Absence of insulinotropic glucagon‐like peptide‐I(7–37) receptors on isolated rat liver hepatocytes

Blackmore, Peter F.; Mojsov, Svetlana; Exton, John H.; Habener, Joel F.

doi:10.1016/0014-5793(91)80541-a

Cited by 53 publications

(20 citation statements)

References 26 publications

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“…There are numerous reports of the presence of GLP-1 receptors in liver (2,42), and in in vitro studies GLP-1 per se has been shown to increase glycogen synthesis in liver (2). However, the presence of such hepatic receptors remains controversial (2,4,6,42). The utilization of a GLP-1 receptor antagonist such as exendin-(9 -39) could be useful in future studies to clarify this mechanistic and important physiological issue.…”

Section: Resultsmentioning

confidence: 99%

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

Dardevet¹,

Moore²,

Neal³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. 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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Section: Resultsmentioning

confidence: 99%

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

Dardevet¹,

Moore²,

Neal³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…Most (4,5,41), but not all (48), investigators have been unable to find evidence of GLP-1 receptor gene expression in hepatic cells. Although most of these analyses have been performed in rat tissues (4,5,41,48), two groups have been unable to find GLP-1 receptor mRNA in extracts from human liver (14,46). Several investigators have demonstrated GLP-1 receptor expression in kidney extracts (5,48), so it is possible that GLP-1 selectively inhibits renal glucose production.…”

Section: Discussionmentioning

confidence: 99%

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Prigeon

Quddusi²,

Paty³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

182

129

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. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003 10.1152/ ajpendo.00024.2003.-Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (R a) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [ 3 H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 Ϯ 14 vs. 113 Ϯ 11 pM; 0.153 Ϯ 0.029 vs. 0.156 Ϯ 0.026 nM; and 64.7 Ϯ 11.5 vs. 65.8 Ϯ 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steadystate levels of 4.8 Ϯ 0.2 to a nadir of 4.1 Ϯ 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in R a, from 22.6 Ϯ 2.8 to 19.1 Ϯ 2.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance GLUCAGON-LIKE PEPTIDE-1 (GLP-1; 7-36 amide) is an intestinal hormone that plays an important role in glucose homeostasis. GLP-1 is a potent insulinotropin that is secreted after meal ingestion, thereby contributing to the incretin effect (the greater insulin release occurring after oral compared with intravenous glucose administration; see Refs. 9, 28, and 35). GLP-1 also decreases glucagon release, either through direct interaction with the ␣-cell or indirectly via stimulation of insulin and somatostatin secretion (10, 47). Thus the overall effect of GLP-1 on pancreatic islet secretion is to decrease circulating glucose concentrations. In addition to the regulation of islet hormones, GLP-1 slows gastric emptying (49), another action that attenuates the rise in plasma glucose after meal ingestion. This broad range of acute effects on processes governing circulating levels of glucose has stimulated interest in using GLP-1 or GLP-1 analogs for the treatment of diabetes.Many investigators have also suggested that GLP-1 has effects on glucose metabolism beyond the regulation of pancreatic islet hormone secretion, e.g., extrapancreatic effects. The first report was from Gutniak and colleagues (20)...

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“…The effects of intraportal GLP-1 on impulse traffic in vagal afferent sensory nerve fibers were also resistant to exendin 9 -39 (219). The liver has repeatedly been reported to be a target for GLP-1, although initial careful studies indicated that hepatocytes did not express GLP-1 receptor (17). Thus GLP-1 has been reported to bind to rat hepatic membranes but without influencing adenylate cyclase activity, as expected from the classical GLP-1 receptor (308).…”

Section: Whole Body Effects Peripheral Effects and Effects On Inmentioning

confidence: 96%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,637

2,385

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Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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Absence of insulinotropic glucagon‐like peptide‐I(7–37) receptors on isolated rat liver hepatocytes

Cited by 53 publications

References 26 publications

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

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

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

The Physiology of Glucagon-like Peptide 1

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