Exendin-4 Agonist and Exendin(9-39)amide Antagonist of the GLP-1(7-36)amide Effects in Liver and Muscle

Alcántara, Ana; Morales, Mónica; Delgado, Elena; López‐Delgado, M. I.; Clemente, Felipe; Luque, Miguel Angel Limón; Malaisse, Willy; Valverde, Isabel; Villanueva-Peñacarrillo, María Luisa

doi:10.1006/abbi.1997.9951

Cited by 72 publications

(57 citation statements)

References 25 publications

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“…Previously believed to be mere enhancers of ␤-cell function, the incretins are being shown to possess numerous non-insulin-dependent functions, including stimulation of cell survival and modulation of peripheral energy disposal (liver and muscle) (50). The findings of this study corroborate such reports and further exemplify the importance of the non-insulinotropic effects of GIP and GLP-1 in the regulation of glucose homeostasis.…”

Section: Discussionsupporting

confidence: 82%

“…In one such study, Terrettaz et al (29) tested HGO and GDR responses in obese Zucker rats over a wide range of insulin concentrations, allowing a comprehensive evaluation of both responsiveness (the efficacy or magnitude of the response to insulin) and sensitivity (the potency or EC 50 of the response to insulin) to the hormone. The authors concluded that the obese animals demonstrate marked hepatic insulin resistance (characterized by a fully responsive yet right-shifted HGO and severely impaired glucose disposal (characterized by a total lack of responsiveness over a wide range of insulin concentrations) compared with lean littermates (29).…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat

et al. 2002

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Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and ␤-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg ⅐ kg -1 ⅐ day -1 for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU ⅐ kg -1 ⅐ min -1 and included a constant infusion of [ 3 H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction ϳ6 mol ⅐ kg -1 ⅐ min -1 ) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in ␤-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat

et al. 2002

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“…We had previously observed in normal rats that Ex-4, but not Ex-9, stimulated muscle glycogen synthesis, through an increase in the activity of glycogen synthase a, and also glucose oxidation and utilization, as did GLP-1 (7). In the present study, we found that, in normal rat skeletal muscle, Ex-4 enhanced glucose uptake, with an equal and higher potency, respectively, than that previously reported for insulin and GLP-1 (28).…”

Section: Discussionmentioning

confidence: 78%

“…Ex-4, like GLP-1, is insulinotropic (4), and has GLP-1-and insulin-like effects on parameters related to glucose or lipid metabolism in extrapancreatic tissues. Ex-4 increases glucose transport in rat adipocytes (5) and human myocytes (6), and glycogen synthase a activity in rat liver and rat and human muscle (7,8), and stimulates lipogenesis and lipolysis in rat fat tissue (5). The reported extrapancreatic effects of Ex-4 seem to be dependent on certain kinases, some of which also participate in GLP-1 action (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…The Ex-4 truncated form, exendin(9-39)amide (Ex-9), is an antagonist of GLP-1 receptor in several cell systems (3,13) and of its insulinotropic effects in rat pancreas (14), and of GLP-1 action upon glucose metabolism in rat liver cells and muscle tissue (7); however, in adipocyte (15) and myocyte (16) cell lines, and in normal human muscle (6,8), Ex-9 acts as an agonist of GLP-1 action.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle

Arnés

González²,

Tornero-Esteban³

et al. 2008

Int J Mol Med

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Abstract. Exendin-4, a peptide 53% structurally homologous with glucagon-like peptide 1 (GLP-1), is insulinotropic and has an antidiabetic effect even more prolonged than that of GLP-1. Exendin-9 is an antagonist of GLP-1 receptor and action in several cell systems, but shows GLP-1-and exendin-4-agonistic characteristics in human muscle cells and tissue. The action of GLP-1 upon glucose transport and metabolism in muscle is mediated by specific receptors. In this study we investigated the effect of both exendin-4 and -9, relative to that of GLP-1, upon glucose transport and metabolism in the skeletal muscle from a streptozotocin-induced type 2 diabetic rat model, compared to normal. In normal rats, exendin-4, like GLP-1 and insulin, enhanced glucose uptake. This effect, which is mediated to a certain extent by some kinases (PI3K/ PKB, p70s6k and MAPKs), may be caused by the peptide acting, at least in part, through the muscle GLP-1 receptors. Exendin-9 also stimulated the same kinases, except for PKB, but failed to modify basal glucose uptake. Type 2 diabetic rats showed lower than normal basal muscle glucose transport and oxidation value, and higher glycogen synthase a activity and pyruvate release; however, no modification of glucose uptake by GLP-1 or exendin-4 was detected, at variance with insulin, and basal activity of PI3K/PKB was lower than normal, while that of p70s6k and MAPKs was higher. GLP-1 failed to affect the activity of any of the kinases, while exendin-4 increased the activity of PI3K, p70s6k and MAPKs, but not PKB, suggesting that this enzyme plays a major role in exendin-4 effect upon glucose transport in muscle.

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Gut Peptide Agonism in the Treatment of Obesity and Diabetes

Grandl

Novikoff

DiMarchi

et al. 2019

Comprehensive Physiology

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Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism.

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Exendin-4 Agonist and Exendin(9-39)amide Antagonist of the GLP-1(7-36)amide Effects in Liver and Muscle

Cited by 72 publications

References 25 publications

Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat

Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat

Characteristics of GLP-1 and exendins action upon glucose transport and metabolism in type 2 diabetic rat skeletal muscle

Gut Peptide Agonism in the Treatment of Obesity and Diabetes

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