A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral Insulin (ORAMED)

Insulin therapy is an absolute requirement in type 1 diabetic patients. Multiple injections
present a barrier to achieving normal/near-normal glucose control in diabetic patients (1).
Therefore, there has been considerable interest in developing alternative routes of insulin
administration. ORAMED has developed an oral insulin that, in preliminary studies, has shown
promise. In the present study investigators will perform a pharmacodynamic/pharmacokinetic
study to evaluate this novel insulin preparation as a potential therapeutic option in type 1
diabetic patients.

10 type 1 diabetic subjects will be studied.

Each subject will be studied on three occasions with an interval of 3 days to 4 weeks between
each study. During each study subjects will receive one intervention at a time in random
order: (i) two 8 mg ORAMED capsule containing insulin; (ii) three 8 mg ORAMED capsules
containing insulin; (iii) one 16 mg ORAMED capsule containing insulin. If the fasting plasma
glucose is >200mg/dl on the procedure day, the procedure will be rescheduled.

Prior to each study subjects will refrain from eating (except water) after 10 at night and
report to the Clinical Research Center at approximately 7 in the morning. A catheter will be
placed in an antecubital vein and a prime (40 microCuries x fasting plasma glucose/100) -
continuous (0.4 microCuries/min) infusion of tritiated glucose will be started and continued
until the end of the study. Plasma glucose will be monitored and if necessary during the 1st
hour of tracer equilibration, a small amount of IV regular insulin will be administered to
obtain a fasting plasma glucose of 100-130mg/dl. After a 3-hour tracer equilibration,
subjects will ingest the ORAMED capsule containing insulin and a variable infusion of 20%
glucose will be started to maintain the plasma glucose concentration between 100-120 mg/dl.
Plasma samples for glucose, insulin, glucagon, and free fatty acid (FFA) concentrations and
tritiated glucose radioactivity will be obtained every 5-15 minutes for 4 hours following the
ingestion of the ORAMED capsule containing insulin.

Calculations: Following an overnight fast, steady state conditions prevail and the basal rate
of glucose appearance equals the rate of glucose disappearance and is calculated as the
tritiated glucose infusion rate divided by the tritiated glucose specific activity. Under
postabsorptive conditions, Basal rate of glucose appearance primarily reflects hepatic
glucose production (2). Following the ingestion of oral insulin, non-steady state conditions
prevail and Ra and Rd are calculated using Steele's equation (3). Endogenous (primarily
reflects liver) glucose production is calculated by subtracting the exogenous glucose
infusion rate from the tracer-derived rate of glucose appearance. Endogenous rate of glucose
disappearance reflects glucose uptake by all tissues in the body, but primarily reflects
skeletal muscle (4).

Sample Size: The present study represents a pilot study to gain information about the
absorption of oral insulin and its effect on hepatic and peripheral (skeletal muscle) glucose
metabolism. This information will be used to determine whether the ORAMED oral insulin
preparation represents a viable option to treat diabetic subjects, to gain information about
the dose response effect of ORAMED insulin on glucose metabolism, and to provide quantitative
data about the effect of oral insulin on hepatic and peripheral (muscle) glucose metabolism.
Therefore, the investigators conservatively have set the sample size at 10.

Inclusion Criteria:

- Must be between 18 and 70 years of age

- Must have type 1 diabetes

- Must be in good general health by routine history and physical exam

- A1c <10.0%

- BMI = 18-40 kg/m2

- On no medications known to affect glucose metabolism other than insulin

- Hematocrit ≥ 34 vol%

- Liver Function Tests < 3 x Upper Normal Limit

- Plasma creatinine < 1.8 mg/dl

Exclusion Criteria:

- Under 18 years of age and over 70 years of age

- Does not have type 1 diabetes

- A1c > 10.0%

- BMI < 18 or > 40 kg.m2

- On medications known to affect glucose metabolism other than insulin

- Hematocrit ≤ 34 vol%

- Liver Function Tests >3 x Upper Normal Limit

- Plasma creatinine > 1.8 mg/dl