a simple definition of partial remission in type 1 diabetes that reflects both residual beta-cell function and efficacy of insulin treatment. RESEARCH DESIGN AND METHODS A total of 275 patients aged <16 years were followed from onset of type 1 diabetes. After 1, 6, and 12 months, stimulated C-peptide during a challenge was used as a measure of residual beta-cell function. RESULTS By multiple regression analysis, a negative association between stimulated C-peptide and A1C (regression coefficient -0.21, P < 0.001) and insulin dose (-0.94, P < 0.001) was shown. These results suggested the definition of an insulin dose-adjusted A1C (IDAA1C) as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)]. A calculated IDAA1C < or =9 corresponding to a predicted stimulated C-peptide >300 pmol/l was used to define partial remission. The IDAA1C < or =9 had a significantly higher agreement (P < 0.001) with residual beta-cell function than use of a definition of A1C < or =7.5%. Between 6 and 12 months after diagnosis, for IDAA1C < or =9 only 1 patient entered partial remission and 61 patients ended partial remission, for A1C < or =7.5% 15 patients entered partial remission and 53 ended, for a definition of insulin dose < or =0.5 units . kg(-1) . 24 h(-1) 5 patients entered partial remission and 66 ended, and for stimulated C-peptide (>300 pmol/l) 9 patients entered partial remission and 49 ended. IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6 and 12 months. CONCLUSIONS A new definition of partial remission is proposed, including both glycemic control and insulin dose. It reflects residual beta-cell function and has better stability compared with the conventional definitions.

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A: The thresholds for partial remission based on IDAA1C ≤9 (solid green line) and A1C ≤7.5% and insulin doses ≤0.5 units · kg−1 · 24 h−1 (rectangular dashed box). Each diagonal red line corresponds to one IDAA1C value. The numbers in boxes are the predicted values for stimulated C-peptide concentrations for a 10-year-old boy at the relevant IDAA1C value and, as illustrated, other threshold values for IDAA1C correspond to different predicted C-peptide values. The + signs give the distribution of 257 patients with type 1 diabetes after 6 months' duration. B: Age at onset influences the rate of partial remission as assessed by IDAA1C in children with type 1 diabetes. The proportion of partial remission is lowest in the youngest age-group (0–;4.9 years). Because of lower insulin sensitivity, the proportions of partial remission in the old age-group (≥10 years) and the school-age children (5–;9.9 years) seem to be similar despite higher residual β-cell function. C: The proportion of children in partial remission according to the different definitions. From 3 to 12 months, the curves for IDAA1C (curve 1), C-peptide (curve 2), and insulin dose (curve 4) show close agreement. Using the new definition, partial remission occurred in 61% at 3 months, in 44% at 6 months, and in 18% after 12 months. D: Agreement between definitions of those in partial remission, A1C ≤7.5% (left panel, dashed vertical line), IDAA1C ≤9 (right panel, dashed vertical line), and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 12 months. The arrows point to the areas showing that A1C ≤7.5% disagrees significantly more than IDAA1C ≤9 with C-peptide >300 pmol/l, probably because the children receive more exogenous insulin, which is accounted for in the insulin dose–;adjusted model. E: The relationship of IDAA1C ≤9 (dashed vertical line) and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 6 and 12 months. Individual observations are shown by age-groups. The regression lines for 6 (——) and 12 (– – –) months show the linear correlation of IDAA1C and C-peptide over a continuum of stimulated C-peptide values.
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Figure 1: A: The thresholds for partial remission based on IDAA1C ≤9 (solid green line) and A1C ≤7.5% and insulin doses ≤0.5 units · kg−1 · 24 h−1 (rectangular dashed box). Each diagonal red line corresponds to one IDAA1C value. The numbers in boxes are the predicted values for stimulated C-peptide concentrations for a 10-year-old boy at the relevant IDAA1C value and, as illustrated, other threshold values for IDAA1C correspond to different predicted C-peptide values. The + signs give the distribution of 257 patients with type 1 diabetes after 6 months' duration. B: Age at onset influences the rate of partial remission as assessed by IDAA1C in children with type 1 diabetes. The proportion of partial remission is lowest in the youngest age-group (0–;4.9 years). Because of lower insulin sensitivity, the proportions of partial remission in the old age-group (≥10 years) and the school-age children (5–;9.9 years) seem to be similar despite higher residual β-cell function. C: The proportion of children in partial remission according to the different definitions. From 3 to 12 months, the curves for IDAA1C (curve 1), C-peptide (curve 2), and insulin dose (curve 4) show close agreement. Using the new definition, partial remission occurred in 61% at 3 months, in 44% at 6 months, and in 18% after 12 months. D: Agreement between definitions of those in partial remission, A1C ≤7.5% (left panel, dashed vertical line), IDAA1C ≤9 (right panel, dashed vertical line), and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 12 months. The arrows point to the areas showing that A1C ≤7.5% disagrees significantly more than IDAA1C ≤9 with C-peptide >300 pmol/l, probably because the children receive more exogenous insulin, which is accounted for in the insulin dose–;adjusted model. E: The relationship of IDAA1C ≤9 (dashed vertical line) and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 6 and 12 months. Individual observations are shown by age-groups. The regression lines for 6 (——) and 12 (– – –) months show the linear correlation of IDAA1C and C-peptide over a continuum of stimulated C-peptide values.

