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

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 (HbA_1c) 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 withGCKmutations.

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 99GCKmutation 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 HbA_1cwas 6.9% in patients with theGCKmutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients withGCKhad 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 withGCKhad 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 withGCKnor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients withGCKpatients 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 vsGCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients withGCK(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 withGCKhad 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 aGCKmutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.