Oral Insulin Delivery in a Physiologic Context: Review

Abstract

Insulin remains indispensable to the treatment of diabetes, but its availability in injectable form only has hampered its timely and broader use. The development of an oral insulin remains an ultimate goal to both enhance ease of use, and to provide therapeutic advantages rooted in its direct delivery to the portal vein and liver. By mimicking the physiological path taken by pancreatic insulin, oral insulin is expected to have a distinct effect on the hepatic aspect of carbohydrate metabolism, hepatic insulin resistance, and, at the same time, avoid hyperinsulinemia and minimize the risk of hypoglycemia. With oral insulin approaching late stages of development, the goal of this review is to examine oral insulin in a physiological context and report on recent progress in its development.

Keywords: glycemic stability; hypoglycemia; oral insulin; type 1 diabetes; type 2 diabetes.

Figure 1.

The pathways and targets of secreted versus subcutaneously injected insulin. The differences in routes taken by and targets of secreted versus subcutaneously delivered insulin may play a role in iatrogenic hypoglycemia, weight gain and glycemic variability. Left panel: The physiologic pathway and hepatic clearance of endogenous insulin. Following caloric intake, insulin (black arrows) is secreted from β-cells at concentrations sufficient to partially suppress secretion of glucagon (white arrows) from α-cells (paracrine action). The insulin and glucagon flow into the portal-hepatic vein at a ratio that allows for glucose disposition by the liver and peripheral tissue. Up to 80% of the secreted insulin is taken up by the liver and the rest reaches the systemic circulation, creating a portal/peripheral insulin gradient. Only a small fraction of glucagon is taken up by the liver. Due to receptor binding and its short plasma half-life, insulin is rapidly cleared from the circulation. Right panel: Insulin delivered by injection is ferried to the systemic circulation, with equal distribution in tissues; a portal/peripheral insulin gradient is absent. Lack or insufficient insulin levels at the islet level lead to inadequate suppression of glucagon secretion, resulting in hyperglucagonemia, and a perturbed insulin/glucagon ratio in the portal vein. In consequence, the balance between hepatic glucose production and storage of hepatic glycogen is disrupted, yielding hyperglycemia. Attempts to control the resulting hyperglucagonemia and resulting hyperglycemia with intensification of treatment by increasing the doses of injected insulin, may cause hypoglycemia.