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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">problendo</journal-id><journal-title-group><journal-title xml:lang="ru">Проблемы Эндокринологии</journal-title><trans-title-group xml:lang="en"><trans-title>Problems of Endocrinology</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">0375-9660</issn><issn pub-type="epub">2308-1430</issn><publisher><publisher-name>Endocrinology Research Centre</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.14341/probl13090</article-id><article-id custom-type="elpub" pub-id-type="custom">problendo-13090</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>Нарушения углеводного обмена</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>Carbohidrates metabolism disturbancies</subject></subj-group></article-categories><title-group><article-title>Две модели развития инсулинорезистентности и стратегия борьбы с возрастзависимыми заболеваниями: обзор литературы</article-title><trans-title-group xml:lang="en"><trans-title>Two models of insulin resistance development and the strategy to combat age-related diseases: literature review</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1193-1287</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Мартюшев-Поклад</surname><given-names>А. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Martyushev-Poklad</surname><given-names>A. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Мартюшев-Поклад Андрей Васильевич - кандидат медицинских наук.</p><p>107031, Москва, Петровка ул., д. 25, стр. 2.</p><p>SPIN-код: 3505-7526</p></bio><bio xml:lang="en"><p>Andrey V. Martyushev-Poklad - MD, PhD.</p><p>25 bld 2 Petrovka street, 107031 Moscow.</p><p>SPIN-код: 3505-7526</p></bio><email xlink:type="simple">avmp2007@gmail.com</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-5143-7366</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Янкевич</surname><given-names>Д. С.</given-names></name><name name-style="western" xml:lang="en"><surname>Yankevich</surname><given-names>D. S.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Янкевич Дмитрий Станиславович - кандидат медицинских наук.</p><p>107031, Москва, Петровка ул., д. 25, стр. 2.</p><p>SPIN-код: 6506-8058</p></bio><bio xml:lang="en"><p>Dmitry S. Yankevich - MD, PhD.</p><p>25 bld 2 Petrovka street, 107031 Moscow.</p><p>SPIN-код: 6506-8058</p></bio><email xlink:type="simple">yanson_d@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4272-0957</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Петрова</surname><given-names>М. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Petrova</surname><given-names>M. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Петрова Марина Владимировна - доктор медицинских наук, профессор.</p><p>107031, Москва, Петровка ул., д. 25, стр. 2.</p><p>SPIN-код: 9132-4190</p></bio><bio xml:lang="en"><p>Marina V. Petrova - MD, PhD, Professor.</p><p>25 bld 2 Petrovka street, 107031 Moscow.</p><p>SPIN-код: 9132-4190</p></bio><email xlink:type="simple">mail@petrovamv.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8674-1632</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Савицкая</surname><given-names>Н. Г.</given-names></name><name name-style="western" xml:lang="en"><surname>Savitskaya</surname><given-names>N. G.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Савицкая Наталия Геннадьевна – кандидат медицинских наук.</p><p>107031, Москва, Петровка ул., д. 25, стр. 2.</p><p>SPIN-код: 1459-6085</p></bio><bio xml:lang="en"><p>Nataliya G. Savitskaya - MD, PhD.</p><p>25 bld 2 Petrovka street, 107031 Moscow.</p><p>SPIN-код: 1459-6085</p></bio><email xlink:type="simple">elirom@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Федеральный научно-клинический центр реаниматологии и реабилитологии</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2022</year></pub-date><pub-date pub-type="epub"><day>30</day><month>05</month><year>2022</year></pub-date><volume>68</volume><issue>4</issue><fpage>59</fpage><lpage>68</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Мартюшев-Поклад А.В., Янкевич Д.С., Петрова М.В., Савицкая Н.Г., 2022</copyright-statement><copyright-year>2022</copyright-year><copyright-holder xml:lang="ru">Мартюшев-Поклад А.В., Янкевич Д.С., Петрова М.В., Савицкая Н.Г.</copyright-holder><copyright-holder xml:lang="en">Martyushev-Poklad A.V., Yankevich D.S., Petrova M.V., Savitskaya N.G.