FP02-6 First Report of Successful Transition From Insulin to Oral Sulfonylurea Therapy in a Patient With Monogenic Neonatal Diabetes Due to the P333L Mutation in KCNJ11

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP02-Obesity and Diabetes: Drugs & Interventions
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:25 AM
Room 303 (Moscone Center)

Poster Board SAT-759
Katherine Quinn Philla*1, Andrew Jacob Bauer1 and Siri Atma W Greeley2
1Walter Reed National Military Medical Center, Bethesda, MD, 2Univ of Chicago, Chicago, IL
Background: Although monogenic neonatal diabetes may be caused by mutations in over 20 different genes, the most common are activating heterozygous mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, highly expressed in pancreatic beta-cells and brain. Mutated KATPchannels typically have decreased sensitivity to ATP inhibition, hampering insulin secretion even during hyperglycemia. Oral sulfonylureas (SU) have been demonstrated as an effective treatment in the majority of cases, where the likelihood of success is largely predicted by the particular mutation. The few previous reports of the P333L mutation suggested insensitivity to SU therapy.

Clinical Case: A 13-month old (mo) Caucasian male was diagnosed at 3 mo with insulin-requiring diabetes complicated by diabetic ketoacidosis. He was otherwise healthy and had normal growth and development. His insulin dose was 0.3 units/kg/day delivered via an insulin pump and most recent HbA1c was 9.5% (eAG 226 mg/dL). Given his young age of diabetes onset, genetic testing was ordered and revealed the dominant heterozygous KCNJ11mutation P333L.  Previously reported cases with this mutation failed an attempt to transition to SU. However, inpatient transition from insulin to SU therapy was attempted for this patient. Glyburide (glibenclamide) titrated up to a 0.3mg/kg/day was successful with complete discontinuation of insulin after 6 days. Pre-SU fasting c-peptide was <0.1 ng/mL (normal fasting 0.80-3.10 ng/mL) but post-SU fasting c-peptide increased to 0.47 ng/mL after 3 days of therapy and was normalized further to 1.86 ng/mL by 3-month outpatient follow up. HbA1c decreased to 6.7% (eAG 146mg/dl) at the 7 month follow-up. There were no adverse events observed. Complete blood count and complete metabolic profile results as well as neurodevelopment remained normal throughout treatment. Excellent diabetes control on oral SU monotherapy has been sustained throughout his 12-month follow up and the patient’s family regularly voices satisfaction on the decreased intensity of care required on the new oral regimen.

Conclusion: This case demonstrates the critical importance of molecular genetic diagnosis leading to the first successful transition from insulin to SU therapy in a patient with the P333L mutation in KCNJ11 mutation after few previously reported cases were unable to transition off of insulin and exhibited neurodevelopmental disability. Further study of these important rare cases will help to clarify the factors that influence the likelihood of successful SU treatment and neurodevelopmental outcome. Furthermore, this case highlights the variability of predicted response based exclusively on genotype and reemphasizes the importance, and potential life-altering impact, of genetic screening for patients suspected of having monogenic forms of diabetes.

Nothing to Disclose: KQP, AJB, SAWG

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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