Oral insulin: the rationale for this approach and current developments

Abstract

Insulin remains the most effective and durable hypoglycemic agent for the treatment of diabetes. The addition of an effective oral insulin dosage form to the antidiabetes armamentarium may have significant benefits in terms of fostering compliance and adherence among patients, as well as physiologic advantages due to the fact that such a dosage form replicates the natural route of insulin secretion and absorption through the portal vein and targets the liver directly. Several companies have developed technological platforms that protect polypeptides and proteins from enzymatic hydrolysis, enable their transport across the epithelial lining, and promote their absorption from the gastrointestinal tract. A review of the potential physiological rationale and advantages, as well as of current pertinent technologies used specifically with insulin, is herewith provided.

Figure 1.

Hepatic glucose output (HGO): role of (portal) insulin. Left: (1) nondiabetic individuals in postabsorptive (1A) and fed (1B) states. Right: (2) diabetic individuals (type 2 diabetes mellitus, T2DM) in postabsorptive (2A) and fed (2B) states. (1A) For nondiabetic individuals in the fasting state, plasma glucose is derived from glycogenolysis and is secreted tonically under the control of basal insulin. (1B) For nondiabetic individuals in the fed state, plasma glucose is derived from the ingestion of nutrients, HGO is governed by gluconeogenesis, and glycogenolysis is restrained under the control of insulin with the net effect of a physiologic postprandial glucose excursion. (2A) For individuals with diabetes (T2DM) in the fasting state, because of insulin deficiency in the portal circulation, HGO governed by glycogenolysis and gluconeogenesis in the liver is unrestrained and manifests as elevated fasting blood glucose. (2B) For individuals with diabetes in the fed state, again because of insulin deficiency in the portal circulation, suppression of HGO is ineffective, resulting in elevated hepatic glucose production, which now adds up to plasma glucose derived from the ingestion of nutrients with the net effect of postprandial hyperglycemia. GIT, gastrointestinal tract.

Figure 2.

Glucose, C-peptide, and insulin plasma concentrations vs time (150–300 minutes). An illustrative case from a pharmacokinetic and pharmacodynamic study in healthy subjects: The capsule of oral insulin (8 mg insulin/capsule) given at time 0. After a lag of ∼200 minutes, insulin appears in plasma with a corollary decrease in C-peptide and glucose.