Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes
Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes Kyohei Yamamoto 1 , Hitoshi Hashimoto 1 , Shuhei Tomimoto 1 , Norihito Shintani 1 , Jun-ichi Miyazaki 2 , Fumi Tashiro 2 , Hiroyuki Aihara 2 , Takao Nammo 3 , Min...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2003-05, Vol.52 (5), p.1155-1162 |
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| creator | YAMAMOTO, Kyohei HASHIMOTO, Hitoshi MIYAGAWA, Jun-Ichiro MATSUZAWA, Yuji KAWABATA, Yuki FUKUYAMA, Yuji KOGA, Kazumi MORI, Wakaba TANAKA, Kazuhiro MATSUDA, Toshio BABA, Akemichi TOMIMOTO, Shuhei SHINTANI, Norihito MIYAZAKI, Jun-Ichi TASHIRO, Fumi AIHARA, Hiroyuki NAMMO, Takao LI, Ming YAMAGATA, Kazuya |
| description | Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced
Diabetes
Kyohei Yamamoto 1 ,
Hitoshi Hashimoto 1 ,
Shuhei Tomimoto 1 ,
Norihito Shintani 1 ,
Jun-ichi Miyazaki 2 ,
Fumi Tashiro 2 ,
Hiroyuki Aihara 2 ,
Takao Nammo 3 ,
Ming Li 3 ,
Kazuya Yamagata 3 ,
Jun-ichiro Miyagawa 3 ,
Yuji Matsuzawa 3 ,
Yuki Kawabata 1 ,
Yuji Fukuyama 1 ,
Kazumi Koga 1 ,
Wakaba Mori 1 ,
Kazuhiro Tanaka 1 ,
Toshio Matsuda 4 and
Akemichi Baba 1 5
1 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
2 Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan
3 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
4 Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
5 Laboratory of Molecular Pharmacology, Osaka University Medical School, Suita, Osaka, Japan
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon
family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP’s
pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human
insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets,
specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between
PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose
loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic
mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive β-cells in the streptozotocin-treated transgenic mice was observed
but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference
between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play
an important role in the proliferation of β-cells.
Footnotes
Address correspond |
| doi_str_mv | 10.2337/diabetes.52.5.1155 |
| format | Article |
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Diabetes
Kyohei Yamamoto 1 ,
Hitoshi Hashimoto 1 ,
Shuhei Tomimoto 1 ,
Norihito Shintani 1 ,
Jun-ichi Miyazaki 2 ,
Fumi Tashiro 2 ,
Hiroyuki Aihara 2 ,
Takao Nammo 3 ,
Ming Li 3 ,
Kazuya Yamagata 3 ,
Jun-ichiro Miyagawa 3 ,
Yuji Matsuzawa 3 ,
Yuki Kawabata 1 ,
Yuji Fukuyama 1 ,
Kazumi Koga 1 ,
Wakaba Mori 1 ,
Kazuhiro Tanaka 1 ,
Toshio Matsuda 4 and
Akemichi Baba 1 5
1 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
2 Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan
3 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
4 Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
5 Laboratory of Molecular Pharmacology, Osaka University Medical School, Suita, Osaka, Japan
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon
family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP’s
pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human
insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets,
specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between
PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose
loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic
mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive β-cells in the streptozotocin-treated transgenic mice was observed
but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference
between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play
an important role in the proliferation of β-cells.
Footnotes
Address correspondence and reprint requests to Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of
Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: baba{at}phs.osaka-u.ac.jp .
Received for publication 12 December 2001 and accepted in revised form 24 January 2003.