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.probl-endojournals.ru/jour/article/view/13090">https://www.probl-endojournals.ru/jour/article/view/13090</self-uri><abstract><sec><title>АКТУАЛЬНОСТЬ</title><p>АКТУАЛЬНОСТЬ. В основе многих возрастзависимых заболеваний (ВЗЗ), важнейшей проблемы современного здравоохранения, лежит инсулинорезистентность (ИР), поэтому адекватное понимание механизмов развития ИР необходимо для действенной профилактики ВЗЗ.</p></sec><sec><title>ЦЕЛЬ</title><p>ЦЕЛЬ. Проанализировать существующие модели, отражающие причины и механизмы развития ИР, для обоснования наиболее результативной стратегии профилактики ВЗЗ.</p></sec><sec><title>МАТЕРИАЛЫ И МЕТОДЫ</title><p>МАТЕРИАЛЫ И МЕТОДЫ. Анализ источников из elibrary.ru, PubMed и Google Scholar по ИР и гиперинсулинемии.</p></sec><sec><title>РЕЗУЛЬТАТЫ</title><p>РЕЗУЛЬТАТЫ. В обзоре проанализированы две модели развития ИР и взаимосвязей между ИР, гиперинсулинемией (ГИ) и ожирением. Преобладающая модель рассматривает ожирение (нарушение баланса между калорийностью рациона и расходованием энергии) как основной фактор развития ИР, а ГИ — как следствие ИР, малозначимое для исходов ИР. Эта модель противоречит многим экспериментальным и клиническим данным. Соответствующая ей стратегия борьбы с ВЗЗ — гипокалорийный рацион и фармакотерапия ИР — показала недостаточную результативность.</p><p>Альтернативная модель (ИР как следствие ГИ, а ожирение — одно из проявлений ИР) лучше согласуется с современными экспериментальными и клиническими данными и позволяет более точно объяснять механизмы развития ВЗЗ и эффективнее корректировать неблагоприятные факторы образа жизни. Ей соответствует иная стратегия борьбы с ВЗЗ (акцент на низкоуглеводном рационе и достаточной пищевой паузе с учетом других факторов развития ИР).</p></sec><sec><title>ЗАКЛЮЧЕНИЕ</title><p>ЗАКЛЮЧЕНИЕ. Пересмотр преобладающей модели развития ИР открывает возможности для повышения результативности ранней профилактики широкого спектра ВЗЗ, в которых значима роль ИР.</p></sec></abstract><trans-abstract xml:lang="en"><sec><title>BACKGROUND</title><p>BACKGROUND: Insulin resistance (IR) is the root cause of most age-related diseases (ARD), the major challenge for today’s health systems. Therefore, adequate understanding of the mechanisms underlying IR is essential to build effective ARD prevention.</p></sec><sec><title>OBJECTIVE</title><p>OBJECTIVE: Analyze the existing models of IR causation and progression in order to justify the most effective ARD prevention strategy.</p></sec><sec><title>METHODS</title><p>METHODS: Search and analysis of publications on IR and hyperinsulinemia (HI) from databases elibrary.ru, PubMed, and Google Scholar.</p></sec><sec><title>RESULTS</title><p>RESULTS: Two models of IR development are analyzed along with the relationship between IR, HI, and obesity. The prevailing model considers obesity (imbalance of caloric intake and energy expenditure) as the main factor in the development of IR; HI is seen as a consequence of IR, mostly insignificant for the outcomes of IR. The model contradicts many experimental and clinical findings. The strategy to combat ARDs that follows from the model (hypocaloric diet and pharmacotherapy of IR) has proven mostly ineffective.</p><p>The alternative model (IR as a consequence of HI, and obesity as one of IR manifestations) is more consistent with the pool of experimental and clinical data. It more precisely predicts ARD development and allows more adequate correction of adverse lifestyle factors. It corresponds to a different strategy for combating ARD: emphasis on low-carb diet and longer fasting window combined with consideration of other factors of IR.</p></sec><sec><title>CONCLUSION</title><p>CONCLUSION: If the prevailing model of IR development is revised, this should open up opportunities for more effective early prevention of a wide range of chronic diseases in which the role of IR is significant.</p></sec></trans-abstract><kwd-group xml:lang="ru"><kwd>инсулинорезистентность</kwd><kwd>гиперинсулинемия</kwd><kwd>ожирение</kwd><kwd>митохондриальная дисфункция</kwd><kwd>возрастзависимые заболевания</kwd><kwd>профилактика</kwd></kwd-group><kwd-group xml:lang="en"><kwd>insulin resistance</kwd><kwd>hyperinsulinemia</kwd><kwd>obesity</kwd><kwd>mitochondrial dysfunction</kwd><kwd>age-related diseases</kwd><kwd>prevention</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">Аналитическое исследование выполнено в рамках государственного задания № 075-00483-21-01 «Превентивные технологии персонализированной геропротекции».