Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients
Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients Douglas E. Befroy 1 , Kitt Falk Petersen 1 , Sylvie Dufour 2 , Graeme F. Mason 3 , Robin A. de Graaf 3 , Douglas L. Rothman 3 and Gerald I. Shulman 1 2 4 1 Department of Internal Medicine,...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2007-05, Vol.56 (5), p.1376-1381 |
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| creator | BEFROY, Douglas E FALK PETERSEN, Kitt DUFOUR, Sylvie MASON, Graeme F DE GRAAF, Robin A ROTHMAN, Douglas L SHULMAN, Gerald I |
| description | Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients
Douglas E. Befroy 1 ,
Kitt Falk Petersen 1 ,
Sylvie Dufour 2 ,
Graeme F. Mason 3 ,
Robin A. de Graaf 3 ,
Douglas L. Rothman 3 and
Gerald I. Shulman 1 2 4
1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
3 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Gerald I. Shulman, MD, PhD, Howard Hughes Medical Institute, Yale University
School of Medicine, The Anlyan Center, S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu
Abstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the
mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased
mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type
2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes.
To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using
13 C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive
control subjects underwent 13 C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13 C label into C 4 glutamate during a [2- 13 C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by
30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g −1 · min −1 , P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g −1 · min −1 ). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated
with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial
oxidative phosphorylation.
COX, cytochrome oxidase
FID, free induction decay
IMCL, intram |
| doi_str_mv | 10.2337/db06-0783 |
| format | Article |
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Douglas E. Befroy 1 ,
Kitt Falk Petersen 1 ,
Sylvie Dufour 2 ,
Graeme F. Mason 3 ,
Robin A. de Graaf 3 ,
Douglas L. Rothman 3 and
Gerald I. Shulman 1 2 4
1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
3 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Gerald I. Shulman, MD, PhD, Howard Hughes Medical Institute, Yale University
School of Medicine, The Anlyan Center, S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu
Abstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the
mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased
mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type
2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes.
To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using
13 C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive
control subjects underwent 13 C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13 C label into C 4 glutamate during a [2- 13 C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by
30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g −1 · min −1 , P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g −1 · min −1 ). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated
with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial
oxidative phosphorylation.
COX, cytochrome oxidase
FID, free induction decay
IMCL, intramyocellular lipid
IRS-1, insulin receptor substrate-1
ISI, insulin sensitivity index
MRS, magnetic resonance spectroscopy
PDH, pyruvate dehydrogenase
PGC, peroxisome proliferator–activated receptor-γ coactivator
SDH, succinate dehydrogenase
TCA, tricarboxylic acid
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-0783.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 31, 2007.
Received July 6, 2006.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db06-0783</identifier><identifier>PMID: 17287462</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adult ; Biological and medical sciences ; Body Mass Index ; Carbon Isotopes ; Chemical properties ; Citric Acid Cycle ; Diabetes ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fatty acids ; Female ; Glucose Tolerance Test ; Health aspects ; Humans ; Hypotheses ; Insulin resistance ; Insulin Resistance - physiology ; Kinases ; Kinetics ; Life Style ; Lipids ; Magnetic Resonance Spectroscopy ; Male ; Medical sciences ; Metabolism ; Metabolites ; Mitochondria, Muscle - metabolism ; Models, Biological ; Musculoskeletal system ; Nuclear Family ; Oxidation ; Oxidation-Reduction ; Oxidation-reduction reaction ; Oxidation-reduction reactions ; Pathogenesis ; Phosphorylation ; Physiological aspects ; Spectrum analysis ; Type 2 diabetes</subject><ispartof>Diabetes (New York, N.Y.), 2007-05, Vol.56 (5), p.1376-1381</ispartof><rights>2007 INIST-CNRS</rights><rights>COPYRIGHT 2007 American Diabetes Association</rights><rights>Copyright American Diabetes Association May 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c681t-152fbf78c1733ff6d3c12d64fc43d544422d0c2ca7107fcbafa2abab89e9cd0c3</citedby><cites>FETCH-LOGICAL-c681t-152fbf78c1733ff6d3c12d64fc43d544422d0c2ca7107fcbafa2abab89e9cd0c3</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/PMC2995532/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995532/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18737323$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17287462$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BEFROY, Douglas E</creatorcontrib><creatorcontrib>FALK PETERSEN, Kitt</creatorcontrib><creatorcontrib>DUFOUR, Sylvie</creatorcontrib><creatorcontrib>MASON, Graeme F</creatorcontrib><creatorcontrib>DE GRAAF, Robin A</creatorcontrib><creatorcontrib>ROTHMAN, Douglas L</creatorcontrib><creatorcontrib>SHULMAN, Gerald I</creatorcontrib><title>Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients
Douglas E. Befroy 1 ,
Kitt Falk Petersen 1 ,
Sylvie Dufour 2 ,
Graeme F. Mason 3 ,
Robin A. de Graaf 3 ,
Douglas L. Rothman 3 and
Gerald I. Shulman 1 2 4
1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
3 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Gerald I. Shulman, MD, PhD, Howard Hughes Medical Institute, Yale University
School of Medicine, The Anlyan Center, S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu
Abstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the
mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased
mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type
2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes.
