Neonatal diabetes tied to gene defect

April 23, 2001

An international team of researchers has identified the cause of a rare form of diabetes that affects newborn children. In a Brief Report in the May 24, 2001, issue of The New England Journal of Medicine, a team led by geneticists and physicians from the Universities of Chicago and Bergen, Norway; in collaborations with physicians from San Raffaele Scientific Institute, Italy, describe two cases of neonatal diabetes resulting from a complete deficiency of glucokinase, an enzyme that plays a crucial role in the regulation of blood-sugar levels.

Permanent neonatal diabetes mellitus is a rare disorder, occurring in about one in 400,000 live births. The two children described in the paper required insulin treatment beginning soon after birth.

"We believe this is the most common cause of permanent neonatal diabetes and urge physicians to look for glucokinase mutations in infants with diabetes, especially if the child has relatives with elevated blood sugar," said senior author Graeme Bell, Ph.D., professor of biochemistry & molecular biology, medicine, and human genetics and a member of the Howard Hughes Medical Institute at the University of Chicago.

In 1992, a team led by Bell discovered that glucokinase mutations were one cause of a sub-type of diabetes called maturity onset diabetes of the young (MODY). That defect appears to be relatively common and underdiagnosed.

"Finding glucokinase mutations that result in relatively mild disease as well as severe neonatal diabetes makes us suspect that there is a spectrum of glucose-regulation disorders that can be traced to different abnormalities of this gene," said Bell.

The parents of the Norwegian child were first cousins. The mother had type-1 diabetes and the father had elevated glucose levels, which he controls with diet. The patient's sister developed type-1 diabetes at age seven. The child, a girl, also had situs inversus, an unusual, probably genetic, condition in which the internal organs are arranged abnormally.

The Italian child, also a girl, has required insulin treatment since birth. She has no other health problems. Her mother has elevated blood-sugar levels and her father has impaired glucose tolerance, an early sign of diabetes.

Both children have mutations in both of their copies of the glucokinase gene. Both Norwegian parents and the sister with diabetes have one abnormal copy. Several other family members who have diabetes or hyperglycemia also have one abnormal copy.

The Italian girl has two copies of a different mutation of the same gene. Both parents have one copy of the same mutation.

Tests showed that both the Norwegian and Italian mutations rendered the enzyme inactive. Neither child with neonatal diabetes secrets any insulin.

The genetics of diabetes have proved to be very complex. Bell's team has isolated four different genes that cause MODY and last year pinpointed the first of several genes that increase susceptibility to the most common form of diabetes.

"This new role for glucokinase is another piece of the puzzle," he said. Not only are there many genes involved but "different mutations and combinations may cause differing forms of the disease."
-end-
Researchers from The University of Pennsylvania; The National Hospital, Oslo, Norway; and Vanderbilt University, Nashville, Tennessee, contributed to this study.

Funding for the study came from the National Institutes of Health, the Norwegian Research Council, the Norwegian Diabetes Council, the Novo Nordic Foundation, the Unger-Vetlesen Charitable Fund, the U.S.-Norway Fulbright Foundation, the Telethon Foundation, the Blum-Kovler Foundation and the Howard Hughes Medical Institute.

University of Chicago Medical Center

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