</funding-statement></funding-group></article-meta></front><back><ref-list><ref id="cit1"><element-citation><name><surname>Bauer</surname> <given-names>Ursula E</given-names> </name> <name><surname>Briss</surname> <given-names>Peter A</given-names> </name> <name><surname>Goodman</surname> <given-names>Richard A</given-names> </name> <name><surname>Bowman</surname> <given-names>Barbara A</given-names> </name> <article-title>Prevention of chronic disease in the 21st century: elimination of the leading preventable causes of premature death and disability in the USA</article-title> <source>The Lancet</source> <year>2014</year> <month>07</month> <fpage>45</fpage> <lpage>52</lpage> <volume>384</volume> <issue>9937</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/s0140-6736(14)60648-6</object-id></element-citation></ref><ref id="cit2"><mixed-citation publication-type="commun" publication-format="web"><source>Eurostat</source> [Internet]. <article-title>Preventable and treatable mortality statistics.</article-title> Available from: https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Preventable_and_treatable_mortality_statistics [cited: 08.01.<year>2022</year>]</mixed-citation></ref><ref id="cit3"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Lawrence</surname> <given-names>RD.</given-names></name> <article-title>An insulin resistant case of diabetes.</article-title> <source>Proceedings of the Royal Society of Medicine.</source> <year>1927</year>;<issue>21(2)</issue>: <fpage>250</fpage>-<lpage>251</lpage>.</mixed-citation></ref><ref id="cit4"><element-citation><name><surname>Reaven</surname> <given-names>Gerald M</given-names> </name> <article-title>Role of Insulin Resistance in Human Disease</article-title> <source>Diabetes</source> <year>2013</year> <month>09</month> <fpage>1595</fpage> <lpage>1607</lpage> <volume>37</volume> <issue>12</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/diab.37.12.1595</object-id></element-citation></ref><ref id="cit5"><element-citation><name><surname>Van Cauter</surname> <given-names>E</given-names> </name> <name><surname>Blackman</surname> <given-names>J D</given-names> </name> <name><surname>Roland</surname> <given-names>D</given-names> </name> <name><surname>Spire</surname> <given-names>J P</given-names> </name> <name><surname>Refetoff</surname> <given-names>S</given-names> </name> <name><surname>Polonsky</surname> <given-names>K S</given-names> </name> <article-title>Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.</article-title> <source>Journal of Clinical Investigation</source> <year>2008</year> <month>02</month> <fpage>934</fpage> <lpage>942</lpage> <volume>88</volume> <issue>3</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1172/jci115396</object-id></element-citation></ref><ref id="cit6"><element-citation><name><surname>Barbour</surname> <given-names>Linda A.</given-names> </name> <name><surname>McCurdy</surname> <given-names>Carrie E.</given-names> </name> <name><surname>Hernandez</surname> <given-names>Teri L.</given-names> </name> <name><surname>Kirwan</surname> <given-names>John P.</given-names> </name> <name><surname>Catalano</surname> <given-names>Patrick M.</given-names> </name> <name><surname>Friedman</surname> <given-names>Jacob E.</given-names> </name> <article-title>Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes</article-title> <source>Diabetes Care</source> <year>2007</year> <month>06</month> <fpage>S112</fpage> <lpage>S119</lpage> <volume>30</volume> <issue>Supplement_2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/dc07-s202</object-id></element-citation></ref><ref id="cit7"><element-citation><name><surname>Kampmann</surname> <given-names>Ulla</given-names> </name> <name><surname>Knorr</surname> <given-names>Sine</given-names> </name> <name><surname>Fuglsang</surname> <given-names>Jens</given-names> </name> <name><surname>Ovesen</surname> <given-names>Per</given-names> </name> <article-title>Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview</article-title> <source>Journal of Diabetes Research</source> <year>2019</year> <month>11</month> <fpage>1</fpage> <lpage>9</lpage> <volume>2019</volume> <object-id pub-id-type="doi" specific-use="metadata">10.1155/2019/5320156</object-id></element-citation></ref><ref id="cit8"><element-citation><name><surname>Kelsey</surname> <given-names>Megan M.</given-names> </name> <name><surname>Zeitler</surname> <given-names>Philip S.