As can be gleaned from many of the previous blogs, the diagnosis of diabetes defines many types that require different treatments. Indeed, it has only been recently that we have eliminated the term "juvenile diabetes" as we now know that type 1, or autoimmune diabetes, can occur well into the fifth decade. We also now know that what was formerly called "adult onset diabetes" can now occur as early as middle childhood due to the melding of familial predisposition and lifestyle. Thus, the simplistic definition of diabetes - too much sugar in the blood - has many different variations of both presentation and treatment.
Over the last 10 years due to the increased ability to analyze DNA through sequencing, "SNIPS" etc., researchers have been able to delineate genetic forms of diabetes that occur to DNA mutations that may present symptomatically as either type 1 or type 2 diabetes. Diabetologists were aware of the MODY presentation of diabetes in which patients with the most common forms of MODY present typically like people with mild Type 2 diabetes. The inheritance pattern is typically autosomal dominant and patients are treated symptomatically, usually with oral medication.
About four years ago, the Chicago Tribune and People Magazine featured a child who was diagnosed as an infant with type 1 diabetes and treated with insulin. It was discovered that she had a very rare form of diabetes caused by a mutation in the KCNJ11 region. Prior to this article, Dr. Andrew Hattersley and others published several articles in the New England Journal of Medicine (2004), in which he was able to transition many of these people with the KCNJ11 mutation off insulin to a high dose sulfonylurea-an oral medicine typically used to treat type 2 diabetes in low doses.
What is the physiologic basis behind this remarkable transition? The KCNJ11 mutation does not allow the release of insulin that is produced by the islet cells of the pancreas due to the blocking of different ion channels in the cell membrane. It was discovered that oral hypoglycemics, such as the sulfonylureas (glyburide, for example) could open these channels and allow the insulin to be released appropriately.
It was an extremely dramatic discovery: seemingly infants, children, and adults with presumed type 1 diabetes who would require insulin injections indefinitely were able to be weaned off insulin to oral medications and be treated like mild type 2 patients, similar to the other genetic forms of MODY. Dr. Louis Philipson, director of the University of Chicago Diabetes Program, was one of the first U.S. physicians to begin working with these children and set up an IRB approved research study to obtain DNA from saliva (Oragene assay) to diagnose the different forms of permanent neonatal diabetes (there are different varients that have been discovered, including the KCNJ11, ABCC8, INS mutations among others). The child profiled in the media was one of his first patients to be weaned off insulin as an inpatient in his Clinical Research Center. One can only imagine the joy the family must have experienced after being told that their child would be able to forego insulin injections indefinitely and could now be treated with oral medications.
The incidence of Permanent Neonatal Diabetes is extremely rare. Indeed, the prevalence is 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.
Initially, physicians and families with children diagnosed with type 1 diabetes under 1 year of age began contacting Dr. Philipson after the Chicago Tribune and People articles (as well as internet research) and children were successfully weaned off insulin to oral glyburide after genetic testing by the University Chicago lab confirmed the presence of these mutations. Keep in mind that the diagnosis of Permanent Neonatal Diabetes (PND) may have other associated features separate from diabetes including severe Developmental Delay (DEND syndrome), dysmorphic physical features, seizure disorders, and cognitive or learning disabilities.
My own experience with PND began in 2006 when, after the publicity in regard to Dr. Philipson's patient become widespread, one of our Nurse Practitioners indicated that she cared for an 18-year-old patient with type 1 diabetes that was diagnosed at age 3 weeks. Could it be PND? Indeed, after our patient's spit sample was sent to Dr. Philipson (my former friend and colleague at the University of Chicago) for DNA analysis, the results turned out to be positive for the KCNJ11 mutation. However, my 18-year-old young man with newly diagnosed PND wished to be treated as an outpatient instead of being admitted to the Clinical Research Center at the University of Chicago (in which rapid transition from insulin to oral medication was possible). We used the outpatient protocol as developed by Dr. Andrew Hattersley and modified by Dr. Philipson (and ultimately by myself in consultation with Dr. Philipson) and eventually over 12 months we successfully weaned our 18-year-old off insulin to glyburide. (Review our paper: Monaghan, Stoy, Streisand, Philipson and Cogen, Clinical Diabetes Volume 27, #1, pages 25-29: Case Study: Transition from Insulin to Glyburide in Permanent Neonatal Diabetes: Medical and Psychosocial Issues in an 18-year-old Young Man).
As we gain more experience with our PND patients, other medications are being tried to help maximize endogenous insulin secretion more effectively (including metformin and sometimes Sitagliptin, medications typically used for Type 2 diabetes).
The new millennium is an exciting time for research-both in the discovery of myriad diabetes presentations and treatments and the possibility that there may be superior forms of therapy unique to your own personal type of diabetes.
Take home message: If your child has been diagnosed with type 1 diabetes under the age of 1 year, please get your child tested for PND. There is now a commercial laboratory that can analyze DNA by blood sampling and confirm the diagnosis.
Published On: April 27, 2010