Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Ellingsgaard, Helga; Häuselmann, Irina; Schuler, Beat; Habib, Abdella M.; Baggio, Laurie L.; Meier, Daniel T.; Eppler, Elisabeth; Bouzakri, Karim; Wueest, Stephan; Müller, Yannick D.; Hansen, Ann Maria Kruse; Reinecke, Manfred; Konrad, Daniel; Gassmann, Max; Reimann, Frank; Halban, Philippe A.; Gromada, Jesper; Drucker, Daniel J.; Gribble, Fiona M.; Ehses, Jan A.; Donath, Marc Y.

doi:10.1038/nm.2513

Cited by 772 publications

(700 citation statements)

References 57 publications

Supporting

Mentioning

624

Contrasting

Unclassified

Order By: Relevance

“…Consistent with these findings, the overexpression of CT-1 in the liver efficiently protects rats from fulminant hepatic failure after subtotal hepatectomy [8]. Furthermore, the CT-1-related cytokine IL-6 has been shown to act as a protective agent against apoptosis induced by pro-inflammatory cytokines in murine islets [9] while also impacting beta cell function indirectly through induction of glucagon-like peptide-1 (GLP-1) secretion from neighbouring alpha cells [10]. In this context, Il6-null mice showed altered carbohydrate and lipid metabolism as well as impairment in glucose homeostasis [11].…”

Section: Introductionmentioning

confidence: 64%

“…Moreover, CT-1 treatment promotes the protection of MIN6B1 cells from apoptotic stimuli such as serum deprivation through the upregulation of pro-survival protein BCL-xL, as has been shown for cofamily member IL-6 in various cell types, including murine islets [29]. It is important to note that IL-6 has also been shown to improve beta cell function in mice mainly through an indirect route involving the induction of GLP-1 secretion from neighbouring alpha cells [10]. It will be interesting in future studies to investigate whether CT-1 also impacts alpha cell function.…”

Section: Discussionmentioning

confidence: 89%

See 1 more Smart Citation

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development.Methods The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 −/− ) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes. Results CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 −/− mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion. Conclusions/interpretation The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes.

show abstract

Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 89%

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Primary antibodies were: guinea pig polyclonal anti-swine insulin (A0564; DAKO, Carpinteria, CA, USA); mouse monoclonal anti-human/ mouse glucagon (MAB1249, clone 181402; R&D Systems, Abingdon, UK); rat monoclonal anti-somatostatin (ab30788; Abcam, Cambridge, UK); rabbit polyclonal anti-GLP-1 (ab22625; Abcam), which reacts with the mid to C terminal region of GLP-1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], enabling immunoreactivity with N terminal truncated and C terminally extended forms of GLP-1; mouse monoclonal anti-GLP-1 (HYB 147-06; BioPorto Diagnostic, Gentofte, Denmark), which is specific for the amidated C-terminus of the peptide [20]; and rabbit polyclonal antibody to PC1/3 and PC2 (Chemicon, Rosemont, IL, USA). Secondary antibodies were: Alexa Fluor 488: goat anti-guinea pig IgG, goat anti-rabbit IgG, and goat anti-mouse IgG; and Alexa Fluor 594: goat anti-mouse IgG and goat antirabbit IgG (all from Invitrogen, Molecular Probes, Leiden, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

“…Purified cell preparations were tested with 5.5 mmol/l glucose and 5.5 mmol/l glucose plus 20 mmol/l arginine. In addition, GLP-1 and glucagon release were measured from batches of 50 islets of similar size from non-diabetic and type 2 diabetic preparations, kept in M199 culture medium for 4 h. Finally, to test the bioactivity of islet-released GLP-1, experiments were performed similarly to methods previously reported [17,18], by assessing insulin release from islets exposed to cell culture medium from untreated non-diabetic human islets; this was done at 11 mmol/l glucose, and in the absence or presence of the GLP-1 receptor antagonist, exendin(9-39) (0.5 μmol/l).…”

Section: Methodsmentioning

confidence: 99%

“…More recently, a study mainly focused on the alpha cell line, αTC1-6, showed the processing of proglucagon to GLP-1, with the incretin also found in rat and human islets [16], while investigators working on the Psammomys obesus gerbil incidentally observed that human islets could release GLP-1 [17]. Finally, an extensive study in rats showed that interleukin-6 could increase GLP-1 release from L cells and alpha cells, with some of the results reproduced with human islets [18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. MethodsThe presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption-ionisation-time of flight (MALDI-TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. Diabetologia (2012) 55:3262-3272 DOI 10.1007/s00125-012-2716 Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2716-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Results Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from nondiabetic isolated islets. Conclusions/interpretation We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.

show abstract

Interorgan crosstalk in pancreatic islet function and pathology

Evans

Wei

2022

FEBS Letters

View full text Add to dashboard Cite

Pancreatic b cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance b-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.

show abstract

Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Cited by 772 publications

References 57 publications

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets

Interorgan crosstalk in pancreatic islet function and pathology

Contact Info

Product

Resources

About