</given-names> </name> <article-title>Insulin Resistance of Puberty</article-title> <source>Current Diabetes Reports</source> <year>2016</year> <month>05</month> <volume>16</volume> <issue>7</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1007/s11892-016-0751-5</object-id></element-citation></ref><ref id="cit9"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Makisheva</surname> <given-names>R.T.</given-names></name> <article-title>Adaptivnyi smysl insulinorezistentnosti</article-title> // <source>Vestnik novykh meditsinskikh tekhnologii.</source> [Internet]. — <year>2016</year>. — №<month>1</month>. — S. <fpage>60</fpage>-<lpage>67</lpage>. Dostupno po: https://cyberleninka.ru/article/n/adaptivnyy-smysl-insulinorezistentnosti [Ssylka aktivna na 14.07.2021].</mixed-citation></ref><ref id="cit10"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Petersen</surname> <given-names>MC</given-names></name>, <name><surname>Shulman</surname> <given-names>GI.</given-names></name> <article-title>Mechanisms of Insulin Action and Insulin Resistance.</article-title> <source>Physiol Rev.</source> <year>2018</year>;<issue>98(4)</issue>:<fpage>2133</fpage>-<lpage>2223</lpage>. doi: https://doi.org/<object-id pub-id-type="doi" specific-use="metadata">10.1152/physrev.00063.2017</object-id></mixed-citation></ref><ref id="cit11"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Barsukov</surname> <given-names>I.A.</given-names></name>, <name><surname>Demina</surname> <given-names>A.A.</given-names></name> <article-title>Ozhirenie i insulinorezistentnost': mekhanizmy razvitiya i puti korrektsii</article-title> // <source>RMZh.</source> — <year>2021</year>. — T. <volume>29</volume>. — №<month>2</month>. — S. <fpage>26</fpage>-<lpage>30</lpage>.</mixed-citation></ref><ref id="cit12"><element-citation><name><surname>Kraft</surname> <given-names>Joseph R.</given-names> </name> <article-title>Detection of Diabetes MellitusIn Situ(Occult Diabetes)</article-title> <source>Laboratory Medicine</source> <year>2016</year> <month>03</month> <fpage>10</fpage> <lpage>22</lpage> <volume>6</volume> <issue>2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1093/labmed/6.2.10</object-id></element-citation></ref><ref id="cit13"><element-citation><name><surname>Crofts</surname> <given-names>Catherine</given-names> </name> <name><surname>Schofield</surname> <given-names>Grant</given-names> </name> <name><surname>Zinn</surname> <given-names>Caryn</given-names> </name> <name><surname>Wheldon</surname> <given-names>Mark</given-names> </name> <name><surname>Kraft</surname> <given-names>Joseph</given-names> </name> <article-title>Identifying hyperinsulinaemia in the absence of impaired glucose tolerance: An examination of the Kraft database</article-title> <source>Diabetes Research and Clinical Practice</source> <year>2016</year> <month>06</month> <fpage>50</fpage> <lpage>57</lpage> <volume>118</volume> <object-id pub-id-type="doi" specific-use="metadata">10.1016/j.diabres.2016.06.007</object-id></element-citation></ref><ref id="cit14"><element-citation><name><surname>DiNicolantonio</surname> <given-names>James J</given-names> </name> <name><surname>Bhutani</surname> <given-names>Jaikrit</given-names> </name> <name><surname>OKeefe</surname> <given-names>James H</given-names> </name> <name><surname>Crofts</surname> <given-names>Catherine</given-names> </name> <article-title>Postprandial insulin assay as the earliest biomarker for diagnosing pre-diabetes, type 2 diabetes and increased cardiovascular risk</article-title> <source>Open Heart</source> <year>2017</year> <month>11</month> <fpage>e000656</fpage> <volume>4</volume> <issue>2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1136/openhrt-2017-000656</object-id></element-citation></ref><ref id="cit15"><element-citation><name><surname>Taubes</surname> <given-names>G.</given-names> </name> <article-title>The science of obesity: what do we really know about what makes us fat? An essay by Gary Taubes</article-title> <source>BMJ</source> <year>2013</year> <month>04</month> <fpage>f1050</fpage> <lpage>f1050</lpage> <volume>346</volume> <issue>apr15 5</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1136/bmj.f1050</object-id></element-citation></ref><ref id="cit16"><element-citation><name><surname>Newburgh</surname> <given-names>L. H.