This study was designed to determine plasma
glucose and
insulin levels after administration of three escalating doses of the oral
insulin product
hexyl-insulin monoconjugate 2 (HIM2) in fasting,
insulin-deprived adult patients with
type 1 diabetes. The study was also designed to assess the safety of the product. Sixteen patients with daily
insulin requirements of 27-60 units and
glycosylated hemoglobin levels of 5.8-11.1% completed the study. Patients'
regular insulin regimens were discontinued at bedtime, and they fasted overnight.
Blood glucose levels were stabilized overnight by intravenous
insulin infusion. In the morning, intravenous
insulin was discontinued 30 min prior to an oral dose of HIM2 (0.6, 0.8, or 1.0 mg/kg). A second oral dose of HIM2 was administered 120 min later. Plasma
glucose and
insulin levels were measured during a 240-min evaluation period after the first HIM2 dose. Identical HIM2 dosing and study procedures were repeated 1 week later with the same patients. Stable or declining plasma
glucose levels were observed on 31 out of a total of 32 dosing days beginning at 20 min after the initial administration of HIM2. After plasma
glucose levels declined or were stable for 30 min to 2 h, increases were observed for some patients. However, for the majority of patients (68.8%), plasma
glucose levels were <150% of predose levels throughout the postdose evaluation period. Similar results were observed after repeating the study procedures 1 week later. Also, plasma
glucose area under the concentration-time curves (AUCs) were inversely correlated with plasma
insulin AUCs. HIM2 appeared to be safe and well-tolerated in this study; no episodes of symptomatic
hypoglycemia were observed. Thus, HIM2 prevented the expected rise in plasma
glucose concentrations in
insulin-deprived adult patients with
type 1 diabetes. The lack of
hypoglycemic events in this exploratory study is encouraging and suggests that there may be less risk of severe
hypoglycemia associated with HIM2 when compared with
injectable insulin. The promising data in this study support the hypothesis that oral HIM2 reproduces the physiological pathway of
insulin secreted by the pancreas - through the portal vein directly to the liver - suggesting a therapeutic advantage in the management of
type 1 diabetes mellitus.