Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia
Authors: Anna M. Steele, Beverley M. Shields, Kirsty J. Wensley, Kevin Colclough, Sian Ellard, Andrew T. Hattersley
Journal: JAMA (2014)

<h3>Importance</h3> Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (<i>GCK)</i>mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA<sub>1c</sub>) level that mimics recommended levels for type 1 and type 2 diabetes. <h3>Objective</h3> To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with<i>GCK</i>mutations. <h3>Design, Setting, and Participants</h3> 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<i>GCK</i>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). <h3>Main Outcomes and Measures</h3> Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease. <h3>Results</h3> Median HbA<sub>1c</sub>was 6.9% in patients with the<i>GCK</i>mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with<i>GCK</i>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%],<i>P</i>=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%],<i>P</i>&lt;.001). Thirty percent of patients with<i>GCK</i>had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%,<i>P</i>=.007) and 63% of patients with YT2D (95% CI, 51%-73%,<i>P</i>&lt;.001). Neither patients with<i>GCK</i>nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (<i>P</i>&lt;.001). Neither patients with<i>GCK</i>patients nor controls had proteinuria and microalbuminuria was rare (<i>GCK</i>, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (<i>P</i>&lt;.001 vs<i>GCK</i>) and 21% (95% CI, 13%-32%) had microalbuminuria (<i>P</i>&lt;.001). Neuropathy was rare in patients with<i>GCK</i>(2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (<i>P</i>&lt;.001). Patients with<i>GCK</i>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%];<i>P</i>=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%],<i>P</i>&lt;.001). <h3>Conclusions and Relevance</h3> Despite a median duration of 48.6 years of hyperglycemia, patients with a<i>GCK</i>mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.