Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes
Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM....
Gespeichert in:
| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2010-07, Vol.59 (7), p.1626-1634 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1634 |
|---|---|
| container_issue | 7 |
| container_start_page | 1626 |
| container_title | Diabetes (New York, N.Y.) |
| container_volume | 59 |
| creator | GERMAN, Jonathan P WISSE, Brent E SCHWARTZ, Michael W MORTON, Gregory J THALER, Joshua P OH-I, Shinsuke SARRUF, David A OGIMOTO, Kayoko KAIYALA, Karl J FISCHER, Jonathan D MATSEN, Miles E TABORSKY, Gerald J |
| description | Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.
Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.
Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.
We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency. |
| doi_str_mv | 10.2337/db09-1918 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2889761</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A232888748</galeid><sourcerecordid>A232888748</sourcerecordid><originalsourceid>FETCH-LOGICAL-c608t-723feb8bbe2f9da38eef5257d7cce94bd1f8614952ae94dddcecc09d2ef9c8ae3</originalsourceid><addsrcrecordid>eNp9kl-L1DAUxYMo7rj64BeQooj40DV_Ok3yIiyzui4MLIgLvoU0ua1ZOsnYtOJ8e2_ZcXVkkDyU5P7uyW3OIeQ5o2dcCPnON1SXTDP1gCyYFroUXH59SBaUMl4yqeUJeZLzLaW0xvWYnHBa8QpbF2S9hu0YYnEBbXABotsVKztlyMVVzFOPlc-QQx5tdIBHfnLgi2ZX3ESX4jikvsf9RbANjJCfkket7TM8239Pyc3HD19Wn8r19eXV6nxdupqqsZRctNCopgHeam-FAmiXfCm9dA501XjWqppVesktbr33Dpyj2nNotVMWxCl5f6e7nZoNYBknsb3ZDmFjh51JNpjDSgzfTJd-GK6UljVDgTd7gSF9nyCPZhOyg763EdKUjRRiSbkWFMmX_5C3aRoi_p2RnDOuJa8RenUHdbYHE2Kb8FY3S5pzLvBSJSuFVHmE6iACjpgiGoDHB_zZER6Xh01wRxveHjTMDsHPsUM_s1GX6_8Ns2fdbGgHBu1aXR_VdkPKeYD2_rUZNXMIzRxCM4cQ2Rd_23NP_k4dAq_3gM3O9u2A6Qr5Dyfw7bmsxS89A-Iz</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>722129726</pqid></control><display><type>article</type><title>Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>GERMAN, Jonathan P ; WISSE, Brent E ; SCHWARTZ, Michael W ; MORTON, Gregory J ; THALER, Joshua P ; OH-I, Shinsuke ; SARRUF, David A ; OGIMOTO, Kayoko ; KAIYALA, Karl J ; FISCHER, Jonathan D ; MATSEN, Miles E ; TABORSKY, Gerald J</creator><creatorcontrib>GERMAN, Jonathan P ; WISSE, Brent E ; SCHWARTZ, Michael W ; MORTON, Gregory J ; THALER, Joshua P ; OH-I, Shinsuke ; SARRUF, David A ; OGIMOTO, Kayoko ; KAIYALA, Karl J ; FISCHER, Jonathan D ; MATSEN, Miles E ; TABORSKY, Gerald J</creatorcontrib><description>Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.
Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.
Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.
