Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

Moffett, R. Charlotte; Vasu, Srividya; Thorens, Bernard; Drucker, Daniel J.; Flatt, Peter R.

doi:10.1371/journal.pone.0096863

Cited by 68 publications

(64 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is indeed known that PC1 expression and GLP-1 release from ␣ cells is increased in a variety of mouse models of hyperglycemia (19,(35)(36)(37). Also, circulating bile acid concentrations are elevated in type 2 diabetes (38 -41) and could potentially mediate such effects.…”

Section: Discussionmentioning

confidence: 99%

Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

Kumar

Asgharpour

Mirshahi

et al. 2016

Journal of Biological Chemistry

110

View full text Add to dashboard Cite

The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic ␤ cells by bile acids induces insulin secretion. Glucagon released from pancreatic ␣ cells and glucagonlike peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic ␣ cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases ␤ cell mass and function in a paracrine manner. (11,12). Recently, TGR5 receptors have been identified on both pancreatic islet ␣ and ␤ cells (13,14). We have previously demonstrated that TGR5 activation on ␤ cells can increase insulin secretion (14). However, the function and physiological role of TGR5 in ␣ cells remain obscure.Glucagon and GLP-1 are produced from a common precursor proglucagon by alternate splicing mediated by proconvertase-2 (PC2) and PC1, respectively (15,16). Whereas the L cells express PC1 only, the pancreatic islet ␣ cells express both PC1 and PC2 (17). Under euglycemic conditions, PC2 activity predominates, and ␣ cells secrete mainly glucagon (18). We hypothesized that TGR5 activation by bile acids under hyperglycemia would activate PC1 as seen in L cells and switch the ␣ cell secretory phenotype from glucagon to GLP-1, which would have a trophic effect on adjacent ␤ cells in a paracrine manner. A combination of decreased systemic glucagon secretion and increased local GLP-1 production would be expected to improve insulin resistance and maintain islet ␤ cell mass. Indeed, several mouse models of diabetes such as streptozotocin-induced diabetes, prediabetic NOD mice, and both ob/ob and db/db mice are associated with increased ␣ cell PC1 and GLP-1 expression, although the mechanisms are not fully understood (19,20).

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

Kumar

Asgharpour

Mirshahi

et al. 2016

Journal of Biological Chemistry

110

View full text Add to dashboard Cite

show abstract

“…Of note, GLP2 and GLP2R expression might change following HFD, as reported in gut tissue (Rotondo et al 2011b, Baldassano et al 2013. Moreover, recent studies on glucose-dependent insulinotrophic polypeptide (GIP) and GLP1 have pointed out that both hormones are synthesized and secreted from islet α-cells under conditions of cellular stress imposed by β cytotoxic attack or increased insulin demand (Fujita et al 2010, Donath & Burcekin 2013, Moffett et al 2014. Increased expression of PC1/3 relative to PC2 in islet α-cells directs proglucagon processing away from glucagon towards GLP1 in these conditions (Wideman et al 2007, Marchetti et al 2012.…”

Section: Mechanistic Insightmentioning

confidence: 98%

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Amato¹,

Baldassano²,

Mulè³

2016

Journal of Endocrinology

View full text Add to dashboard Cite

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes.

show abstract

“…Up-regulation of GLP-1 expression in α cells has been observed in models of β cell expansion and regeneration, such as neonatal and pregnant mice, suggesting GLP-1 produced within the islets likely promotes β cell proliferation (Kilimnik et al 2010; Moffett, et al 2014; Vasu, et al 2014). Indeed, GLP-1 receptor knockout mice have been shown to have impaired β cell mass adaptation to pregnancy or in response to insulin resistance (Moffett et al 2014; Vasu et al 2014). Analysis of circulating GLP-1 concentration and intra-islet GLP-1 content indicates pregnancy or metabolic stress-induced β cell mass compensation is mediated by locally produced GLP-1 (Moffett et al 2014; Vasu et al 2014).…”

Section: The Functionality Of Intra-islet Produced Glp-1mentioning

confidence: 99%

“…Indeed, GLP-1 receptor knockout mice have been shown to have impaired β cell mass adaptation to pregnancy or in response to insulin resistance (Moffett et al 2014; Vasu et al 2014). Analysis of circulating GLP-1 concentration and intra-islet GLP-1 content indicates pregnancy or metabolic stress-induced β cell mass compensation is mediated by locally produced GLP-1 (Moffett et al 2014; Vasu et al 2014). This view is further supported by studies showing PC1/3 overexpression in α cells results in increased β cell proliferation and improved protection against STZ-induced diabetes.…”

Section: The Functionality Of Intra-islet Produced Glp-1mentioning

confidence: 99%

Intra-islet glucagon-like peptide 1

Fava

Dong

2016

Journal of Diabetes and its Complications

View full text Add to dashboard Cite

Purpose Glucagon-like peptide-1 (GLP-1) is originally identified in the gut as an incretin hormone, and it is potent in stimulating insulin secretion in the pancreas. However, increasing evidence suggests that GLP-1 is also produced locally within pancreatic islets. This review focuses on the past and current discoveries regarding intra-islet GLP-1 production and its functions. Main findings There has been a long-standing debate with regard to whether GLP-1 is produced in the pancreatic α cells. Early controversies lead to the widely accepted conclusion that the vast majority of proglucagon is processed to form glucagon in the pancreas, whereas an insignificant amount is cleaved to produce GLP-1. With technological advancements, recent studies have shown that bioactive GLP-1 is produced locally in the pancreas, and the expression and secretion of GLP-1 within islets are regulated by various factors such as cytokines, hyperglycemia, and β cell injury. Conclusions GLP-1 is produced by the pancreatic α cells, and it is fully functional as an incretin. Therefore, intra-islet GLP-1 may exert insulinotropic and glucagonostatic effects locally via paracrine and/or autocrine actions, under both normal and diabetic conditions.

show abstract

Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

Cited by 68 publications

References 63 publications

Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Intra-islet glucagon-like peptide 1

Contact Info

Product

Resources

About