Mentions: The multivariate analysis showed a negative correlation between stimulated C-peptide, A1C, and insulin dose, with a significant effect of age (estimate 0.09/year, P < 0001) but not sex (estimate comparing female with male patients −0.01, P = 0.91) at 6 months after diagnosis. It would be natural to include an age effect in the formula, if the aim of the study had purely been to predict the stimulated C-peptide level. However, because the purpose was to suggest a new measure for remission, it was anticipated that the suggested formula for IDAA1C could be useful on its own and therefore age was not included. From the regression coefficients at 6 months (A1C −0.21 and insulin dosage −0.94), it was seen that there was a factor of ∼4.4 between the coefficients for these parameters. The R2 value was 0.30. Results at 6 and 12 months were similar. This finding inspired the suggestion of a combined expression of insulin dose and A1C, formulated as a specific definition of the IDAA1C = A1C (percent) + 4 × [insulin dose (units per kilogram per 24 h)]. The factor of 4.4 was substituted by 4 to obtain simple numbers. Based on the slope of the regression line between stimulated C-peptide, A1C, and insulin dose, a predicted C-peptide value can be calculated from any given set of corresponding A1C and insulin dose. The distribution of patients according to individual A1C and insulin dosages at 6 months' duration are shown in Fig. 1A, in which each diagonal red line corresponds to one IDDA1C value. According to this model an IDAA1C threshold ≤9 corresponds to a predicted level of >300 pmol/l for the corresponding stimulated C-peptide. This expression can be used as a qualitative measure of partial remission, and in alignment with the DCCT “C-peptide responders” (200–500 pmol/l), we have chosen IDAA1C ≤9 to define partial remission. Other threshold values for IDAA1C could have been chosen, corresponding to different predicted C-peptide values. Compared with the partial remission definition, insulin dose ≤0.5 units · kg−1 · 24 h−1 and A1C ≤7.5% (Fig. 1A, rectangular dashed box), our definition has been extended with the triangular area above and to the right side of the rectangular dashed box. As an indicator of more aggressive insulin therapy at some of the centers, there are more patients placed in the triangle to the right of the dashed line that marks an insulin dose ≤0.5 units · kg−1 · 24 h−1 than in the upper triangle above the dashed line, marking an A1C ≤7.5%.


New definition for the partial remission period in children and adolescents with type 1 diabetes.

