Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine
Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potenti...
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creator | Li, Changhong Liu, Chengyang Nissim, Itzhak Chen, Jie Chen, Pan Doliba, Nicolai Zhang, Tingting Nissim, Ilana Daikhin, Yevgeny Stokes, David Yudkoff, Marc Bennett, Michael J. Stanley, Charles A. Matschinsky, Franz M. Naji, Ali |
description | Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels.
Background: β-Cells regulate α-cells via paracrine mechanisms.
Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by γ-hydroxybutyrate produced by β-cells but is stimulated by glycine via plasma membrane receptors.
Conclusion: γ-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion.
Significance: Amino acids and their metabolites are central regulators of α-cell function. |
doi_str_mv | 10.1074/jbc.M112.385682 |
format | Article |
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Background: β-Cells regulate α-cells via paracrine mechanisms.
Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by γ-hydroxybutyrate produced by β-cells but is stimulated by glycine via plasma membrane receptors.
Conclusion: γ-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion.
Significance: Amino acids and their metabolites are central regulators of α-cell function.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M112.385682</identifier><identifier>PMID: 23266825</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Diabetes ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes Mellitus, Type 2 - pathology ; Female ; GABA Shunt ; gamma-Aminobutyric Acid - metabolism ; Glucagon - metabolism ; Glucagon Secretion ; Glucagon-Secreting Cells - metabolism ; Glucagon-Secreting Cells - pathology ; Glucose - metabolism ; Glycine - metabolism ; Glycine Receptors ; Humans ; Insulin Secretion ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; Male ; Metabolism ; Middle Aged ; Receptors, GABA - metabolism ; Receptors, Glycine - metabolism ; Sodium Oxybate - metabolism ; β-Cell ; γ-Hydroxybutyrate</subject><ispartof>The Journal of biological chemistry, 2013-02, Vol.288 (6), p.3938-3951</ispartof><rights>2013 © 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-bacaa68d78ff4ac0e908d62ca58866f073139bb2eb25a093bb7e4d689dc865d33</citedby><cites>FETCH-LOGICAL-c443t-bacaa68d78ff4ac0e908d62ca58866f073139bb2eb25a093bb7e4d689dc865d33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567647/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567647/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23266825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Changhong</creatorcontrib><creatorcontrib>Liu, Chengyang</creatorcontrib><creatorcontrib>Nissim, Itzhak</creatorcontrib><creatorcontrib>Chen, Jie</creatorcontrib><creatorcontrib>Chen, Pan</creatorcontrib><creatorcontrib>Doliba, Nicolai</creatorcontrib><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Nissim, Ilana</creatorcontrib><creatorcontrib>Daikhin, Yevgeny</creatorcontrib><creatorcontrib>Stokes, David</creatorcontrib><creatorcontrib>Yudkoff, Marc</creatorcontrib><creatorcontrib>Bennett, Michael J.</creatorcontrib><creatorcontrib>Stanley, Charles A.</creatorcontrib><creatorcontrib>Matschinsky, Franz M.</creatorcontrib><creatorcontrib>Naji, Ali</creatorcontrib><title>Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels.
Background: β-Cells regulate α-cells via paracrine mechanisms.
Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by γ-hydroxybutyrate produced by β-cells but is stimulated by glycine via plasma membrane receptors.
Conclusion: γ-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion.
Significance: Amino acids and their metabolites are central regulators of α-cell function.</description><subject>Adult</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetes Mellitus, Type 2 - pathology</subject><subject>Female</subject><subject>GABA Shunt</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glucagon - metabolism</subject><subject>Glucagon Secretion</subject><subject>Glucagon-Secreting Cells - metabolism</subject><subject>Glucagon-Secreting Cells - pathology</subject><subject>Glucose - metabolism</subject><subject>Glycine - metabolism</subject><subject>Glycine Receptors</subject><subject>Humans</subject><subject>Insulin Secretion</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Male</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Receptors, GABA - metabolism</subject><subject>Receptors, Glycine - metabolism</subject><subject>Sodium Oxybate - metabolism</subject><subject>β-Cell</subject><subject>γ-Hydroxybutyrate</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kctu1DAUhi0EotPCmh3ykk2mviSOs0FCLcxUKiBxkdhZvpwMrpy42ElFnov36DPh6ZQKFnhj6_jzf478IfSCkjUlbX16Zez6PaVszWUjJHuEVpRIXvGGfnuMVoQwWnWskUfoOOcrUlbd0afoiHEmCt6sUP8JdnPQk48jjj3ehNnqXTl_BpvgrupH_CGmQQesR4fPvTalbvF2HvSIL3KAKWOz4Ntf1XZxKf5czDwtSU9wx2_CYv0Iz9CTXocMz-_3E_T13dsvZ9vq8uPm4uzNZWXrmk-V0VZrIV0r-77WlkBHpBPM6kZKIXrScso7YxgY1mjScWNaqJ2QnbNSNI7zE_T6kHs9mwGchXFKOqjr5AedFhW1V__ejP672sUbxRvRirotAa_uA1L8MUOe1OCzhRD0CHHOijIpurplYt_r9IDaFHNO0D-0oUTt7ahiR-3tqIOd8uLl39M98H90FKA7AFD-6MZDUtl6GC04n8BOykX_3_DfgJehuQ</recordid><startdate>20130208</startdate><enddate>20130208</enddate><creator>Li, Changhong</creator><creator>Liu, Chengyang</creator><creator>Nissim, Itzhak</creator><creator>Chen, Jie</creator><creator>Chen, Pan</creator><creator>Doliba, Nicolai</creator><creator>Zhang, Tingting</creator><creator>Nissim, Ilana</creator><creator>Daikhin, Yevgeny</creator><creator>Stokes, David</creator><creator>Yudkoff, Marc</creator><creator>Bennett, Michael J.</creator><creator>Stanley, Charles A.</creator><creator>Matschinsky, Franz M.</creator><creator>Naji, Ali</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130208</creationdate><title>Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine</title><author>Li, Changhong ; Liu, Chengyang ; Nissim, Itzhak ; Chen, Jie ; Chen, Pan ; Doliba, Nicolai ; Zhang, Tingting ; Nissim, Ilana ; Daikhin, Yevgeny ; Stokes, David ; Yudkoff, Marc ; Bennett, Michael J. ; Stanley, Charles A. ; Matschinsky, Franz M. ; Naji, Ali</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-bacaa68d78ff4ac0e908d62ca58866f073139bb2eb25a093bb7e4d689dc865d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetes Mellitus, Type 2 - pathology</topic><topic>Female</topic><topic>GABA Shunt</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>Glucagon - metabolism</topic><topic>Glucagon Secretion</topic><topic>Glucagon-Secreting Cells - metabolism</topic><topic>Glucagon-Secreting Cells - pathology</topic><topic>Glucose - metabolism</topic><topic>Glycine - metabolism</topic><topic>Glycine Receptors</topic><topic>Humans</topic><topic>Insulin Secretion</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Male</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Receptors, GABA - metabolism</topic><topic>Receptors, Glycine - metabolism</topic><topic>Sodium Oxybate - metabolism</topic><topic>β-Cell</topic><topic>γ-Hydroxybutyrate</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Changhong</creatorcontrib><creatorcontrib>Liu, Chengyang</creatorcontrib><creatorcontrib>Nissim, Itzhak</creatorcontrib><creatorcontrib>Chen, Jie</creatorcontrib><creatorcontrib>Chen, Pan</creatorcontrib><creatorcontrib>Doliba, Nicolai</creatorcontrib><creatorcontrib>Zhang, Tingting</creatorcontrib><creatorcontrib>Nissim, Ilana</creatorcontrib><creatorcontrib>Daikhin, Yevgeny</creatorcontrib><creatorcontrib>Stokes, David</creatorcontrib><creatorcontrib>Yudkoff, Marc</creatorcontrib><creatorcontrib>Bennett, Michael J.</creatorcontrib><creatorcontrib>Stanley, Charles A.</creatorcontrib><creatorcontrib>Matschinsky, Franz M.</creatorcontrib><creatorcontrib>Naji, Ali</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Changhong</au><au>Liu, Chengyang</au><au>Nissim, Itzhak</au><au>Chen, Jie</au><au>Chen, Pan</au><au>Doliba, Nicolai</au><au>Zhang, Tingting</au><au>Nissim, Ilana</au><au>Daikhin, Yevgeny</au><au>Stokes, David</au><au>Yudkoff, Marc</au><au>Bennett, Michael J.</au><au>Stanley, Charles A.</au><au>Matschinsky, Franz M.</au><au>Naji, Ali</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2013-02-08</date><risdate>2013</risdate><volume>288</volume><issue>6</issue><spage>3938</spage><epage>3951</epage><pages>3938-3951</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels.
Background: β-Cells regulate α-cells via paracrine mechanisms.
Results: A GABA shunt defect impairs glucose suppression of glucagon secretion in diabetic human islets. Glucagon secretion is inhibited by γ-hydroxybutyrate produced by β-cells but is stimulated by glycine via plasma membrane receptors.
Conclusion: γ-Hydroxybutyrate and glycine serve as counterbalancing receptor-based regulators of glucagon secretion.
Significance: Amino acids and their metabolites are central regulators of α-cell function.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23266825</pmid><doi>10.1074/jbc.M112.385682</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Diabetes Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - pathology Female GABA Shunt gamma-Aminobutyric Acid - metabolism Glucagon - metabolism Glucagon Secretion Glucagon-Secreting Cells - metabolism Glucagon-Secreting Cells - pathology Glucose - metabolism Glycine - metabolism Glycine Receptors Humans Insulin Secretion Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - pathology Male Metabolism Middle Aged Receptors, GABA - metabolism Receptors, Glycine - metabolism Sodium Oxybate - metabolism β-Cell γ-Hydroxybutyrate |
title | Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by γ-Hydroxybutyrate and Glycine |
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