</given-names> </name> <name><surname>Johnston</surname> <given-names>Margaret Woodwell</given-names> </name> <article-title>THE NATURE OF OBESITY 12</article-title> <source>Journal of Clinical Investigation</source> <year>2008</year> <month>02</month> <fpage>197</fpage> <lpage>213</lpage> <volume>8</volume> <issue>2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1172/jci100260</object-id></element-citation></ref><ref id="cit17"><element-citation><name><surname>Noakes</surname> <given-names>Timothy David</given-names> </name> <article-title>So What Comes First: The Obesity or the Insulin Resistance? And Which Is More Important?</article-title> <source>Clinical Chemistry</source> <year>2018</year> <month>01</month> <fpage>7</fpage> <lpage>9</lpage> <volume>64</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1373/clinchem.2017.282962</object-id></element-citation></ref><ref id="cit18"><element-citation><name><surname>Ludwig</surname> <given-names>David S.</given-names> </name> <name><surname>Ebbeling</surname> <given-names>Cara B.</given-names> </name> <article-title>The Carbohydrate-Insulin Model of Obesity</article-title> <source>JAMA Internal Medicine</source> <year>2018</year> <month>07</month> <fpage>1098</fpage> <volume>178</volume> <issue>8</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1001/jamainternmed.2018.2933</object-id></element-citation></ref><ref id="cit19"><element-citation><name><surname>Templeman</surname> <given-names>Nicole M</given-names> </name> <name><surname>Skovsø</surname> <given-names>Søs</given-names> </name> <name><surname>Page</surname> <given-names>Melissa M</given-names> </name> <name><surname>Lim</surname> <given-names>Gareth E</given-names> </name> <name><surname>Johnson</surname> <given-names>James D</given-names> </name> <article-title>A causal role for hyperinsulinemia in obesity</article-title> <source>Journal of Endocrinology</source> <year>2017</year> <month>01</month> <fpage>R173</fpage> <lpage>R183</lpage> <volume>232</volume> <issue>3</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1530/joe-16-0449</object-id></element-citation></ref><ref id="cit20"><element-citation><name><surname>Paris</surname> <given-names>Maryline</given-names> </name> <name><surname>Bernard-Kargar</surname> <given-names>Catherine</given-names> </name> <name><surname>Berthault</surname> <given-names>Marie-France</given-names> </name> <name><surname>Bouwens</surname> <given-names>Luc</given-names> </name> <name><surname>Ktorza</surname> <given-names>Alain</given-names> </name> <article-title>Specific and Combined Effects of Insulin and Glucose on Functional Pancreatic β-Cell Mass in Vivo in Adult Rats</article-title> <source>Endocrinology</source> <year>2003</year> <month>05</month> <fpage>2717</fpage> <lpage>2727</lpage> <volume>144</volume> <issue>6</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1210/en.2002-221112</object-id></element-citation></ref><ref id="cit21"><element-citation><name><surname>Mahler</surname> <given-names>Richard J.</given-names> </name> <article-title>The relationship between the hyperplastic pancreatic islet and insulin insensitivity in obesity</article-title> <source>Acta Diabetologica Latina</source> <year>2005</year> <month>08</month> <fpage>1</fpage> <lpage>17</lpage> <volume>18</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1007/bf02056101</object-id></element-citation></ref><ref id="cit22"><element-citation><name><surname>Astley</surname> <given-names>Christina M</given-names> </name> <name><surname>Todd</surname> <given-names>Jennifer N</given-names> </name> <name><surname>Salem</surname> <given-names>Rany M</given-names> </name> <name><surname>Vedantam</surname> <given-names>Sailaja</given-names> </name> <name><surname>Ebbeling</surname> <given-names>Cara B</given-names> </name> <name><surname>Huang</surname> <given-names>Paul L</given-names> </name> <name><surname>Ludwig</surname> <given-names>David S</given-names> </name> <name><surname>Hirschhorn</surname> <given-names>Joel N</given-names> </name> <name><surname>Florez</surname> <given-names>Jose C</given-names> </name> <article-title>Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity</article-title> <source>Clinical Chemistry</source> <year>2018</year> <month>01</month> <fpage>192</fpage> <lpage>200</lpage> <volume>64</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1373/clinchem.2017.280727</object-id></element-citation></ref><ref id="cit23"><element-citation><name><surname>Corkey</surname> <given-names>Barbara E.