Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region

Abstract

. Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab 287: E75-E81, 2004. First published March 16, 2004 10.1152/ ajpendo.00035.2004.-Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two-and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 (ϳ200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 Ϯ 2.91 and 14.67 Ϯ 2.09 vs. 4.22 Ϯ 1.57 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively). In conclusion: GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.glucagon-like peptide-1; glucose uptake; portal infusion; dog GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is synthesized from proglucagon in the L cells of the duodenum, distal ileum, and colon in response to meal absorption, after which it is rapidly released into the portal vein (22, 37). The main and active form of GLP-1, GLP-1-(7-36), is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) into GLP-1-(9 -36) in the intestinal tissues as well as in the blood (23, 27). The consequence is a rapid elimination of GLP-1 from plasma with a half-life estimated at 1-2 min in several species (22). The earliest biological effect of GLP-1 discovered was its ability to increase glucose-dependent insulin secretion (18, 28) as well as the transcription of the proinsulin gene and biosynthesis of insulin (12). The glucose-dependent effect of GLP-1 on insulin secretion has suggested a potential use of this agent in the treatment of diabetes without deleterious hypoglycemia. Indeed, it lowers postprandial glucose levels in both healthy and human subjects with type 2 diabetes by stimulating insulin secretion but also by inhibiting glucagon secretion from the ␣-cell and delaying gastric emptying (1,17,40).GLP-1 receptors are present on ␤-cells (38), and there are numerous reports of GLP-1 receptors on glucose-consuming tissues suc...

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