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

Study Questions:

What is the prevalence and severity of microvascular and macrovascular complications in patients with heterozygous, inactivating glucokinase (GCK) mutations who have mild fasting hyperglycemia from birth?


This was a cross-sectional study in the United Kingdom. Recruitment was from 2008 through 2010. Individuals known to have GCK mutation through genetic testing at a United Kingdom testing center were invited to participate. The authors assessed microvascular and macrovascular complications in 99 GCK mutation carriers, along with 91 nondiabetic, familial, nonmutation carriers (control) and 83 individuals with young-onset type 2 diabetes mellitus (YT2D).


The median age of the GCK mutation carriers was 48.6 years. Patients with GCK had a low 1% prevalence of clinically significant microvascular complications (95% confidence interval [CI], 0%-5%) that was not significantly different from that in controls (2%; 95% CI, 0.3%-8%; p = 0.52) and lower than that in patients with YT2D (36%; 95% CI, 25%-47%; p < 0.001). Patients with GCK also had a low 4% prevalence of clinically significant macrovascular complications (95% CI, 1%-10%) that was not significantly different from that in controls (11%; 95% CI, 5%-19%; p = 0.09) and lower than that in patients with YT2D (30%; 95% CI, 21%-41%; p < 0.001).


The authors concluded that patients with GCK mutations have a low prevalence of microvascular and macrovascular complications, no different than nondiabetic, familial, nonmutation carriers.


While limited by a small number of patients with GCK mutations, the authors provide convincing evidence that isolated hyperglycemia in patients with GCK mutations has a negligible association with complication development. In a creative comparison of GCK mutation carriers to unaffected relatives, the authors provide a wealth of information about the complications that may be associated with mild, isolated, stable hyperglycemia. Florez notes the following in an accompanying editorial: “That the incidence of complications over a median of 48 years is nearly indistinguishable among those with GCK mutations versus nondiabetic controls (with the possible exception of mild background retinopathy, not requiring laser therapy) is indeed reassuring.” Future studies should clarify if and how these findings may be extrapolated to those with type 1 and type 2 diabetes and potentially inform treatment targets.

Keywords: Mutation, Prevalence, Glucokinase

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