</given-names> </name> <article-title>Banting Lecture 2011</article-title> <source>Diabetes</source> <year>2011</year> <month>12</month> <fpage>4</fpage> <lpage>13</lpage> <volume>61</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/db11-1483</object-id></element-citation></ref><ref id="cit24"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Katsyuba</surname> <given-names>E</given-names></name>, <name><surname>Romani</surname> <given-names>M</given-names></name>, <name><surname>Hofer</surname> <given-names>D</given-names></name>, <name><surname>Auwerx</surname> <given-names>J.</given-names></name> <article-title>NAD+ homeostasis in health and disease.</article-title> <source>Nat Metab.</source> <year>2020</year>;<issue>2(1)</issue>:<fpage>9</fpage>-<lpage>31</lpage>. doi: https://doi.org/10.1038/s42255-019-0161-5</mixed-citation></ref><ref id="cit25"><element-citation><name><surname>Maiese</surname> <given-names>Kenneth</given-names> </name> <article-title>Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders</article-title> <source>Current Neurovascular Research</source> <year>2021</year> <month>01</month> <fpage>134</fpage> <lpage>149</lpage> <volume>18</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2174/1567202617999210104220334</object-id></element-citation></ref><ref id="cit26"><element-citation><name><surname>Kopp</surname> <given-names>Wolfgang</given-names> </name> <article-title>&lt;p&gt;Development of Obesity: The Driver and the Passenger&lt;/p&gt;</article-title> <source>Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy</source> <year>2020</year> <month>11</month> <fpage>4631</fpage> <lpage>4642</lpage> <volume>Volume 13</volume> <object-id pub-id-type="doi" specific-use="metadata">10.2147/dmso.s280146</object-id></element-citation></ref><ref id="cit27"><element-citation><name><surname>Kopp</surname> <given-names>Wolfgang</given-names> </name> <article-title>High-insulinogenic nutrition—an etiologic factor for obesity and the metabolic syndrome?</article-title> <source>Metabolism</source> <year>2003</year> <month>07</month> <fpage>840</fpage> <lpage>844</lpage> <volume>52</volume> <issue>7</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/s0026-0495(02)05294-0</object-id></element-citation></ref><ref id="cit28"><element-citation><name><surname>Kopp</surname> <given-names>Wolfgang</given-names> </name> <article-title>&lt;p&gt;How Western Diet And Lifestyle Drive The Pandemic Of Obesity And Civilization Diseases&lt;/p&gt;</article-title> <source>Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy</source> <year>2019</year> <month>10</month> <fpage>2221</fpage> <lpage>2236</lpage> <volume>Volume 12</volume> <object-id pub-id-type="doi" specific-use="metadata">10.2147/dmso.s216791</object-id></element-citation></ref><ref id="cit29"><element-citation><name><surname>Mehran</surname> <given-names>Arya E.</given-names> </name> <name><surname>Templeman</surname> <given-names>Nicole M.</given-names> </name> <name><surname>Brigidi</surname> <given-names>G. Stefano</given-names> </name> <name><surname>Lim</surname> <given-names>Gareth E.</given-names> </name> <name><surname>Chu</surname> <given-names>Kwan-Yi</given-names> </name> <name><surname>Hu</surname> <given-names>Xiaoke</given-names> </name> <name><surname>Botezelli</surname> <given-names>Jose Diego</given-names> </name> <name><surname>Asadi</surname> <given-names>Ali</given-names> </name> <name><surname>Hoffman</surname> <given-names>Bradford G.</given-names> </name> <name><surname>Kieffer</surname> <given-names>Timothy J.</given-names> </name> <name><surname>Bamji</surname> <given-names>Shernaz X.</given-names> </name> <name><surname>Clee</surname> <given-names>Susanne M.</given-names> </name> <name><surname>Johnson</surname> <given-names>James D.</given-names> </name> <article-title>Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production</article-title> <source>Cell Metabolism</source> <year>2012</year> <month>12</month> <fpage>723</fpage> <lpage>737</lpage> <volume>16</volume> <issue>6</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/j.cmet.2012.10.019</object-id></element-citation></ref><ref id="cit30"><element-citation><name><surname>Le Stunff</surname> <given-names>Catherine</given-names> </name> <name><surname>Bougnères</surname> <given-names>Pierre</given-names> </name> <article-title>Early Changes in Postprandial Insulin Secretion, Not in Insulin Sensitivity, Characterize Juvenile Obesity</article-title> <source>Diabetes</source> <year>2013</year> <month>09</month> <fpage>696</fpage> <lpage>702</lpage> <volume>43</volume> <issue>5</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/diab.43.5.696</object-id></element-citation></ref><ref id="cit31"><element-citation><name><surname>Schofield</surname> <given-names>C. J.