Permanent Neonatal Diabetes: One Gene Makes All The Difference

Imagine your delighted shock if, after living with type 1 diabetes since infancy, you suddenly learned that you weren’t type 1 after all. If you were diagnosed with type 1 diabetes within the first six months of life, especially if your birth weight was low, there’s a chance that instead you have permanent neonatal diabetes mellitus (PNDM).

It’s a rare form that has nothing to do with auto-immunity at all. In fact, the beta cells are just fine, but the excretion of insulin from them is blocked. The result is the same as in type 1, in that no insulin is produced naturally. However, this form of diabetes is caused by a single mutation in gene KCNJ11, and it can be treated with common oral sulfonylureas instead of insulin shots.

Around a third to a half of patients diagnosed with neonatal diabetes before six months of age have this mutation in the KCNJ11 gene. Ninety percent of the time it’s a spontaneous, not inherited, mutation. The KCNJ11 gene directs the creation of a protein, Kir6.2. Kir6.2 forms little gates for the movement of potassium through the membranes of the beta cells.

When all is working as it should, the potassium gates are opened and closed by changes in the level of ATP, the energy-storing compound of the body. When ATP levels are low and the potassium gates are open, tiny calcium gates remain closed, and insulin release is thus prevented. When ATP levels increase, the potassium gates react by closing. When the potassium gates shut down, the tiny calcium gates open and insulin is secreted.

In children with mutated Kir6.2, the potassium gates’ sensitivity to ATP is impaired, preventing the gates from closing. When they can’t close, the calcium gates can’t open; thus, the release of insulin is prevented. Sulfonylureas apparently bind to the potassium gates, causing their closure independent of ATP. This makes the calcium gates open, allowing insulin secretion in response to blood glucose.

Diagnosis of the condition is made by DNA testing of a sample of saliva. The test can cost up to $600, but sometimes testing is available for no charge as part of a research effort. To find institutions that perform genetic testing, go to

So far only about twenty or so cases of PNDM involving mutated KCNJ11 have been diagnosed in the United States, but the actual incidence could be much higher. So if you or your child was diagnosed with type 1 within the first six months of life, think about seeing your doctor to find out if genetic testing would be appropriate for you. It just might be worth a shot – or a lifetime of shots.

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Sources: University of Chicago Genetic Services Laboratories
National Diabetes Information Clearinghouse
Monogenic Diabetes ISPAD guidelines

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