To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using
13 C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive
control subjects underwent 13 C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13 C label into C 4 glutamate during a [2- 13 C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by
30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g −1 · min −1 , P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g −1 · min −1 ). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated
with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial
oxidative phosphorylation.
COX, cytochrome oxidase
FID, free induction decay
IMCL, intramyocellular lipid
IRS-1, insulin receptor substrate-1
ISI, insulin sensitivity index
MRS, magnetic resonance spectroscopy
PDH, pyruvate dehydrogenase
PGC, peroxisome proliferator–activated receptor-γ coactivator
SDH, succinate dehydrogenase
TCA, tricarboxylic acid
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-0783.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 31, 2007.
Received July 6, 2006.
DIABETES</description><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Body Mass Index</subject><subject>Carbon Isotopes</subject><subject>Chemical properties</subject><subject>Citric Acid Cycle</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Fatty acids</subject><subject>Female</subject><subject>Glucose Tolerance Test</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Insulin resistance</subject><subject>Insulin Resistance - physiology</subject><subject>Kinases</subject><subject>Kinetics</subject><subject>Life Style</subject><subject>Lipids</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Mitochondria, Muscle - metabolism</subject><subject>Models, Biological</subject><subject>Musculoskeletal system</subject><subject>Nuclear Family</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Oxidation-reduction reaction</subject><subject>Oxidation-reduction reactions</subject><subject>Pathogenesis</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Spectrum analysis</subject><subject>Type 2 diabetes</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkl2LEzEUhgdR3Lp64R-QQVBYZNZ8zExmboSl6lroUtEVvAuZ5GSaZZp0k4zu_vtNbbFWyrlIyHnOe5KTN8teYnROKGXvVYfqArGGPsomuKVtQQn7-TibIIRJgVnLTrJnIdwghOoUT7MTzEjDyppMMjdbrYXxoPIrE51cOqu8EUP-fexC9CJCvrgzSkTjbG5sfjUGOUDudD6zYRyMLb5BMCEKG_OF1mHtje036ev7NeQk_2hEB9HI_GuSABvD8-yJFkOAF7v1NPvx-dP19EsxX1zOphfzQtYNjgWuiO40ayRmlGpdKyoxUXWpZUlVVZYlIQpJIgXDiGnZCS2I6ETXtNDKlKGn2Yet7nrsVqBk6u3FwNP9VsLfcycMP8xYs-S9-8VJ21YVJUng7U7Au9sRQuQrEyQMg7DgxsAZKquyxXUCX_8H3rjR2_Q4TnBdNhS3VYKKLdSLAbix2qWmsgcLqbezoE06vkh4TVlbbUTPj_ApFKyMPFpwdlCQmAh3sRdjCLy5nB-yxTFWumGAHnj6h-niqLb0LgQP-u8YMeIbA_KNAfnGgIl99e_c9-TOcQl4swNEkGLQXlhpwp5rGGVp_Il7t-WWpl_-Tg7l6o-XIOw3Vc0rjimr6QMA4PGj</recordid><startdate>20070501</startdate><enddate>20070501</enddate><creator>BEFROY, Douglas E</creator><creator>FALK PETERSEN, Kitt</creator><creator>DUFOUR, Sylvie</creator><creator>MASON, Graeme F</creator><creator>DE GRAAF, Robin A</creator><creator>ROTHMAN, Douglas L</creator><creator>SHULMAN, Gerald I</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>20070501</creationdate><title>Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients</title><author>BEFROY, Douglas E ; FALK PETERSEN, Kitt ; DUFOUR, Sylvie ; MASON, Graeme F ; DE GRAAF, Robin A ; ROTHMAN, Douglas L ; SHULMAN, Gerald I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c681t-152fbf78c1733ff6d3c12d64fc43d544422d0c2ca7107fcbafa2abab89e9cd0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Body Mass Index</topic><topic>Carbon Isotopes</topic><topic>Chemical properties</topic><topic>Citric Acid Cycle</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Fatty acids</topic><topic>Female</topic><topic>Glucose Tolerance Test</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Insulin resistance</topic><topic>Insulin Resistance - physiology</topic><topic>Kinases</topic><topic>Kinetics</topic><topic>Life Style</topic><topic>Lipids</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Mitochondria, Muscle - metabolism</topic><topic>Models, Biological</topic><topic>Musculoskeletal system</topic><topic>Nuclear Family</topic><topic>Oxidation</topic><topic>Oxidation-Reduction</topic><topic>Oxidation-reduction reaction</topic><topic>Oxidation-reduction reactions</topic><topic>Pathogenesis</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Spectrum analysis</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BEFROY, Douglas E</creatorcontrib><creatorcontrib>FALK PETERSEN, Kitt</creatorcontrib><creatorcontrib>DUFOUR, Sylvie</creatorcontrib><creatorcontrib>MASON, Graeme F</creatorcontrib><creatorcontrib>DE GRAAF, Robin A</creatorcontrib><creatorcontrib>ROTHMAN, Douglas L</creatorcontrib><creatorcontrib>SHULMAN, Gerald I</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>BEFROY, Douglas E</au><au>FALK PETERSEN, Kitt</au><au>DUFOUR, Sylvie</au><au>MASON, Graeme F</au><au>DE GRAAF, Robin A</au><au>ROTHMAN, Douglas L</au><au>SHULMAN, Gerald I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2007-05-01</date><risdate>2007</risdate><volume>56</volume><issue>5</issue><spage>1376</spage><epage>1381</epage><pages>1376-1381</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients
Douglas E. Befroy 1 ,
Kitt Falk Petersen 1 ,
Sylvie Dufour 2 ,
Graeme F. Mason 3 ,
Robin A. de Graaf 3 ,
Douglas L. Rothman 3 and
Gerald I. Shulman 1 2 4
1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
3 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to Gerald I. Shulman, MD, PhD, Howard Hughes Medical Institute, Yale University
School of Medicine, The Anlyan Center, S269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu
Abstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the
mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased
mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type
2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes.
To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using
13 C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive
control subjects underwent 13 C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13 C label into C 4 glutamate during a [2- 13 C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by
30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g −1 · min −1 , P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g −1 · min −1 ). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated
with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial
oxidative phosphorylation.
COX, cytochrome oxidase
FID, free induction decay
IMCL, intramyocellular lipid
IRS-1, insulin receptor substrate-1
ISI, insulin sensitivity index
MRS, magnetic resonance spectroscopy
PDH, pyruvate dehydrogenase
PGC, peroxisome proliferator–activated receptor-γ coactivator
SDH, succinate dehydrogenase
TCA, tricarboxylic acid
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-0783.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 31, 2007.
Received July 6, 2006.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>17287462</pmid><doi>10.2337/db06-0783</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2007-05, Vol.56 (5), p.1376-1381 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70454916 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adult Biological and medical sciences Body Mass Index Carbon Isotopes Chemical properties Citric Acid Cycle Diabetes Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Fatty acids Female Glucose Tolerance Test Health aspects Humans Hypotheses Insulin resistance Insulin Resistance - physiology Kinases Kinetics Life Style Lipids Magnetic Resonance Spectroscopy Male Medical sciences Metabolism Metabolites Mitochondria, Muscle - metabolism Models, Biological Musculoskeletal system Nuclear Family Oxidation Oxidation-Reduction Oxidation-reduction reaction Oxidation-reduction reactions Pathogenesis Phosphorylation Physiological aspects Spectrum analysis Type 2 diabetes |
| title | Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients |
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