Gene Mutation of MODY May Provide Insights into Diabetes

Miriam E. Tucker

January 15, 2014

Patients with a genetic mutation that causes stable, mildly elevated blood glucose levels rarely develop typical diabetes-related complications, a new study finds.

The results, which may provide insight into the isolated role of glucose in the development of complications among patients with other types of diabetes, were published in the January 14 issue of the Journal of the American Medical Association by Anna M. Steele, PhD, of the National Institute for Health Research, Exeter Medical School, United Kingdom, and colleagues.

Mutation in the GCK gene causes abnormalities in the action of glucokinase, which regulates the secretion of insulin from the pancreatic beta cells in response to blood glucose levels. As a result, higher glucose concentrations are required to trigger insulin release.

Patients with this mutation, one of several associated with "maturity-onset diabetes of youth" (MODY), typically don't require glucose-lowering treatment outside of pregnancy, and their blood pressure and lipid levels are similar to those of the general population. Previous studies have suggested that, despite having mild hyperglycemia from birth, these patients rarely experience diabetes-related eye, kidney, nerve, and cardiovascular complications. But no trial has systematically assessed this, Dr. Steele and colleagues say.

The study's cross-sectional design, in which complication rates among patients with GCK mutations were compared with those of individuals with type 2 diabetes and those of the general population, was deemed "clever and informative" by Jose C. Florez, MD, PhD, from the Center for Human Genetic Research at Massachusetts General Hospital, Boston, who wrote an accompanying editorial.

"Glucokinase MODY can be viewed as the natural experiment by which humans are exposed to permanent levels of mild hyperglycemia in an isolated or 'pure' framework, ie, without other contributing factors such as obesity, hyperlipidemia, hypertension, or even autoimmunity," he writes.

However, both Dr. Florez and the paper's authors stress that the results in MODY patients may not be easily extrapolated to the general type 1 or type 2 diabetes population, given other differences between the groups. For example, carriers of GCK mutations have more stable glucose levels than people with either common form of diabetes and typically lack the other risk factors that accompany the metabolic syndrome.

Complication Rates Low, Despite High Blood Sugar

The study included 99 adults with the GCK mutation (heterozygous), 91 unaffected family members (controls), and 83 patients who had been diagnosed with type 2 diabetes before the age of 45 years. All were older than 35 years at the time of the study. The duration of hyperglycemia was 48.6 years for the GCK group (ie, their age) and 17 years for those with type 2 diabetes. The controls had a mean age of 52.2 years, and the type 2 group 54.7 years.

Average HbA1c levels were 5.8% for the controls, 6.9% for the GCK group, and 7.8% for the group with type 2 diabetes. The HbA1c of the GCK group falls within the current American Diabetes Association's recommendation of less than 7% for people with type 1 and type 2 diabetes, the authors point out.

The overall prevalence of clinically significant retinopathy, persistent microalbuminuria, or proteinuria was just 1% in the GCK mutation group, not significantly different from the 2% seen in the controls. In contrast, 36% of the type 2 diabetes patients had evidence of 1 or more clinically significant microvascular complications (P < .001 vs the GCK group).

There was a higher prevalence of any level of retinopathy among the GCK group compared with the controls, 30% vs 14% (P = .007), but all had just background retinopathy, with fewer than 5 microaneurysms. In contrast, two-thirds (63%) of those with type 2 diabetes had any retinopathy, and a third of those were classified as more severe (P < .001 vs GCK patients).

Similarly, the prevalence of clinically diagnosed macrovascular complications was also low in the GCK group, at 4%, and in the controls, at 11%. In the type 2 group, in contrast, 30% had macrovascular complications (P < .001 vs GCK). Ischemic heart disease, for example, was present in just 2% of the GCK group and 5% of the controls, compared with 16% of the type 2 patients (P = .001 vs GCK patients).

"In these [GCK-mutation] patients, an average of nearly 50 years of isolated hyperglycemia within current target ranges for diabetes control has a negligible association with complication development. This work is, to our knowledge, the first systematic assessment of complication development in patients with a GCK mutation," the authors note.

Implications for Garden-variety Diabetes

The findings are encouraging, says Dr. Florez in his editorial: "That the incidence of complications over a median of 48 years is nearly indistinguishable among those with GCK mutations vs nondiabetic controls (with the possible exception of mild background retinopathy not requiring laser therapy) is indeed reassuring."

But the extent to which these findings can be extrapolated to more common diabetes populations is somewhat limited, Dr. Florez and the authors note. For one, GCK carriers have more stable glycemic levels than do those with type 1 or type 2 diabetes, and there is some evidence to suggest that the variability itself may play a role in the development of complications even at equivalent HbA1c levels.

Moreover, because those with the GCK mutation are affected from birth, they may have adapted in such a way that their cells and tissues are more impervious to hyperglycemia. On the other hand, it's possible that they may develop complications further down the line.

Nevertheless, Dr. Florez writes, "This study by Steele et al sheds light on the extent to which decades of isolated mild hyperglycemia promote diabetes complications, and with key caveats expressed here, this study supports current treatment goals and lays the groundwork for more extended follow-up of this unique population."

He adds that this study "illustrates how clinical insights gained from the study of monogenic syndromes can improve understanding of complex diseases."

This study was funded by a grant from Diabetes UK and the National Institute of Health Research. The research leading to these results also received funding from the European Community's Seventh Framework Programme. The authors have reported no relevant financial relationships. Dr. Florez has received consulting fees from Eli Lilly, Pfizer, and Novartis.

JAMA. 2014;311:279-286, 249-251. Abstract Editorial

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