Mortensen HB, Hougaard P, Swift P, Hansen L, Holl RW, Hoey H, Bjoerndalen H, de Beaufort C, Chiarelli F, Danne T, Schoenle EJ, Aman J, Hvidoere Study Group on Childhood Diabet - Diabetes Care (2009)

A: The thresholds for partial remission based on IDAA1C ≤9 (solid green line) and A1C ≤7.5% and insulin doses ≤0.5 units · kg−1 · 24 h−1 (rectangular dashed box). Each diagonal red line corresponds to one IDAA1C value. The numbers in boxes are the predicted values for stimulated C-peptide concentrations for a 10-year-old boy at the relevant IDAA1C value and, as illustrated, other threshold values for IDAA1C correspond to different predicted C-peptide values. The + signs give the distribution of 257 patients with type 1 diabetes after 6 months' duration. B: Age at onset influences the rate of partial remission as assessed by IDAA1C in children with type 1 diabetes. The proportion of partial remission is lowest in the youngest age-group (0–;4.9 years). Because of lower insulin sensitivity, the proportions of partial remission in the old age-group (≥10 years) and the school-age children (5–;9.9 years) seem to be similar despite higher residual β-cell function. C: The proportion of children in partial remission according to the different definitions. From 3 to 12 months, the curves for IDAA1C (curve 1), C-peptide (curve 2), and insulin dose (curve 4) show close agreement. Using the new definition, partial remission occurred in 61% at 3 months, in 44% at 6 months, and in 18% after 12 months. D: Agreement between definitions of those in partial remission, A1C ≤7.5% (left panel, dashed vertical line), IDAA1C ≤9 (right panel, dashed vertical line), and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 12 months. The arrows point to the areas showing that A1C ≤7.5% disagrees significantly more than IDAA1C ≤9 with C-peptide >300 pmol/l, probably because the children receive more exogenous insulin, which is accounted for in the insulin dose–;adjusted model. E: The relationship of IDAA1C ≤9 (dashed vertical line) and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 6 and 12 months. Individual observations are shown by age-groups. The regression lines for 6 (——) and 12 (– – –) months show the linear correlation of IDAA1C and C-peptide over a continuum of stimulated C-peptide values.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713624&req=5

Figure 1: A: The thresholds for partial remission based on IDAA1C ≤9 (solid green line) and A1C ≤7.5% and insulin doses ≤0.5 units · kg−1 · 24 h−1 (rectangular dashed box). Each diagonal red line corresponds to one IDAA1C value. The numbers in boxes are the predicted values for stimulated C-peptide concentrations for a 10-year-old boy at the relevant IDAA1C value and, as illustrated, other threshold values for IDAA1C correspond to different predicted C-peptide values. The + signs give the distribution of 257 patients with type 1 diabetes after 6 months' duration. B: Age at onset influences the rate of partial remission as assessed by IDAA1C in children with type 1 diabetes. The proportion of partial remission is lowest in the youngest age-group (0–;4.9 years). Because of lower insulin sensitivity, the proportions of partial remission in the old age-group (≥10 years) and the school-age children (5–;9.9 years) seem to be similar despite higher residual β-cell function. C: The proportion of children in partial remission according to the different definitions. From 3 to 12 months, the curves for IDAA1C (curve 1), C-peptide (curve 2), and insulin dose (curve 4) show close agreement. Using the new definition, partial remission occurred in 61% at 3 months, in 44% at 6 months, and in 18% after 12 months. D: Agreement between definitions of those in partial remission, A1C ≤7.5% (left panel, dashed vertical line), IDAA1C ≤9 (right panel, dashed vertical line), and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 12 months. The arrows point to the areas showing that A1C ≤7.5% disagrees significantly more than IDAA1C ≤9 with C-peptide >300 pmol/l, probably because the children receive more exogenous insulin, which is accounted for in the insulin dose–;adjusted model. E: The relationship of IDAA1C ≤9 (dashed vertical line) and stimulated C-peptide >300 pmol/l (dashed horizontal line) at 6 and 12 months. Individual observations are shown by age-groups. The regression lines for 6 (——) and 12 (– – –) months show the linear correlation of IDAA1C and C-peptide over a continuum of stimulated C-peptide values.
Mentions: The multivariate analysis showed a negative correlation between stimulated C-peptide, A1C, and insulin dose, with a significant effect of age (estimate 0.09/year, P < 0001) but not sex (estimate comparing female with male patients −0.01, P = 0.91) at 6 months after diagnosis. It would be natural to include an age effect in the formula, if the aim of the study had purely been to predict the stimulated C-peptide level. However, because the purpose was to suggest a new measure for remission, it was anticipated that the suggested formula for IDAA1C could be useful on its own and therefore age was not included. From the regression coefficients at 6 months (A1C −0.21 and insulin dosage −0.94), it was seen that there was a factor of ∼4.4 between the coefficients for these parameters. The R2 value was 0.30. Results at 6 and 12 months were similar. This finding inspired the suggestion of a combined expression of insulin dose and A1C, formulated as a specific definition of the IDAA1C = A1C (percent) + 4 × [insulin dose (units per kilogram per 24 h)]. The factor of 4.4 was substituted by 4 to obtain simple numbers. Based on the slope of the regression line between stimulated C-peptide, A1C, and insulin dose, a predicted C-peptide value can be calculated from any given set of corresponding A1C and insulin dose. The distribution of patients according to individual A1C and insulin dosages at 6 months' duration are shown in Fig. 1A, in which each diagonal red line corresponds to one IDDA1C value. According to this model an IDAA1C threshold ≤9 corresponds to a predicted level of >300 pmol/l for the corresponding stimulated C-peptide. This expression can be used as a qualitative measure of partial remission, and in alignment with the DCCT “C-peptide responders” (200–500 pmol/l), we have chosen IDAA1C ≤9 to define partial remission. Other threshold values for IDAA1C could have been chosen, corresponding to different predicted C-peptide values. Compared with the partial remission definition, insulin dose ≤0.5 units · kg−1 · 24 h−1 and A1C ≤7.5% (Fig. 1A, rectangular dashed box), our definition has been extended with the triangular area above and to the right side of the rectangular dashed box. As an indicator of more aggressive insulin therapy at some of the centers, there are more patients placed in the triangle to the right of the dashed line that marks an insulin dose ≤0.5 units · kg−1 · 24 h−1 than in the upper triangle above the dashed line, marking an A1C ≤7.5%.

