Abstract

Objective – Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide 1 (GLP-1), lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

Research design and methods – Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng/[kg•min]) or placebo (normal saline) over 180 minutes starting with the first bite of a mixed-meal (plus 1 gm of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 hours to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

Results – Compared to placebo, GIP induced an early post-prandial increase in insulin levels. Intriguingly, GIP also induced an early post-prandial augmentation in glucagon, a significant elevation in late post-prandial glucose and a decrease in late post-prandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse α cells. In αTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion.

Conclusions – GIP, given to achieve supra-physiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose lowering effect was lost. GIP infusion further worsened hyperglycemia post-prandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.