β Cell tone is defined by proglucagon peptides through cAMP signaling
Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through...
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| Published in | JCI insight Vol. 4; no. 5 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
07.03.2019
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| Online Access | Get full text |
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| Abstract | Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control. |
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| AbstractList | Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control.
Proglucagon derived peptides from α-cells are essential to determine the tone of insulin secretion in β-cells. Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control. |
| Author | Campbell, Jonathan E Jaffe, Justin L Lewandowski, Sophie L Haldeman, Jonathan M Lin, Haopeng Capozzi, Megan E MacDonald, Patrick E Martin, Mackenzie D Coch, Reilly W D'Alessio, David A Merrins, Matthew J Encisco, Sara E Svendsen, Berit |
| AuthorAffiliation | 5 Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA 2 Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin–Madison, Madison, Wisconsin, USA 1 Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA 3 Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Alberta, Canada 4 Department of Medicine and |
| AuthorAffiliation_xml | – name: 2 Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin–Madison, Madison, Wisconsin, USA – name: 5 Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA – name: 1 Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – name: 3 Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Alberta, Canada – name: 4 Department of Medicine and |
| Author_xml | – sequence: 1 givenname: Megan E surname: Capozzi fullname: Capozzi, Megan E organization: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – sequence: 2 givenname: Berit surname: Svendsen fullname: Svendsen, Berit organization: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – sequence: 3 givenname: Sara E surname: Encisco fullname: Encisco, Sara E organization: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – sequence: 4 givenname: Sophie L surname: Lewandowski fullname: Lewandowski, Sophie L organization: Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, Wisconsin, USA – sequence: 5 givenname: Mackenzie D surname: Martin fullname: Martin, Mackenzie D organization: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – sequence: 6 givenname: Haopeng surname: Lin fullname: Lin, Haopeng organization: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Alberta, Canada – sequence: 7 givenname: Justin L surname: Jaffe fullname: Jaffe, Justin L organization: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA – sequence: 8 givenname: Reilly W surname: Coch fullname: Coch, Reilly W organization: Department of Medicine and – sequence: 9 givenname: Jonathan M surname: Haldeman fullname: Haldeman, Jonathan M organization: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA – sequence: 10 givenname: Patrick E surname: MacDonald fullname: MacDonald, Patrick E organization: Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Alberta, Canada – sequence: 11 givenname: Matthew J surname: Merrins fullname: Merrins, Matthew J organization: Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, Wisconsin, USA – sequence: 12 givenname: David A surname: D'Alessio fullname: D'Alessio, David A organization: Department of Medicine and – sequence: 13 givenname: Jonathan E surname: Campbell fullname: Campbell, Jonathan E organization: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30720465$$D View this record in MEDLINE/PubMed |
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| Title | β Cell tone is defined by proglucagon peptides through cAMP signaling |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/30720465 https://search.proquest.com/docview/2179536527 https://pubmed.ncbi.nlm.nih.gov/PMC6483521 |
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