Direct effect of GLP-1 infusion on endogenous glucose production in humans

Seghieri, Marta; Rebelos, Eleni; Gastaldelli, Amalia; Astiarraga, Brenno; Casolaro, A; Barsotti, Elisabetta; Pocai, Alessandro; Nauck, Michael A.; Muscelli, Elza; Ferrannini, Ele

doi:10.1007/s00125-012-2738-3

Cited by 123 publications

(114 citation statements)

References 30 publications

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“…[22]. It needs to be explained how hypersecretion of GLP-1 can influence glucose metabolism in animals without insulin and glucagon action, but the answer may lie in the recent descriptions of GLP-1 actions on hepatic glucose production [23].…”

Section: Discussionmentioning

confidence: 99%

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

et al. 2015

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Aims/hypothesis Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin-treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) alpha cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance. Methods Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing cells allowing for diphtheria toxin (DT)-induced alpha cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist.Results Near-total alpha cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor alpha cell removal, but did not deteriorate further compared with mice with intact alpha cell mass. Conclusions/interpretation Disruption of glucagon action/ secretion did not improve glucose tolerance in diabetic mice. Near-total alpha cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta cell-deficient diabetes.

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Section: Discussionmentioning

confidence: 99%

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

et al. 2015

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“…levels of GLP-1 (2). Insulin-and glucagon-independent effects of GLP-1 on glucose homeostasis have been recently demonstrated (22,23). We thus determined whether GLP-1 contributes to the improved glycemic profile of Gcgr 2/2 mice, even after b-cell destruction with STZ.…”

Section: Endogenous Fgf21 Improves Glucose Tolerance In Insulin-deficmentioning

confidence: 92%

Fibroblast Growth Factor 21 (FGF21) and Glucagon-Like Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor–Deficient Mice

et al. 2013

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Mice genetically deficient in the glucagon receptor (Gcgr−/−) show improved glucose tolerance, insulin sensitivity, and α-cell hyperplasia. In addition, Gcgr−/− mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin-independent glucose-lowering properties, we investigated whether FGF21 was contributing to diabetes resistance in insulin-deficient Gcgr−/− mice. Plasma FGF21 was 25-fold higher in Gcgr−/− mice than in wild-type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr−/− mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr−/− mice. To investigate the potential antidiabetic actions of FGF21 in insulin-deficient Gcgr−/− mice, an FGF21-neutralizing antibody was administered prior to oral glucose tolerance tests (OGTTs). FGF21 neutralization caused a decline in glucose tolerance in insulin-deficient Gcgr−/− mice during the OGTT. Despite this decline, insulin-deficient Gcgr−/− mice did not develop hyperglycemia. Glucagon-like peptide 1 (GLP-1) also has insulin-independent glucose-lowering properties, and an elevated circulating level of GLP-1 is a known characteristic of Gcgr−/− mice. Neutralization of FGF21, while concurrently blocking the GLP-1 receptor with the antagonist Exendin 9-39 (Ex9-39), resulted in significant hyperglycemia in insulin-deficient Gcgr−/− mice, while blocking with Ex9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.

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“…However, recent studies suggest that there are indeed islet-independent glycemic effects of GLP-1 mediated by the hepatic portal system. Infusion of GLP-1 was found to reduce hepatic glucose production independent of changes in insulin or glucagon levels in dogs (24) and recently in humans (25). The local prevention of GLP-1 inactivation by DPP-4 inhibition in the gut and hepatic portal system may increase portal GLP-1 levels, allowing for such a direct effect of GLP-1 to suppress hepatic glucose output through activating portal GLP-1 receptors, which is also evident from several experimental studies (26,27).…”

Section: Effects Through Insulin-independent Mechanisms Of Glp-1mentioning

confidence: 93%

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

2014

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DPP-4 is an enzyme that is widely expressed throughout the body and abundantly expressed in endothelial cells. It is attached to the intravascular portion of vascular endothelial cells and also exists in a soluble circulating form (4). It is a serine protease that cleaves peptides between the amino acid 2 and 3 from the N-terminal end, particularly if the second amino acid is alanine or proline. GLP-1 has alanine as the second amino acid and is therefore a substrate for DPP-4, which cleaves the intact GLP-1 7-36 to GLP-1 9-36 , which is largely inactive. The

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Direct effect of GLP-1 infusion on endogenous glucose production in humans

Cited by 123 publications

References 30 publications

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

Fibroblast Growth Factor 21 (FGF21) and Glucagon-Like Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor–Deficient Mice

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

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