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Original Investigation |

Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia

Anna M. Steele, PhD1; Beverley M. Shields, PhD1; Kirsty J. Wensley, AdDip(Nursing)1; Kevin Colclough, BSc2; Sian Ellard, PhD1,2; Andrew T. Hattersley, DM1
[+] Author Affiliations
1National Institue for Health Research, Exeter Clinical Research Facility, Exeter Medical School, University of Exeter, Exeter, United Kingdom
2Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, United Kingdom
JAMA. 2014;311(3):279-286. doi:10.1001/jama.2013.283980.
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Importance  Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.

Objective  To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations.

Design, Setting, and Participants  Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years).

Main Outcomes and Measures  Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease.

Results  Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001).

Conclusions and Relevance  Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.

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Figure.
Scatterplot of glycated hemoglobin (HbA1c) by Age in Patients With GCK (n = 117) Compared With Control (n = 105)

Linear regression lines show increasing glycated hemoglobin (HbA1c) with age.

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