We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db09-1918</identifier><identifier>PMID: 20424233</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adipose Tissue - drug effects ; Adipose Tissue - metabolism ; Analysis of Variance ; Animals ; Biological and medical sciences ; Blood glucose ; Blood Glucose - drug effects ; Blood Glucose - metabolism ; Blood sugar ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - metabolism ; Diabetes. Impaired glucose tolerance ; Eating - drug effects ; Eating - physiology ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Glucose metabolism ; Homeostasis - drug effects ; Homeostasis - physiology ; Insulin - metabolism ; Insulin Resistance ; Leptin ; Leptin - metabolism ; Leptin - pharmacology ; Liver - drug effects ; Liver - metabolism ; Male ; Medical sciences ; Metabolism ; Physiological aspects ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>Diabetes (New York, N.Y.), 2010-07, Vol.59 (7), p.1626-1634</ispartof><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 American Diabetes Association</rights><rights>Copyright American Diabetes Association Jul 2010</rights><rights>2010 by the American Diabetes Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c608t-723feb8bbe2f9da38eef5257d7cce94bd1f8614952ae94dddcecc09d2ef9c8ae3</citedby><cites>FETCH-LOGICAL-c608t-723feb8bbe2f9da38eef5257d7cce94bd1f8614952ae94dddcecc09d2ef9c8ae3</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/PMC2889761/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889761/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23029276$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20424233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GERMAN, Jonathan P</creatorcontrib><creatorcontrib>WISSE, Brent E</creatorcontrib><creatorcontrib>SCHWARTZ, Michael W</creatorcontrib><creatorcontrib>MORTON, Gregory J</creatorcontrib><creatorcontrib>THALER, Joshua P</creatorcontrib><creatorcontrib>OH-I, Shinsuke</creatorcontrib><creatorcontrib>SARRUF, David A</creatorcontrib><creatorcontrib>OGIMOTO, Kayoko</creatorcontrib><creatorcontrib>KAIYALA, Karl J</creatorcontrib><creatorcontrib>FISCHER, Jonathan D</creatorcontrib><creatorcontrib>MATSEN, Miles E</creatorcontrib><creatorcontrib>TABORSKY, Gerald J</creatorcontrib><title>Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.
Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.
Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.
We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.</description><subject>Adipose Tissue - drug effects</subject><subject>Adipose Tissue - metabolism</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood glucose</subject><subject>Blood Glucose - drug effects</subject><subject>Blood Glucose - metabolism</subject><subject>Blood sugar</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Eating - drug effects</subject><subject>Eating - physiology</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Glucose metabolism</subject><subject>Homeostasis - drug effects</subject><subject>Homeostasis - physiology</subject><subject>Insulin - metabolism</subject><subject>Insulin Resistance</subject><subject>Leptin</subject><subject>Leptin - metabolism</subject><subject>Leptin - pharmacology</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Physiological aspects</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kl-L1DAUxYMo7rj64BeQooj40DV_Ok3yIiyzui4MLIgLvoU0ua1ZOsnYtOJ8e2_ZcXVkkDyU5P7uyW3OIeQ5o2dcCPnON1SXTDP1gCyYFroUXH59SBaUMl4yqeUJeZLzLaW0xvWYnHBa8QpbF2S9hu0YYnEBbXABotsVKztlyMVVzFOPlc-QQx5tdIBHfnLgi2ZX3ESX4jikvsf9RbANjJCfkket7TM8239Pyc3HD19Wn8r19eXV6nxdupqqsZRctNCopgHeam-FAmiXfCm9dA501XjWqppVesktbr33Dpyj2nNotVMWxCl5f6e7nZoNYBknsb3ZDmFjh51JNpjDSgzfTJd-GK6UljVDgTd7gSF9nyCPZhOyg763EdKUjRRiSbkWFMmX_5C3aRoi_p2RnDOuJa8RenUHdbYHE2Kb8FY3S5pzLvBSJSuFVHmE6iACjpgiGoDHB_zZER6Xh01wRxveHjTMDsHPsUM_s1GX6_8Ns2fdbGgHBu1aXR_VdkPKeYD2_rUZNXMIzRxCM4cQ2Rd_23NP_k4dAq_3gM3O9u2A6Qr5Dyfw7bmsxS89A-Iz</recordid><startdate>20100701</startdate><enddate>20100701</enddate><creator>GERMAN, Jonathan P</creator><creator>WISSE, Brent E</creator><creator>SCHWARTZ, Michael W</creator><creator>MORTON, Gregory J</creator><creator>THALER, Joshua P</creator><creator>OH-I, Shinsuke</creator><creator>SARRUF, David A</creator><creator>OGIMOTO, Kayoko</creator><creator>KAIYALA, Karl J</creator><creator>FISCHER, Jonathan