Effects of Metreleptin in Patients with Extreme Insulin Resistance due to Insulin Receptor Mutations

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 839-872-Diabetes & Obesity Management
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-850
Rebecca J Brown*1, Elaine Cochran2 and Phillip Gorden3
1National Institutes of Health, Bethesda, MD, 2National Institutes of Health, 3NIH - NIDDK, Bethesda, MD
Background: Rabson-Mendenhall syndrome (RMS) is a rare disease caused by mutations of the insulin receptor, and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from microvascular complications of diabetes. In 2004, we reported the glucose-lowering effects of 10 months of recombinant human methionyl leptin (metreleptin) treatment in two siblings with RMS. In this study, we report 10 year effects of metreleptin in these two patients, and 1 year effects in an additional 3 patients.

Methods: We studied 5 patients with homozygous or compound heterozygous mutations of the alpha subunit of the insulin receptor, and a phenotype consistent with RMS, including extreme insulin resistance, dental anomalies, and short stature. In the 2 patients treated for 10 years, metreleptin was given initially at 0.02 mg/kg/day, and titrated up over years.  These 2 patients underwent 3 cycles of leptin withdrawal and reinitiation, with the most recent cycle of metreleptin started at 0.22 mg/kg/day. In the other 3 patients, metreleptin was initiated at 0.22 mg/kg/day. Statistical analysis of metreleptin effects on A1c and body weight were tested using a 12 month period during which all patients were treated with 0.22 mg/kg/day and no changes were made in other diabetes medications. 

Results: All patients had poorly controlled diabetes (A1c 10.1 to 12.8%) at metreleptin initiation. At baseline, A1c (mean±SD) was 11.4±1.1, and decreased to 8.9±2.0 at 5 months, 10.0±0.5 at 8 months, and 9.7±1.6 at 12 months after 0.22 mg/kg/day metreleptin (P=0.0035 for main effect of metreleptin on repeated measures ANOVA). Patients lost weight early in metreleptin treatment (-3.4 kg at 5 months, P=0.04), but regained this weight over time (-1.3 kg at 12 months compared to baseline, P=0.3). In the 2 patients treated for 10 years, each cycle of leptin initiation was associated with a decrease in A1c, and each withdrawal was associated in a rise in A1c. 

Conclusions: Metreleptin treatment was associated with a decrease in A1c in 5 patients with RMS, and may be a promising treatment option for this difficult to control disease.

Nothing to Disclose: RJB, EC, PG

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