Bottom Line: The IDAA1C < or =9 had a significantly higher agreement (P < 0.001) with residual beta-cell function than use of a definition of A1C < or =7.5%.IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6 and 12 months.It reflects residual beta-cell function and has better stability compared with the conventional definitions.

View Article: PubMed Central - PubMed

Affiliation: 1Glostrup University Hospital, Department of Paediatrics, Glostrup, Denmark. hbmo@glo.regionh.dk

ABSTRACT
OBJECTIVE To find a simple definition of partial remission in type 1 diabetes that reflects both residual beta-cell function and efficacy of insulin treatment. RESEARCH DESIGN AND METHODS A total of 275 patients aged <16 years were followed from onset of type 1 diabetes. After 1, 6, and 12 months, stimulated C-peptide during a challenge was used as a measure of residual beta-cell function. RESULTS By multiple regression analysis, a negative association between stimulated C-peptide and A1C (regression coefficient -0.21, P < 0.001) and insulin dose (-0.94, P < 0.001) was shown. These results suggested the definition of an insulin dose-adjusted A1C (IDAA1C) as A1C (percent) + [4 x insulin dose (units per kilogram per 24 h)]. A calculated IDAA1C < or =9 corresponding to a predicted stimulated C-peptide >300 pmol/l was used to define partial remission. The IDAA1C < or =9 had a significantly higher agreement (P < 0.001) with residual beta-cell function than use of a definition of A1C < or =7.5%. Between 6 and 12 months after diagnosis, for IDAA1C < or =9 only 1 patient entered partial remission and 61 patients ended partial remission, for A1C < or =7.5% 15 patients entered partial remission and 53 ended, for a definition of insulin dose < or =0.5 units . kg(-1) . 24 h(-1) 5 patients entered partial remission and 66 ended, and for stimulated C-peptide (>300 pmol/l) 9 patients entered partial remission and 49 ended. IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6 and 12 months. CONCLUSIONS A new definition of partial remission is proposed, including both glycemic control and insulin dose. It reflects residual beta-cell function and has better stability compared with the conventional definitions.

Show MeSH
Related in: MedlinePlus