188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes
Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. System...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2022-06, Vol.71 (Supplement_1) |
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description | Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles. |
doi_str_mv | 10.2337/db22-188-OR |
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There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db22-188-OR</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Adoptive transfer ; Amylin ; Beta cells ; CD25 antigen ; CD4 antigen ; CD8 antigen ; Cell activation ; Cell proliferation ; Chemokines ; Deoxyglucose ; Diabetes ; Diabetes mellitus (insulin dependent) ; Drinking water ; Flow cytometry ; Glycolysis ; Hyperglycemia ; Inflammation ; Insulin ; Lymphocytes ; Lymphocytes T ; Metabolism ; Oxidative phosphorylation ; Peptides ; Phosphorylation ; Splenocytes ; β-Amyloid ; γ-Interferon</subject><ispartof>Diabetes (New York, N.Y.), 2022-06, Vol.71 (Supplement_1)</ispartof><rights>Copyright American Diabetes Association Jun 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>CHAVEZ, MIRANDA D.</creatorcontrib><creatorcontrib>MCDOWELL, RUTH</creatorcontrib><creatorcontrib>TSE, HUBERT M.</creatorcontrib><title>188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes</title><title>Diabetes (New York, N.Y.)</title><description>Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles.</description><subject>Adoptive transfer</subject><subject>Amylin</subject><subject>Beta cells</subject><subject>CD25 antigen</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Cell proliferation</subject><subject>Chemokines</subject><subject>Deoxyglucose</subject><subject>Diabetes</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Drinking water</subject><subject>Flow cytometry</subject><subject>Glycolysis</subject><subject>Hyperglycemia</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Metabolism</subject><subject>Oxidative phosphorylation</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Splenocytes</subject><subject>β-Amyloid</subject><subject>γ-Interferon</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNotkF1LwzAUhoMoWKdX_oGAl1LNx5K03s1tTmEyGL0QvAhpeoKddalJJ_Tf2zo5F-fifXjP4UHompI7xrm6r0rGUppl6WZ7ghKa8zzlTL2dooQQOiQqV-foIsYdIUQOk6D3I_2AX6EzpW9qix8bbz9NBdg7vGp665s-1hHPzR4voDE97j4AzyrfdvUP4CKYfXQQRrroW8AUL2pTQgfxEp0500S4-t8TVDwti_lzut6sXuazdWrllKWyckZkBPjwUGm5s9SoXCoGruJuygVlVoAtrZI5r8iQG8YEB0Yyo5jkjE_QzbG2Df77ALHTO38I--GiZjITIsvFH3V7pGzwMQZwug31lwm9pkSP8vQoTw869GbLfwEAB2AO</recordid><startdate>20220601</startdate><enddate>20220601</enddate><creator>CHAVEZ, MIRANDA D.</creator><creator>MCDOWELL, RUTH</creator><creator>TSE, HUBERT M.</creator><general>American Diabetes Association</general><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20220601</creationdate><title>188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes</title><author>CHAVEZ, MIRANDA D. ; MCDOWELL, RUTH ; TSE, HUBERT M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c642-6dfa580e3606bc3fc1a79672efd3f43512c5ecbc7693d03fca2253e208a726323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adoptive transfer</topic><topic>Amylin</topic><topic>Beta cells</topic><topic>CD25 antigen</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>Cell proliferation</topic><topic>Chemokines</topic><topic>Deoxyglucose</topic><topic>Diabetes</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Drinking water</topic><topic>Flow cytometry</topic><topic>Glycolysis</topic><topic>Hyperglycemia</topic><topic>Inflammation</topic><topic>Insulin</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Metabolism</topic><topic>Oxidative phosphorylation</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Splenocytes</topic><topic>β-Amyloid</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHAVEZ, MIRANDA D.</creatorcontrib><creatorcontrib>MCDOWELL, RUTH</creatorcontrib><creatorcontrib>TSE, HUBERT M.</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHAVEZ, MIRANDA D.</au><au>MCDOWELL, RUTH</au><au>TSE, HUBERT M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2022-06-01</date><risdate>2022</risdate><volume>71</volume><issue>Supplement_1</issue><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Type 1 diabetes (T1D) is a result of insulin-secreting pancreatic β-cell destruction by autoreactive CD4 and CD8 T cells. There is no cure for T1D, but determining the role of immunometabolism in promoting autoreactive CD4+ T cell effector responses may provide a novel target in delaying T1D. Systemically inhibiting glycolysis with 2-deoxyglucose (2-DG) can decrease autoreactive CD8 T cell islet infiltration. However, the effects of 2-DG on CD4 T cell diabetogenicity is unknown. Proinflammatory Th1 cells mediate β-cell destruction prefer glycolysis for maintaining effector responses, while immunosuppressive Treg cells prefer oxidative phosphorylation. We hypothesize that metabolic inhibition of glycolysis will diminish proinflammatory Th1 cell responses and delay β-cell destruction in T1D. Utilizing 2-DG, we performed an adoptive transfer of diabetogenic CD4+ T cells from NOD.BDC-2.5 or NOD.BDC-6.9 mice into NOD.scid mice. Recipient mice were systemically treated with 30 mM 2-DG in the drinking water beginning 4 days prior to adoptive transfer and monitored for hyperglycemia for 80 days post-transfer. NOD.scid mice treated with 2-DG had a significant delay in diabetes onset when transferred with either BDC-2.5 (n=14, p=0.0284) or BDC-6.9 (n=17, p=0.0249) CD4+ T cells compared to vehicle-treated groups. To define the effects of 2-DG on autoreactive CD4 T cell effector responses, NOD.BDC-6.9 splenocytes were in vitro stimulated with their cognate hybrid insulin peptide (HIP; insulin C-peptide and islet amyloid polypeptide) with or without 2-DG. Flow cytometry analysis revealed a decrease in T cell proliferation, T cell activation, and Th1 lineage commitment as shown by Ki67, CD25, and T-bet expression, respectively. Effector responses were also dampened as IFN-γ synthesis was decreased in our 2-DG treatment group compared to HIP only controls. Future studies will investigate the effects of 2-DG on CD4 T cell chemokine secretion, trafficking into the islet, and cellular metabolic profiles.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db22-188-OR</doi></addata></record> |
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subjects | Adoptive transfer Amylin Beta cells CD25 antigen CD4 antigen CD8 antigen Cell activation Cell proliferation Chemokines Deoxyglucose Diabetes Diabetes mellitus (insulin dependent) Drinking water Flow cytometry Glycolysis Hyperglycemia Inflammation Insulin Lymphocytes Lymphocytes T Metabolism Oxidative phosphorylation Peptides Phosphorylation Splenocytes β-Amyloid γ-Interferon |
title | 188-OR: Metabolic Blockade of Glycolysis Can Delay the Adoptive Transfer of Type 1 Diabetes |
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