It has been three years since I addressed Permanent Neonatal diabetes, a relatively recent discovered form of diabetes that can be treated with sulfonylureas depending on the genetic mutation. As a brief introduction, Permanent Neonatal Diabetes (PNDM) came into the public notice with features in both the Chicago Tribune and People Magazine. A child who was originally diagnosed with type 1 diabetes treated with insulin was noted to have a very rare form of diabetes caused by a mutation in the Kir6.2 subunit - KCNJ11. Based on original work by Drs. Andrew Hattersley and Pearson in England and later, Drs. Louis Philipson and Siri Greeley from the University of Chicago, the child was transitioned off insulin to high dose sulfonylurea, an oral medication typically employed in the treatment of type 2 diabetes in low doses.
The physiologic basis behind this ability to transition from insulin to a sulfonylurea (in this case glyburide) is due to a mutation in KCNJ11 in which the release of insulin produced by the pancreatic islet cells is prevented due to the blocking of different ion channels in the cell membrane. It was discovered that oral “hypoglycemics” such as the sulfonylureas (glyburide as an example) could open these channels and allow the insulin to be released appropriately.
The incidence of Permanent Neonatal Diabetes is extremely rare, 1 in 100,000 to 300,000. In a Pediatric Diabetes paper published in 2008, Diagnosis and Treatment of Neonatal Diabetes: an United States Experience, by Stoy, Greeley, Paz, Pastore, Skowron, Lipton, Cogen, Bell and Philipson, mutations in the KCNJ11, ABCC8 and INS cause Permanent Neonatal Diabetes in 50 percent of patients less than 6 months and a small fraction from ages 6 to 12 months.
In newborns and older infants that present with hyperglycemia, one must immediately consider the possibility of “neonatal diabetes” and obtain genetic testing. As recently as 2007, only academic research laboratories were able to determine genetic sequencing for these mutations (University of Chicago) by obtaining saliva samples. At present, commercial laboratories are available to do genetic testing for “Monogenic Diabetes” of which is Permanent Neonatal diabetes is one form.
However, what does the healthcare provider do while awaiting the genetic testing results?
Does one start insulin and/or glyburide in anticipation of the results? In a recent communication with Dr. Greeley based on an abstract pending submission, he notes that “95 percent of PNDM patients with the KCNJ11 or ABCC8 mutations have been successfully treated with high doses of sulfonylureas and have achieved independence from insulin therapy.” Thus, based on the data from the Departments of Pediatric and Adult Endocrinology at the University of Chicago, the recommendation is to start both insulin and glyburide in anticipation of the genetic results. Insulin is usually first initiated with a form of basal insulin (Lantus) and rapid acting insulin (Apidra, Humalog or Novolog) to decrease blood sugars on a more frequent basis. After starting insulin, one might begin adding glyburide at breakfast and dinner with suggested increases over the next several days. Based on the University of Chicago experience, infants usually respond rather quickly to Glyburide if the genetic mutation is responsive. Infants that present with PNDM often have associated neurodevelopmental issues and it has been noted that sulfonylureas may allow for improvement in this domain as well.
Take home message: an infant under 6 months of age diagnosed with insulin dependent diabetes may have a rare genetic form of monogenic diabetes or Permanent Neonatal Diabetes. Depending on the diagnosis (KCNJ11 or ABCC8 mutations), there is an excellent chance that the infant can be transitioned from insulin to an oral sulfonylurea such a glyburide.
For more information re PNDM, please visit the Neonatal Diabetes registry.
I would like to thank Drs. Greeley and Philipson for their guidance in helping our team transition our PNDM patients from insulin to oral glyburide.
Published On: December 09, 2013