Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats

Nie, Ying; Nakashima, Masahiro; Brubaker, Patricia L.; Li, Qiaoling; Perfetti, Riccardo; Jansen, Erik; Zambre, Yasmeen; Pipeleers, Daniël; Friedman, Theodore C.

doi:10.1172/jci7456

Cited by 157 publications

(153 citation statements)

References 71 publications

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Section: Discussionmentioning

confidence: 98%

“…Rats treated with intraperitoneal STZ for 5 days exhibited increased pancreatic levels of prohormone convertase-1, the primary enzyme responsible for liberation of GLP-1 from proglucagon (55). Furthermore, the levels of bioactive GLP-1(7-36 amide) were significantly elevated in the circulation and pancreas of STZ-treated diabetic rats (55). These findings suggest that at least some types of experimental diabetes associated with ␤-cell injury may be characterized by enhanced liberation of both pancreatic and intestinal GLP-1, which may have physiological implications for protection of vulnerable ␤ cells from further cell death.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis

Li¹,

Hansotia²,

Yusta³

et al. 2003

Journal of Biological Chemistry

556

379

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments ␤ cell mass via activation of ␤ cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce ␤ cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced ␤ cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased ␤ cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat ␤ cells exposed to interleukin 1␤, tumor necrosis fator ␣, and interferon ␥ in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of ␤-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of ␤ cell mass in vivo.Glucagon-like peptide-1 (GLP-1) 1 is derived from posttranslational processing of proglucagon in enteroendocrine L cells (1) and is secreted from the distal gut after nutrient ingestion (2). The termination of GLP-1 action by the enzyme dipeptidyl peptidase IV occurs within minutes following GLP-1 secretion (3-5), yet GLP-1 exerts several rapid metabolic actions including stimulation and inhibition of insulin and glucagon secretion, respectively (6 -10). GLP-1 action is essential for glucose homeostasis, because GLP-1 receptor blockade with the antagonist exendin (9 -39) increases blood glucose and decreases levels of circulating insulin in human and rodent studies (11)(12)(13)(14).Activation of GLP-1 receptor signaling leads to enhanced expression of mRNA transcripts for glucokinase, GLUT-2, Pdx-1, and insulin in ␤ cell lines (15-17) and in both normal and diabetic rodents (18 -20). Furthermore, GLP-1 and exendin-4 promote differentiation of exocrine cell lines toward a ␤ cell phenotype (21), a process that appears to depend on the expression of Pdx-1 (22, 23).GLP-1 receptor signaling is also coupled to formation of new ␤ cells through enhanced proliferation of existing ␤ cells (24) and via induction of islet neogenesis (25). The mitogenic actions of GLP-1 are detectable in normal rodents (20,24) and in the setting of experimental diabetes (19,25). Administration of GLP-1 or exendin-4 to newborn rats treated with the ␤ cell toxin streptozotocin (STZ) leads to increased ␤ cell mass at postnatal day 7, which persists and remains increased at 2 months of age. The increased ␤ cell mass in the GLP-1/exendin-4 treated rats was attributed to both enhan...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis

Li¹,

Hansotia²,

Yusta³

et al. 2003

Journal of Biological Chemistry

556

379

View full text Add to dashboard Cite

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“…However the addition of the GLP-1R antagonist Ex (9-39) retarded the recovery of the endocrine pancreas from STZ treatment exhibiting intolerance to glucose. Similarly adult rats in a low dose STZ protocol also exhibited higher levels of circulating GLP-1 and intraislet GLP-1 immunoreactivity (Nie et al, 2000).…”

Section: Effects Of Glp-1r Activation During Pancreatic Development Amentioning

confidence: 91%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

583

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…The alpha cells are in close proximity to the GLP-1 receptors on the beta cells, and alpha cells may, if GLP-1 production is switched on, provide a continuous beneficial supply of GLP-1 to the neighbouring beta cells. In support of this view it has recently been shown that rats with streptozotocin-induced beta cell loss display increased islet GLP-1 production [18,19]. Recently it was elegantly shown by adenovirus introduction of PC1/3 in islet glucagon cells that GLP-1 can be released and act locally to improve islet function [15].…”

Section: Introductionmentioning

confidence: 94%