BrdU, 5-bromo-2-deoxyuridine; GLP-1, glucagon-like peptide 1; MAP, mitogen-activated protein; PACAP, pituitary adenylate cyclase-activating
polypeptide; PAC 1 receptor, PACAP receptor; STZ, streptozotocin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling;
VIP, vasoactive intestinal peptide; VPAC receptor, VIP/PACAP receptor.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/diabetes.52.5.1155</identifier><identifier>PMID: 12716746</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Animals ; Apoptosis ; Biological and medical sciences ; Blotting, Northern ; Diabetes ; Diabetes Mellitus, Experimental - pathology ; Diabetes Mellitus, Experimental - prevention & control ; Fundamental and applied biological sciences. Psychology ; Humans ; Insulin ; Insulin - genetics ; Insulin - metabolism ; Insulin Secretion ; Islets of Langerhans - cytology ; Islets of Langerhans - metabolism ; Islets of Langerhans - pathology ; Islets of Langerhans - physiology ; Kinetics ; Mice ; Mice, Transgenic ; Neuropeptides - genetics ; Organ Specificity ; Pancreatic beta cells ; Physiological aspects ; Pituitary Adenylate Cyclase-Activating Polypeptide ; Polypeptides ; Promoter Regions, Genetic ; RNA, Messenger - genetics ; Time Factors</subject><ispartof>Diabetes (New York, N.Y.), 2003-05, Vol.52 (5), p.1155-1162</ispartof><rights>2003 INIST-CNRS</rights><rights>COPYRIGHT 2003 American Diabetes Association</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-6b524302040292bdf2320bfc141ba57075eb2e6c34e78c2394b5a8653751d0c53</citedby><cites>FETCH-LOGICAL-c522t-6b524302040292bdf2320bfc141ba57075eb2e6c34e78c2394b5a8653751d0c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14771940$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12716746$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YAMAMOTO, Kyohei</creatorcontrib><creatorcontrib>HASHIMOTO, Hitoshi</creatorcontrib><creatorcontrib>MIYAGAWA, Jun-Ichiro</creatorcontrib><creatorcontrib>MATSUZAWA, Yuji</creatorcontrib><creatorcontrib>KAWABATA, Yuki</creatorcontrib><creatorcontrib>FUKUYAMA, Yuji</creatorcontrib><creatorcontrib>KOGA, Kazumi</creatorcontrib><creatorcontrib>MORI, Wakaba</creatorcontrib><creatorcontrib>TANAKA, Kazuhiro</creatorcontrib><creatorcontrib>MATSUDA, Toshio</creatorcontrib><creatorcontrib>BABA, Akemichi</creatorcontrib><creatorcontrib>TOMIMOTO, Shuhei</creatorcontrib><creatorcontrib>SHINTANI, Norihito</creatorcontrib><creatorcontrib>MIYAZAKI, Jun-Ichi</creatorcontrib><creatorcontrib>TASHIRO, Fumi</creatorcontrib><creatorcontrib>AIHARA, Hiroyuki</creatorcontrib><creatorcontrib>NAMMO, Takao</creatorcontrib><creatorcontrib>LI, Ming</creatorcontrib><creatorcontrib>YAMAGATA, Kazuya</creatorcontrib><title>Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced
Diabetes
Kyohei Yamamoto 1 ,
Hitoshi Hashimoto 1 ,
Shuhei Tomimoto 1 ,
Norihito Shintani 1 ,
Jun-ichi Miyazaki 2 ,
Fumi Tashiro 2 ,
Hiroyuki Aihara 2 ,
Takao Nammo 3 ,
Ming Li 3 ,
Kazuya Yamagata 3 ,
Jun-ichiro Miyagawa 3 ,
Yuji Matsuzawa 3 ,
Yuki Kawabata 1 ,
Yuji Fukuyama 1 ,
Kazumi Koga 1 ,
Wakaba Mori 1 ,
Kazuhiro Tanaka 1 ,
Toshio Matsuda 4 and
Akemichi Baba 1 5
1 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
2 Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan
3 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
4 Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
5 Laboratory of Molecular Pharmacology, Osaka University Medical School, Suita, Osaka, Japan
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon
family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP’s
pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human
insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets,
specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between
PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose
loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic
mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive β-cells in the streptozotocin-treated transgenic mice was observed
but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference
between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play
an important role in the proliferation of β-cells.
Footnotes
Address correspondence and reprint requests to Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of
Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: baba{at}phs.osaka-u.ac.jp .
Received for publication 12 December 2001 and accepted in revised form 24 January 2003.
BrdU, 5-bromo-2-deoxyuridine; GLP-1, glucagon-like peptide 1; MAP, mitogen-activated protein; PACAP, pituitary adenylate cyclase-activating
polypeptide; PAC 1 receptor, PACAP receptor; STZ, streptozotocin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling;
VIP, vasoactive intestinal peptide; VPAC receptor, VIP/PACAP receptor.