D</creator><creator>MATSEN, Miles E</creator><creator>TABORSKY, Gerald J</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100701</creationdate><title>Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes</title><author>GERMAN, Jonathan P ; WISSE, Brent E ; SCHWARTZ, Michael W ; MORTON, Gregory J ; THALER, Joshua P ; OH-I, Shinsuke ; SARRUF, David A ; OGIMOTO, Kayoko ; KAIYALA, Karl J ; FISCHER, Jonathan D ; MATSEN, Miles E ; TABORSKY, Gerald J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c608t-723feb8bbe2f9da38eef5257d7cce94bd1f8614952ae94dddcecc09d2ef9c8ae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adipose Tissue - drug effects</topic><topic>Adipose Tissue - metabolism</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood glucose</topic><topic>Blood Glucose - drug effects</topic><topic>Blood Glucose - metabolism</topic><topic>Blood sugar</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Eating - drug effects</topic><topic>Eating - physiology</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Glucose metabolism</topic><topic>Homeostasis - drug effects</topic><topic>Homeostasis - physiology</topic><topic>Insulin - metabolism</topic><topic>Insulin Resistance</topic><topic>Leptin</topic><topic>Leptin - metabolism</topic><topic>Leptin - pharmacology</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Physiological aspects</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GERMAN, Jonathan P</creatorcontrib><creatorcontrib>WISSE, Brent E</creatorcontrib><creatorcontrib>SCHWARTZ, Michael W</creatorcontrib><creatorcontrib>MORTON, Gregory J</creatorcontrib><creatorcontrib>THALER, Joshua P</creatorcontrib><creatorcontrib>OH-I, Shinsuke</creatorcontrib><creatorcontrib>SARRUF, David A</creatorcontrib><creatorcontrib>OGIMOTO, Kayoko</creatorcontrib><creatorcontrib>KAIYALA, Karl J</creatorcontrib><creatorcontrib>FISCHER, Jonathan D</creatorcontrib><creatorcontrib>MATSEN, Miles E</creatorcontrib><creatorcontrib>TABORSKY, Gerald J</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>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GERMAN, Jonathan P</au><au>WISSE, Brent E</au><au>SCHWARTZ, Michael W</au><au>MORTON, Gregory J</au><au>THALER, Joshua P</au><au>OH-I, Shinsuke</au><au>SARRUF, David A</au><au>OGIMOTO, Kayoko</au><au>KAIYALA, Karl J</au><au>FISCHER, Jonathan D</au><au>MATSEN, Miles E</au><au>TABORSKY, Gerald J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2010-07-01</date><risdate>2010</risdate><volume>59</volume><issue>7</issue><spage>1626</spage><epage>1634</epage><pages>1626-1634</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.
Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured.
Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM.
We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>20424233</pmid><doi>10.2337/db09-1918</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2010-07, Vol.59 (7), p.1626-1634 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2889761 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adipose Tissue - drug effects Adipose Tissue - metabolism Analysis of Variance Animals Biological and medical sciences Blood glucose Blood Glucose - drug effects Blood Glucose - metabolism Blood sugar Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - metabolism Diabetes. Impaired glucose tolerance Eating - drug effects Eating - physiology Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Glucose metabolism Homeostasis - drug effects Homeostasis - physiology Insulin - metabolism Insulin Resistance Leptin Leptin - metabolism Leptin - pharmacology Liver - drug effects Liver - metabolism Male Medical sciences Metabolism Physiological aspects Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction |
| title | Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T19%3A00%3A49IST&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=Leptin%20Deficiency%20Causes%20Insulin%20Resistance%20Induced%20by%20Uncontrolled%20Diabetes&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=GERMAN,%20Jonathan%20P&rft.date=2010-07-01&rft.volume=59&rft.issue=7&rft.spage=1626&rft.epage=1634&rft.pages=1626-1634&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/db09-1918&rft_dat=%3Cgale_pubme%3EA232888748%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=722129726&rft_id=info:pmid/20424233&rft_galeid=A232888748&rfr_iscdi=true |