Gene Linked to Both High and Low Blood Sugar Levels

Márta Korbonits, MD, PhD

A research team has revealed a new gene that is believed to be a critical role player in the management of insulin levels and marking the first time a defect in this gene was linked to a disease.

The Queen Mary University of London team, along with colleagues from the University of Exeter and Vanderbilt University, uncovered a disorder in the MAFA gene—the controller of ß cell insulin production—in a family (n = 29) with a unique blood sugar condition and relationship to the development of diabetes.

Despite both having the p.Ser64Phe MAFA mutation, 15 of the individuals in the family had developed diabetes mellitus while 10 others did not. Instead, they developed hyperinsulinemic hypoglycemia secondary to insulinomatosis, leading to insulinomas—tumors in the pancreas that produce insulin and typically cause low levels of blood sugar.

"We identified a new and rare disease due to a mutation in a protein, called MAFA, which normally regulates insulin synthesis. This disease has a complex picture: some patients have a new type of diabetes, others multiple insulin-secreting tumors and in addition, patients with 2 mutated copies in the gene have congenital eye problems," Márta Korbonits, MD, PhD, a professor of endocrinology and the deputy director of the William Harvey Research Institute at Queen Mary University of London, told MD Magazine. "One of the surprising facts is that the same mutation affecting the same cells can cause opposite outcomes—too much insulin—typically in females, or dysregulated insulin resulting in diabetes—more often in males."

Korbonits, along with Donato Iacovazzo, MD, a clinical research fellow with Queen Mary University of London, and colleagues, also noted that the males in the family (n = 12) were more prone to the development of diabetes (male-to-female ratio was 3:1). The females (n = 17), meanwhile, were more likely to develop the insulinomas (male-to-female patient ratio, 1:4), although the reasons for this distinction have yet to be uncovered.

Sian Ellard, PhD

"One exciting avenue to explore will be seeing if we can use this finding to uncover new ways to help regenerate beta cells and treat the more common forms of diabetes," Korbonits said.

The MAFA gene disorder was found in both groups of family members, regardless of their diabetes status, as well as a second and unrelated family member with the same genetic picture. The mutant protein was found to have a longer life in the cell, is unusually stable, and was thus far more abundant in the beta cells than the non-mutated version.

"We believe this gene defect is critical in the development of the disease and we are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas," Iacovazzo said in a statement.

Although not as prevalent as type 1 or type 2 diabetes, it is estimated that 1% to 2% of diabetes is due to maturity-onset diabetes of the young (MODY), a genetic disorder. These affected genes then impact beta cells, leading to disease development.

“While the disease we have characterized is very rare, studying rare conditions helps us understand more about the physiology and the mechanisms underlying more common diseases,” Sian Ellard, PhD, a professor of genomic medicine at the University of Exeter Medical School and overseer of the study, said in a statement. “We hope that in the longer term this research will lead to us exploring new ways to trigger the regeneration of beta cells to treat more common forms of diabetes.”

The authors concluded that the MAFA missense mutation was "the cause of a dual familial condition of diabetes mellitus or hyperinsulinemic hypoglycemia secondary to insulinomatosis." Further, they noted that the data show that the p.Ser64Phe mutation "impairs phosphorylation in the transactivation domain of MAFA, leading to significantly enhanced protein stability and activity in β-cell lines." This is anticipated to further insights on the role of this transcription factor in the β-cell.

"We have a lot to figure out still, but a better understanding of beta cell function will improve diabetes care," Korbonits said. "We need to understand the mechanism how this mutation leads to tumor development in the insulin-secreting cells. We need to understand why some family members develop diabetes and why some develop insulin-secreting tumors. Typically (but not exclusively), males developed diabetes, females insulin-secreting tumors. We need to develop a mouse model to be able to study this disease in more detail in experimental conditions. We also be looking at insulin-secreting cells where we introduced this gene mutation."

The study, “MAFA missense mutation causes familial insulinomatosis and diabetes mellitus” was published in the journal Proceedings of the National Academy of Sciences.

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