The Incretin Approach for Diabetes Treatment

Holst, Jens J.; Ørskov, Cathrine

doi:10.2337/diabetes.53.suppl_3.s197

Cited by 90 publications

(57 citation statements)

References 93 publications

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“…The exploration of mechanisms underlying the function of GLP-1 and another incretin hormone, gastric inhibitory polypeptide (GIP), has led to the development of two categories of novel therapeutic agents, namely GLP-1 analogs and DPP-IV inhibitors, for diabetes and potentially its complications (11,12). In addition to targeting pancreatic ␤-cells, GLP-1 also exerts its function in many other organs or tissues (1,4,7,40).…”

mentioning

confidence: 99%

GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

Shao

Wang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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T. improves ␤-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/␤-catenin signaling in ␤-cells in vitro. Am J Physiol Endocrinol Metab 304: E1263-E1272, 2013. First published April 9, 2013 doi:10.1152/ajpendo.00600.2012.-Recent studies have demonstrated that the COOH-terminal fragment of the incretin hormone glucagonlike peptide-1 (GLP-1), a nonapeptide GLP-1(28 -36)amide, attenuates diabetes and hepatic steatosis in diet-induced obese mice. However, the effect of this nonapeptide in pancreatic ␤-cells remains largely unknown. Here, we show that in a streptozotocin-induced mouse diabetes model, GLP-1(28 -36)amide improved glucose disposal and increased pancreatic ␤-cell mass and ␤-cell proliferation. An in vitro investigation revealed that GLP-1(28 -36)amide stimulates ␤-catenin (␤-cat) Ser 675 phosphorylation in both the clonal INS-1 cell line and rat primary pancreatic islet cells. In INS-1 cells, the stimulation was accompanied by increased nuclear ␤-cat content. GLP-1(28 -36)amide was also shown to increase cellular cAMP levels, PKA enzymatic activity, and cAMP response element-binding protein (CREB) and cyclic AMP-dependent transcription factor-1 (ATF-1) phosphorylation. Furthermore, GLP-1(28 -36)amide treatment enhanced islet insulin secretion and increased the growth of INS-1 cells, which was associated with increased cyclin D1 expression. Finally, PKA inhibition attenuated the effect of GLP-1(28 -36)amide on ␤-cat Ser 675 phosphorylation and cyclin D1 expression in the INS-1 cell line. We have thus revealed the beneficial effect of GLP-1(28 -36)amide in pancreatic ␤-cells in vitro and in vivo. Our observations suggest that GLP-1(28 -36)amide may exert its effect through the PKA/␤-catenin signaling pathway.glucagon-like peptide-1; protein kinase A; Wnt; cAMP response element-binding protein; insulin; bromodeoxyuridine THE PROGLUCAGON GENE encodes both the pancreatic hormone glucagon and the gut incretin hormone glucagon-like peptide-1 (GLP-1) (15,17). The exploration of mechanisms underlying the function of GLP-1 and another incretin hormone, gastric inhibitory polypeptide (GIP), has led to the development of two categories of novel therapeutic agents, namely GLP-1 analogs and DPP-IV inhibitors, for diabetes and potentially its complications (11,12). In addition to targeting pancreatic ␤-cells, GLP-1 also exerts its function in many other organs or tissues (1,4,7,40). The GLP-1 receptor (GLP-1R)-deficient mouse line has been utilized as a powerful tool in studying the function of GLP-1 not only in pancreatic ␤-cells but also in a number of organs that are importantly involved in glucose disposal and metabolic homeostasis (7). However, studies with this mouse model, along with investigations with other tools, suggested that certain functions of GLP-1 may not be mediated by its canonical receptor GLP-1R, whereas a previously assumed inactive form of GLP-1, namely GLP-1(9 -36)amide, has the therapeutic potential in certain cardiovascular disorders (2, 25).Both G...

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confidence: 99%

GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

Shao

Wang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…The rapid degradation (circulating half-life of 2-5 min) of incretin hormones in vivo by the enzyme dipeptidyl-peptidase IV (DP4) (9,10), a significant obstacle in their therapeutic administration, has been addressed by applying natural or synthetic DP4 resistant analogues of GLP-1 (11) and GIP (12,13) instead of the native peptides. The inhibition of DP4 represents a promising approach to prolong the half-life of circulating incretin hormones (14).…”

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confidence: 99%

Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor

Parthier¹,

Kleinschmidt

Neumann³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

229

286

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Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic ␤ cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP 1-42. The hormone binds in an ␣-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, ␣-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class.glucose-dependent insulinotropic polypeptide ͉ hormone binding ͉ diabetes mellitus ͉ x-ray

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“…GLP-1 also suppresses glucagon secretion, gastric emptying, and appetite and improves pancreatic β-cell functions. It is now attracting considerable attention owing to the therapeutic benefits for type 2 diabetes [1][2][3][4][5][6][7] . However, the use of GLP-1 as a therapeutic agent is limited by its low in vivo activity.…”

Section: Introductionmentioning

confidence: 99%

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

et al. 2011

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Objective Glycosylation is generally applicable as a strategy for increasing the activity of bioactive proteins. In this study, we examined the effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1 (GLP-1) as a bioactive peptide for type 2 diabetes.Methods Noninvasive imaging studies were performed using a gamma camera after the Conclusions This study demonstrated that glycosylation significantly decreased the distribution of radiolabeled GLP-1 into the liver and increased the concentration of 2 radiolabeled GLP-1 in plasma. These results suggested that glycosylation is a useful strategy for decreasing the distribution into the liver of bioactive peptides as desirable pharmaceuticals.

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The Incretin Approach for Diabetes Treatment

Cited by 90 publications

References 93 publications

GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor

Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

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