Journal article
Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis
The Journal of biological chemistry, Vol.291(13), pp.6626-6640
03/25/2016
DOI: 10.1074/jbc.M115.699504
PMCID: PMC4807250
PMID: 26757816
Abstract
The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon-like 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 α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases β cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic β cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and β cells by switching from glucagon to GLP-1 to restore β cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus.
Details
- Title: Subtitle
- Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis
- Creators
- Divya P Kumar - Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298Amon Asgharpour - Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298Faridoddin Mirshahi - Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298So Hyun Park - Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507Sichen Liu - Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507Yumi Imai - Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507Jerry L Nadler - Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia 23507John R Grider - Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298Karnam S Murthy - Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298Arun J Sanyal - Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.291(13), pp.6626-6640
- DOI
- 10.1074/jbc.M115.699504
- PMID
- 26757816
- PMCID
- PMC4807250
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: RO1 DK081450, RO1 DK28300
- Language
- English
- Date published
- 03/25/2016
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094401602771
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