Abstract
The intestinal peptides GLP-1 and GIP potentiate glucose-mediated insulin release. Agents that increase GLP-1 action are effective therapies in type 2 diabetes mellitus (T2DM). However, GIP action is blunted in T2DM, and GIP-based therapies have not been developed. Thus, it is important to increase our understanding of the mechanisms of GIP action. We developed mice lacking GIP-producing K cells. Like humans with T2DM, "GIP/DT" animals exhibited a normal insulin secretory response to exogenous GLP-1 but a blunted response to GIP. Pharmacologic doses of xenin-25, another peptide produced by K cells, restored the GIP-mediated insulin secretory response and reduced hyperglycemia in GIP/DT mice. Xenin-25 alone had no effect. Studies with islets, insulin-producing cell lines, and perfused pancreata indicated xenin-25 does not enhance GIP-mediated insulin release by acting directly on the beta-cell. The in vivo effects of xenin-25 to potentiate insulin release were inhibited by atropine sulfate and atropine methyl bromide but not by hexamethonium. Consistent with this, carbachol potentiated GIP-mediated insulin release from in situ perfused pancreata of GIP/DT mice. In vivo, xenin-25 did not activate c-fos expression in the hind brain or paraventricular nucleus of the hypothalamus indicating that central nervous system activation is not required. These data suggest that xenin-25 potentiates GIP-mediated insulin release by activating non-ganglionic cholinergic neurons that innervate the islets, presumably part of an enteric-neuronal-pancreatic pathway. Xenin-25, or molecules that increase acetylcholine receptor signaling in beta-cells, may represent a novel approach to overcome GIP resistance and therefore treat humans with T2DM.
Highlights
An increase in circulating glucagon-like peptide-1 (GLP-1) activity has significant therapeutic benefit in patients with type 2 diabetes mellitus (T2DM) (1, 2, 6 –10)
In contrast to single and double incretin receptor knock-out mice that still exhibit a robust insulin secretory response when challenged with oral glucose [14], plasma insulin levels failed to increase in the glucosedependent insulinotropic polypeptide (GIP)/DT mice 15 min after administration of oral glucose even though GLP-1 release and action were not perturbed [16]
These observations suggest that 1) the GIP/DT mice could be used to identify compounds that can reconstitute the incretin response in vivo and 2) K cells may produce peptides in addition to GIP that are essential for amplifying the insulin secretory response observed 15 min after administration of oral glucose
Summary
An increase in circulating GLP-1 activity has significant therapeutic benefit in patients with T2DM (1, 2, 6 –10). Xenin-25 potentiated in response to the glucose injection 2.3- and 2.1-fold in 16 (p ϭ GIP-mediated insulin release in female GIP/DT mice (Fig. 2B).
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