DIABETES</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Blotting, Northern</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes Mellitus, Experimental - prevention & control</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin - genetics</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Islets of Langerhans - cytology</subject><subject>Islets of Langerhans - metabolism</subject><subject>Islets of Langerhans - pathology</subject><subject>Islets of Langerhans - physiology</subject><subject>Kinetics</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neuropeptides - genetics</subject><subject>Organ Specificity</subject><subject>Pancreatic beta cells</subject><subject>Physiological aspects</subject><subject>Pituitary Adenylate Cyclase-Activating Polypeptide</subject><subject>Polypeptides</subject><subject>Promoter Regions, Genetic</subject><subject>RNA, Messenger - genetics</subject><subject>Time Factors</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptks-KFDEQxhtR3HH1BTxILgoi3eZPpzN9HMZ1XRjZgV3BW0inq2ci3clsktbVR_BxfBCfyQzTMiwMdQgUv6-qvlRl2UuCC8qYeN8a1UCEUHBa8IIQzh9lM1KzOmdUfH2czTAmNCeiFmfZsxC-YYyrFE-zM0IFqURZzbLf19_Bw_3OQwjGWeQ6tF4sF2tkLLr1yoYNWKPRZzcGQGtltQcVU-Lvn3wJfR_Qhd2mLAR0ZcPYJ9UNJCbuaynbosUAvXFepTHRTfSwi-6Xi04bmxvbjhpa9GGy8Tx70qk-wIvpPc--fLy4XX7KV9eXV8vFKtec0phXDaclwxSXmNa0aTvKKG46TUrSKC6w4NBQqDQrQcw1ZXXZcDWvOBOctFhzdp69OdTdeXc3QohyMEEnM8pCsikFoyXHfA_mB3CjepDGdi56pdOHgFe9s9CZlF4QTMpaYFolvjjBp2hhMPqk4O0DQWIi3MeNGkOQ88vVQ5YeWO1dCB46ufNmUP6nJFjuz0H-PwfJqeRyfw5J9GqyOjYDtEfJtP8EvJ4AFbTqu7RxbcKRK4UgdYkT9-7Abc1m-8N4OHY70fYfkdXO6g</recordid><startdate>20030501</startdate><enddate>20030501</enddate><creator>YAMAMOTO, Kyohei</creator><creator>HASHIMOTO, Hitoshi</creator><creator>MIYAGAWA, Jun-Ichiro</creator><creator>MATSUZAWA, Yuji</creator><creator>KAWABATA, Yuki</creator><creator>FUKUYAMA, Yuji</creator><creator>KOGA, Kazumi</creator><creator>MORI, Wakaba</creator><creator>TANAKA, Kazuhiro</creator><creator>MATSUDA, Toshio</creator><creator>BABA, Akemichi</creator><creator>TOMIMOTO, Shuhei</creator><creator>SHINTANI, Norihito</creator><creator>MIYAZAKI, Jun-Ichi</creator><creator>TASHIRO, Fumi</creator><creator>AIHARA, Hiroyuki</creator><creator>NAMMO, Takao</creator><creator>LI, Ming</creator><creator>YAMAGATA, Kazuya</creator><general>American Diabetes Association</general><scope>IQODW</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>8GL</scope><scope>7X8</scope></search><sort><creationdate>20030501</creationdate><title>Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes</title><author>YAMAMOTO, Kyohei ; HASHIMOTO, Hitoshi ; MIYAGAWA, Jun-Ichiro ; MATSUZAWA, Yuji ; KAWABATA, Yuki ; FUKUYAMA, Yuji ; KOGA, Kazumi ; MORI, Wakaba ; TANAKA, Kazuhiro ; MATSUDA, Toshio ; BABA, Akemichi ; TOMIMOTO, Shuhei ; SHINTANI, Norihito ; MIYAZAKI, Jun-Ichi ; TASHIRO, Fumi ; AIHARA, Hiroyuki ; NAMMO, Takao ; LI, Ming ; YAMAGATA, Kazuya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-6b524302040292bdf2320bfc141ba57075eb2e6c34e78c2394b5a8653751d0c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Blotting, Northern</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes Mellitus, Experimental - prevention & control</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin - genetics</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Islets of Langerhans - cytology</topic><topic>Islets of Langerhans - metabolism</topic><topic>Islets of Langerhans - pathology</topic><topic>Islets of Langerhans - physiology</topic><topic>Kinetics</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neuropeptides - genetics</topic><topic>Organ Specificity</topic><topic>Pancreatic beta cells</topic><topic>Physiological aspects</topic><topic>Pituitary Adenylate Cyclase-Activating Polypeptide</topic><topic>Polypeptides</topic><topic>Promoter Regions, Genetic</topic><topic>RNA, Messenger - genetics</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>YAMAMOTO, Kyohei</creatorcontrib><creatorcontrib>HASHIMOTO, Hitoshi</creatorcontrib><creatorcontrib>MIYAGAWA, Jun-Ichiro</creatorcontrib><creatorcontrib>MATSUZAWA, Yuji</creatorcontrib><creatorcontrib>KAWABATA, Yuki</creatorcontrib><creatorcontrib>FUKUYAMA, Yuji</creatorcontrib><creatorcontrib>KOGA, Kazumi</creatorcontrib><creatorcontrib>MORI, Wakaba</creatorcontrib><creatorcontrib>TANAKA, Kazuhiro</creatorcontrib><creatorcontrib>MATSUDA, Toshio</creatorcontrib><creatorcontrib>BABA, Akemichi</creatorcontrib><creatorcontrib>TOMIMOTO, Shuhei</creatorcontrib><creatorcontrib>SHINTANI, Norihito</creatorcontrib><creatorcontrib>MIYAZAKI, Jun-Ichi</creatorcontrib><creatorcontrib>TASHIRO, Fumi</creatorcontrib><creatorcontrib>AIHARA, Hiroyuki</creatorcontrib><creatorcontrib>NAMMO, Takao</creatorcontrib><creatorcontrib>LI, Ming</creatorcontrib><creatorcontrib>YAMAGATA, Kazuya</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>YAMAMOTO, Kyohei</au><au>HASHIMOTO, Hitoshi</au><au>MIYAGAWA, Jun-Ichiro</au><au>MATSUZAWA, Yuji</au><au>KAWABATA, Yuki</au><au>FUKUYAMA, Yuji</au><au>KOGA, Kazumi</au><au>MORI, Wakaba</au><au>TANAKA, Kazuhiro</au><au>MATSUDA, Toshio</au><au>BABA, Akemichi</au><au>TOMIMOTO, Shuhei</au><au>SHINTANI, Norihito</au><au>MIYAZAKI, Jun-Ichi</au><au>TASHIRO, Fumi</au><au>AIHARA, Hiroyuki</au><au>NAMMO, Takao</au><au>LI, Ming</au><au>YAMAGATA, Kazuya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2003-05-01</date><risdate>2003</risdate><volume>52</volume><issue>5</issue><spage>1155</spage><epage>1162</epage><pages>1155-1162</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced
Diabetes
Kyohei Yamamoto 1 ,
Hitoshi Hashimoto 1 ,
Shuhei Tomimoto 1 ,
Norihito Shintani 1 ,
Jun-ichi Miyazaki 2 ,
Fumi Tashiro 2 ,
Hiroyuki Aihara 2 ,
Takao Nammo 3 ,
Ming Li 3 ,
Kazuya Yamagata 3 ,
Jun-ichiro Miyagawa 3 ,
Yuji Matsuzawa 3 ,
Yuki Kawabata 1 ,
Yuji Fukuyama 1 ,
Kazumi Koga 1 ,
Wakaba Mori 1 ,
Kazuhiro Tanaka 1 ,
Toshio Matsuda 4 and
Akemichi Baba 1 5
1 Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
2 Division of Stem Cell Regulation Research, Osaka University Medical School, Osaka, Japan
3 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
4 Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
5 Laboratory of Molecular Pharmacology, Osaka University Medical School, Suita, Osaka, Japan
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon
family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP’s
pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human
insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets,
specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between
PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose
loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic
mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive β-cells in the streptozotocin-treated transgenic mice was observed
but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.
Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference
between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play
an important role in the proliferation of β-cells.
Footnotes
Address correspondence and reprint requests to Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of
Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: baba{at}phs.osaka-u.ac.jp .
Received for publication 12 December 2001 and accepted in revised form 24 January 2003.
BrdU, 5-bromo-2-deoxyuridine; GLP-1, glucagon-like peptide 1; MAP, mitogen-activated protein; PACAP, pituitary adenylate cyclase-activating
polypeptide; PAC 1 receptor, PACAP receptor; STZ, streptozotocin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling;
VIP, vasoactive intestinal peptide; VPAC receptor, VIP/PACAP receptor.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>12716746</pmid><doi>10.2337/diabetes.52.5.1155</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2003-05, Vol.52 (5), p.1155-1162 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_gale_infotracacademiconefile_A101497026 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Apoptosis Biological and medical sciences Blotting, Northern Diabetes Diabetes Mellitus, Experimental - pathology Diabetes Mellitus, Experimental - prevention & control Fundamental and applied biological sciences. Psychology Humans Insulin Insulin - genetics Insulin - metabolism Insulin Secretion Islets of Langerhans - cytology Islets of Langerhans - metabolism Islets of Langerhans - pathology Islets of Langerhans - physiology Kinetics Mice Mice, Transgenic Neuropeptides - genetics Organ Specificity Pancreatic beta cells Physiological aspects Pituitary Adenylate Cyclase-Activating Polypeptide Polypeptides Promoter Regions, Genetic RNA, Messenger - genetics Time Factors |
| title | Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T14%3A54%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Overexpression%20of%20PACAP%20in%20Transgenic%20Mouse%20Pancreatic%20%CE%B2-Cells%20Enhances%20Insulin%20Secretion%20and%20Ameliorates%20Streptozotocin-induced%20Diabetes&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=YAMAMOTO,%20Kyohei&rft.date=2003-05-01&rft.volume=52&rft.issue=5&rft.spage=1155&rft.epage=1162&rft.pages=1155-1162&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/diabetes.52.5.1155&rft_dat=%3Cgale_pubme%3EA101497026%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=73245055&rft_id=info:pmid/12716746&rft_galeid=A101497026&rfr_iscdi=true |