121-LB: Glucose- and Glucagon-Lowering Effect of a Single Oral Leptin Dose in Type 1 Diabetes Patients

Recent understandings of the role of leptin in glucagon and glucose homeostasis, have flagged it as a target for management of type 1 diabetes (T1D). While historically thought to be involved in long-term regulation of appetite and energy expenditure, leptin is now known to regulate food absorption, mucus secretion, intestinal motility and inflammatory processes. Leptin was shown to directly inhibit glucose uptake and reduce glucagon levels and insulin requirements in NOD mice, to ameliorate hyperglycemia in a T1D mouse model, and reduce insulin requirements in patients with insulin-resistant diabetes. Leptin-based drugs are currently only available in injectable forms, and suffer from a short half-life in the circulation. ORMD-0701 is an oral leptin drug, specially formulated to protect the active ingredient from degradative forces in the gut and enhance its uptake across the intestinal mucosa. This first-in-human study assessed the short-term effects of a single ORMD-0701 dose (3 mg leptin) administered to fasting patients with T1D. Patients on an insulin pump and with glucose levels >100 mg% and <280 mg%, received an ORMD-0701 (n=7) or placebo (n=3) capsule. Basal insulin pump rates were then lowered to 50% of the regular program and blood glucose, glucagon and leptin levels were monitored for 3 h. Glucagon area under the curve 30-120-min post-treatment (AUC_30-120) was 0.60 ng*min/L lower than baseline values, while it rose by 0.69 ng*min/L in the placebo group. Similar trends were recorded for glucose AUC_30-120 measures, with an 0.43 mmol*min/L decrease from baseline AUC in the active group versus a 0.24 mmol*min/L increase in the placebo group. By the end of the monitoring period, glucose and glucagon levels returned to baseline levels in all patients. No significant changes in blood leptin levels were detected in either cohort. These preliminary findings set the stage for further assessment of oral leptin and its impact on normalizing the insulin-glucagon balance in patients with T1D.