Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice

Song, Youngmi; Koehler, Jacqueline A.; Baggio, Laurie L.; Powers, Alvin C.; Sandoval, Darleen A.; Drucker, Daniel J.

doi:10.1016/j.cmet.2019.08.009

Cited by 96 publications

(85 citation statements)

References 50 publications

(83 reference statements)

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“…2A,B), consistent with the higher number of GLP-1-positive cells observed in Fig. 1 as well as with a recent work comparing mouse vs. human pancreatic GLP-1 16 . We then tested whether paracrine GLP-1 signaling is necessary for normal glucose-stimulated insulin secretion by performing static GSIS studies in the presence of exendin-(9-39) (Ex9), a specific GLP-1 receptor (GLP-1R) antagonist 17 .…”

Section: Resultssupporting

confidence: 92%

“…All animals used in this study were housed in facilities with a standard light-dark cycle and fed ad libitum. Pancreatic mouse islets were isolated from male [12][13][14][15][16] week old C57BL/6J and B6.Cg-Lep ob /J (ob/ob) (Jackson Laboratory, ME) as described previously 52 . Briefly, islets were isolated by collagenase digestion and Histopaque gradient (Sigma, #10771).…”

Section: Methodsmentioning

confidence: 99%

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Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

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Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.The precise control of blood glucose is dependent on the islets of Langerhans located within the pancreas. Pancreatic islets are complex structures consisting of several types of cells, including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing α-cells. After feeding, nutrients stimulate insulin release by the β-cell and the circulating hormone acts on peripheral tissues lowering blood glucose. The full stimulation of insulin secretion after food intake depends on the incretin effect of gut-derived peptide hormones and paracrine signaling within the islet 1 .We and others discovered that two classic gut hormones, glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), are also produced by pancreatic islets 2-5 . GLP-1 is a peptide hormone mainly secreted by intestinal L-cells and is known to decrease blood glucose levels by enhancing β-cell insulin secretion 6 . CCK is a peptide hormone mainly secreted by intestinal I-cells and is involved in the digestion of nutrients 7 and regulation of food intake 8 . The production of both GLP-1 and CCK in the islet has been associated with β-cell expansion and survival in response to metabolic stress 5,9 . While each of these gut-derived hormones can contribute to improvements in glucose homeostasis 10,11 , it is unclear whether their local production in the islet contributes to β-cell function. Moreover, it is unknown whether CCK stimulates insulin release in human islets. Here, we describe experiments with GLP-1 and CCK receptor antagonists in isolated mouse and human islets to ass...

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…The reason for this discrepancy may be that different parts of intestine were investigated (the lower ileum in our study, while the proximal duodenum in Gu et al ’s study16). A recent study showed that deletion of Gcg gene in the mouse distal gut reduced the plasma active GLP-1 levels, highlighting the essential role of the distal gut in the regulation of GLP-1 secretion 30. Considering the distribution of L-cells, the lower ileum was more suitable for evaluating L-cell mass and GLP-1 content than the proximal duodenum.…”

Section: Discussionmentioning

confidence: 99%

“…Of course, further studies investigating L-cells in the entire intestinal tract are needed to provide detailed changes of the L-cell mass. Although gut-derived GLP-1 is essential for glucose homeostasis,30 it is worth noting that we could not exclude other sources of GLP-1. For example, our previous study showed that pancreatic α-cells could express PC1/3 and process Gcg into GLP-1 after GCGR mAb treatment,6 suggesting that the increased plasma GLP-1 level might also derive from pancreatic α-cells.…”

Section: Discussionmentioning

confidence: 99%

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Lang

Yang

et al. 2020

BMJ Open Diab Res Care

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ObjectiveGlucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified.Research design and methodsREMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways.ResultsTreatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production.ConclusionsThe elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D.

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“…We purchased male and female C57BL/6 mice for use in experiments and breeding from the Jackson Laboratory. Lepr cre , Ppg cre , and Ppg fl mice have been described (16,20,34,35) and were propagated by intercrossing homozygous mice of the same genotype. Cck cre mice were purchased from the Jackson Laboratory (stock no.…”

Section: Methodsmentioning

confidence: 99%

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

Cheng¹,

Ndoka²,

Hutch³

et al. 2020

JCI Insight

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Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice

Cited by 96 publications

References 50 publications

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

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