Gut-derived incretin hormones and new therapeutic approaches.

Abstract

This is the first of a series of articles on presentations at the American Diabetes Association Annual Meeting, Orlando, Florida, 4–8 June 2004, addressing an important theme of the meeting: new therapeutic approaches based on gut-derived incretin hormones. ### Physiology of glucagon-like peptide 1 action Alan Cherrington (Nashville, TN) described a series of studies of peripheral and hepatic arterial and portal vein flow measurement and sampling that allowed for the assessment of hepatic glucose balance and effects of glucagon-like peptide (GLP)-1. In a study comparing peripheral with portal venous glucose delivery during hyperglycemia (glucose increased from 75 to 150 mg/dl), with somatostatin to suppress endogenous insulin and glucagon and administration of glucagon to replace basal levels and insulin to levels approximately four times greater than basal, there was a similar increase in the hepatic glucose load, from ∼25 to 50 mg · kg−1 · min−1, but portal glucose delivery doubled hepatic glucose uptake. Net hepatic glucose uptake remained considerably greater with intraportal glucose delivery when the hepatic glucose load was varied from 50 to 75 to 100 mg · kg−1 · min−1. Thus, Cherrington suggested, hepatic glucose entry depends on insulin and glucose levels and a “portal signal.” Portal glucose delivery, then, can be said to “activate the liver,” which may be in part the mechanism of increased hepatic glucose uptake following oral glucose delivery. When measuring hepatic sinusoidal insulin, as levels increase, the net hepatic glucose uptake increases but there is further uptake with activation of the portal glucose signal. In further studies varying peripheral and portal vein glucose delivery and maintaining hyperinsulinemia, a fivefold increase in hepatic glucose uptake was demonstrated, as portal glucose delivery ranged from nil to 100%. Conversely, when glucose was infused peripherally versus in the portal vein at 2.5 mg · kg−1 · min …