Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus

León, Diva D. De; Crutchlow, Michael F.; Ham, J. Nina; Stoffers, Doris A.

doi:10.1016/j.biocel.2005.07.011

Cited by 82 publications

(65 citation statements)

References 158 publications

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“…Glucose tolerance testing on day 15 did not reveal a deleterious impact of tacrolimus on glucose tolerance over this time frame, and Ex-4 exerted its well described beneficial effects on glucose tolerance independent of tacrolimus administration (supplemental Fig. 3) (15). No differences in body weight or insulin sensitivity were detected among the four treatment groups (supplemental Fig.…”

Section: Resultsmentioning

confidence: 76%

“…The GLP-1 receptor agonist exendin-4 (Ex-4) improves rodent ␤-cell replication and survival in multiple models (15). GLP-1 receptor activation has been implicated in increasing rodent ␤-cell replication through multiple trophic pathways, including MAP kinase (16) and downstream of the epidermal growth factor receptor (EGFR) (17), but many of its effects have been associated with the activation of CREB.…”

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confidence: 99%

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Calcineurin Signaling Regulates Human Islet β-Cell Survival

Soleimanpour

Crutchlow

Ferrari

et al. 2010

Journal of Biological Chemistry

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143

114

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The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic ␤-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant ␤-cell failure. We sought to determine the effect of calcineurin inhibition on ␤-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue ␤-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human ␤-cell apoptosis was significantly increased. Although we detected no human ␤-cell replication, tacrolimus significantly decreased rodent ␤-cell replication. Ex-4 nearly normalized both human ␤-cell survival and rodent ␤-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/ Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in ␤-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurinsensitive manner. Ex-4 restored Irs2 expression in tacrolimustreated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human ␤-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.New onset diabetes mellitus is a major complication following solid organ transplantation, often leading to decreased graft survival and increased mortality (1-3). As with other forms of diabetes, hyperglycemia ensues when there is inadequate pancreatic ␤-cell mass to meet insulin demand (4). Post-transplant diabetes is strongly associated with the use of calcineurin inhibitors, antirejection medications that are widely used in clinical solid organ transplantation (5). This association has prompted long-standing speculation that the calcineurin inhibitors are ␤-cell toxic and pathogenic in transplant-related ␤-cell failure.Calcineurin is a calcium-activated cytosolic phosphatase that is critical for antigen-stimulated T lymphocyte activation (6). Therefore, pharmacologic calcineurin inhibition is highly effective in preventing allograft rejection. However, calcineurin is also expressed in ␤-cells where it has two well described molecular targets, the nuclear factor of activated T cell (NFAT) 2 family of transcription factors (7), and the cAMP-responsive element-binding protein (CREB) transcriptional co-activator, transducer of regulated CREB activity-2 (TO...

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Section: Resultsmentioning

confidence: 76%

mentioning

confidence: 99%

Calcineurin Signaling Regulates Human Islet β-Cell Survival

Soleimanpour

Crutchlow

Ferrari

et al. 2010

Journal of Biological Chemistry

Self Cite

143

114

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“…Previous studies have shown both GIP and GLP-1 stimulate β-cell proliferation, differentiation, and prevent apoptosis [3][4][5][6]. GLP-1 also has some actions such as inhibition of glucagon secretion and food intake, glucose homeostasis and slowing the gastric emptying [7][8][9]. However, GLP-1 has a short half-life of 1-2 min following secretion in response to the nutrients ingestion because of its inactivation by dipeptidyl peptidase-IV (DPP-IV) [10], resulting in loss of insulinotropic activities.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase-IV Inhibitory Activity of Peptides in Porcine Skin Gelatin Hydrolysates

Hsu¹,

Tung²,

Huang³

et al. 2013

Bioactive Food Peptides in Health and Disease

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“…The beneficial effects of glucagon-like peptide 1 (GLP-1) and its related substances such as inhibitors of dipeptidyl peptidase IV, its degrading enzyme, on the pancreatic b-cells have been reported; these agents enhance insulin release, increase (pro)insulin biosynthesis, promote b-cell development/ replication, and prevent b-cell exhaustion under the diabetic conditions (Drucker 2003, Leon et al 2005. These effects are considered to result from an increase in the b-cell cAMP content (Thorens 1992), while cAMP-independent mechanisms of GLP-1 have also been suggested in other types of cells (Montrose-Rafizadeh et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

Tsunekawa

Yamamoto

Tsukamoto

et al. 2007

Journal of Endocrinology

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The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic b-cells against their cell death. In in vivo experiments, we used b-cell-specific calmodulinoverexpressing mice where massive apoptosis takes place in their b-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1 a, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in b-cellspecific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic b-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

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Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus

Cited by 82 publications

References 158 publications

Calcineurin Signaling Regulates Human Islet β-Cell Survival

Calcineurin Signaling Regulates Human Islet β-Cell Survival

Dipeptidyl Peptidase-IV Inhibitory Activity of Peptides in Porcine Skin Gelatin Hydrolysates

Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

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