Patients with hyperglycemia, gene mutation exhibit low prevalence of vascular complications

Patients with a mutation in the gene encoding the enzyme glucokinase demonstrated a low prevalence for microvascular and macrovascular complications, research suggests.

It has been established within the literature that patients with GCK mutations have mild fasting hyperglycemia from birth, leading to elevated HbA1c levels imitating recommended levels for those with diabetes.

In a cross-sectional study design, Anna M. Steele, PhD, of the National Institute for Health Research at Exeter Clinical Research Facility in the United Kingdom, and colleagues measured the prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease and cardiovascular disease in 99 GCK mutation carriers (median age, 48.6 years), 91 familial controls (median age, 52.2 years) and 83 patients with young-onset type 2 diabetes, diagnosed at age 45 years or younger.

Differences in data

Data indicate the median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls and 7.8% in patients with young-onset type 2 diabetes. Those with GCK demonstrated a low prevalence of significant microvascular complications (1%; 95% CI, 0-5), with no difference in the control group (2%; 95% CI, 0.3-8), but lower than patients with young-onset type 2 diabetes (36%; 95% CI, 25-47), researchers wrote.

Retinopathy was observed in 30% of patients with the GCK mutation (95% CI, 21-41) compared with 14% of familial controls (95% CI, 7-23) and 63% of patients with young-onset type 2 diabetes (95% CI, 51-73), according to data. However, patients with the GCK mutation and those in the control group did not require laser therapy for retinopathy, whereas 28% of patients with young-onset type 2 diabetes required laser therapy (P<.001), researchers wrote.

Moreover, proteinuria was not evident among patients with the GCK mutation and the control group, and microalbuminuria was rare among GCK mutation carriers (1%; 95% CI, 0.2-6) and the control group (2%; 95% CI, 0.2-8). However, patients with young-onset type 2 diabetes displayed proteinuria (10%; 95% CI, 4-19) and microalbuminuria (21%; 95% CI, 13-32), according to data.

Neuropathy was another rare finding among patients with the GCK mutation (2%; 95% CI, 0.3-8) and the control group (0%; 95% CI, 0-4), whereas 29% of those with young-onset type 2 diabetes demonstrated the condition (P<.001), researchers wrote.

Overall, data indicate that patients with the GCK mutation had a lower prevalence of significant macrovascular complications (4%; 95% CI, 1-10), which was not significantly different from the control group (11%; 95% CI, 5-19). This prevalence was lower than in patients with young-onset type 2 diabetes (30%; 95% CI, 21-41), according to data.

The ‘glucose hypothesis’

In an accompanying editorial, Jose C. Florez, MD, PhD, of the diabetes unit at the Center for Human Genetic Research at Massachusetts General Hospital, wrote the data reported by Steele and colleagues contributes to the ongoing debate of glycemic targets within the diabetes population.

“By comparing GCK mutation carriers with unaffected relatives, it is as if the investigators had collaborated with nature to perform a randomized clinical trial of mild hyperglycemia, with randomization occurring at the time of allele assortment in meiosis,” Florez wrote.

Still, Florez said the study sheds light on the complications associated with isolated hyperglycemia, and he is supportive of current treatment goals.

For more information:

Florez JC. JAMA. 2014; 311:249-251.

Steele AM. JAMA. 2014;311:279-286.

Disclosure: Florez has consulted for Eli Lilly, Novartis and Pfizer. All other researchers report no relevant financial disclosures.