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Observational Study
. 2013 Jun 14;8(6):e65326.
doi: 10.1371/journal.pone.0065326. Print 2013.

Use of HbA1c in the Identification of Patients With Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies

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Free PMC article
Observational Study

Use of HbA1c in the Identification of Patients With Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies

Anna M Steele et al. PLoS One. .
Free PMC article

Abstract

Aims: HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria.

Methods: Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups.

Results: HbA1c reference ranges in subjects with GCK mutations were: 38-56 mmol/mol (5.6-7.3%) if aged ≤40years; 41-60 mmol/mol (5.9-7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009).

Conclusions: Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. HbA1c increases with age in both GCK and controls.
GCK indicated by black circles and black line, controls indicated by white circles and dashed line.
Figure 2
Figure 2. Receiver operator characteristic curves to identify mutation patients with a GCK mutation from controls using HbA1c.
(A) all ages AUC 0.97 (B) ≤40 years of age AUC 0.99 (C) >40 years of age AUC 0.98.
Figure 3
Figure 3. Receiver operator characteristic curves to identify mutation patients with a GCK mutation from controls using FPG.
(A) all ages AUC 0.97 (B) ≤40 years of age AUC 0.98, (C) >40 years of age AUC 0.97.
Figure 4
Figure 4. Receiver operator characteristic curves to identify mutation patients with a GCK mutation from those with type 1 or type 2 diabetes using HbA1c.
(A) mutation carrying patients from those with type 1 diabetes AUC 0.94 (B) mutation carrying patients from those with type 2 diabetes AUC 0.86 and (C) mutation carrying patients from those with type 1 or type 2 diabetes (types combined) AUC 0.89.
Figure 5
Figure 5. Density plots to show the distribution of HbA1c results for GCK, type 1 and type 2 diabetes.
GCK  =  solid black line, type 1 =  dashed line and type 2 =  grey solid line. To convert values for HbA1c in% into mmol/mol, subtract 2.15 and multiply by 10.929.

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References

    1. ADA (2009) International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care 32: 1327–1334. - PMC - PubMed
    1. Organisation W (2011) Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. - PubMed
    1. Feigerlova E, Pruhova S, Dittertova L, Lebl J, Pinterova D, et al. (2006) Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr 165: 446–452. - PubMed
    1. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, et al. (2001) High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia 44: 898–905. - PubMed
    1. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, et al. (1993) Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328: 697–702. - PubMed

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