</given-names> </name> <name><surname>Sutherland</surname> <given-names>C.</given-names> </name> <article-title>Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes</article-title> <source>Diabetic Medicine</source> <year>2012</year> <month>03</month> <fpage>972</fpage> <lpage>979</lpage> <volume>29</volume> <issue>8</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1111/j.1464-5491.2012.03655.x</object-id></element-citation></ref><ref id="cit32"><element-citation><name><surname>Nolan</surname> <given-names>Christopher J</given-names> </name> <name><surname>Prentki</surname> <given-names>Marc</given-names> </name> <article-title>Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift</article-title> <source>Diabetes and Vascular Disease Research</source> <year>2019</year> <month>02</month> <fpage>118</fpage> <lpage>127</lpage> <volume>16</volume> <issue>2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1177/1479164119827611</object-id></element-citation></ref><ref id="cit33"><element-citation><name><surname>Tricò</surname> <given-names>Domenico</given-names> </name> <name><surname>Natali</surname> <given-names>Andrea</given-names> </name> <name><surname>Arslanian</surname> <given-names>Silva</given-names> </name> <name><surname>Mari</surname> <given-names>Andrea</given-names> </name> <name><surname>Ferrannini</surname> <given-names>Ele</given-names> </name> <article-title>Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents</article-title> <source>JCI Insight</source> <year>2018</year> <month>12</month> <volume>3</volume> <issue>24</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1172/jci.insight.124912</object-id></element-citation></ref><ref id="cit34"><element-citation><name><surname>van Vliet</surname> <given-names>Stephan</given-names> </name> <name><surname>Koh</surname> <given-names>Han-Chow E.</given-names> </name> <name><surname>Patterson</surname> <given-names>Bruce W.</given-names> </name> <name><surname>Yoshino</surname> <given-names>Mihoko</given-names> </name> <name><surname>LaForest</surname> <given-names>Richard</given-names> </name> <name><surname>Gropler</surname> <given-names>Robert J.</given-names> </name> <name><surname>Klein</surname> <given-names>Samuel</given-names> </name> <name><surname>Mittendorfer</surname> <given-names>Bettina</given-names> </name> <article-title>Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance</article-title> <source>Diabetes</source> <year>2020</year> <month>07</month> <fpage>2112</fpage> <lpage>2119</lpage> <volume>69</volume> <issue>10</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/db20-0377</object-id></element-citation></ref><ref id="cit35"><element-citation><name><surname>Gregory</surname> <given-names>Justin M.</given-names> </name> <name><surname>Cherrington</surname> <given-names>Alan D.</given-names> </name> <name><surname>Moore</surname> <given-names>Daniel J.</given-names> </name> <article-title>The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes</article-title> <source>Diabetes</source> <year>2020</year> <month>04</month> <fpage>837</fpage> <lpage>847</lpage> <volume>69</volume> <issue>5</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2337/dbi19-0026</object-id></element-citation></ref><ref id="cit36"><element-citation><name><surname>Thomas</surname> <given-names>Dylan D</given-names> </name> <name><surname>Corkey</surname> <given-names>Barbara E</given-names> </name> <name><surname>Istfan</surname> <given-names>Nawfal W</given-names> </name> <name><surname>Apovian</surname> <given-names>Caroline M</given-names> </name> <article-title>Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction</article-title> <source>Journal of the Endocrine Society</source> <year>2019</year> <month>08</month> <fpage>1727</fpage> <lpage>1747</lpage> <volume>3</volume> <issue>9</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1210/js.2019-00065</object-id></element-citation></ref><ref id="cit37"><element-citation><name><surname>Zhang</surname> <given-names>Anni M.Y.</given-names> </name> <name><surname>Wellberg</surname> <given-names>Elizabeth A.</given-names> </name> <name><surname>Kopp</surname> <given-names>Janel L.</given-names> </name> <name><surname>Johnson</surname> <given-names>James D.</given-names> </name> <article-title>Hyperinsulinemia in Obesity, Inflammation, and Cancer</article-title> <source>Diabetes &amp; Metabolism Journal</source> <year>2021</year> <month>03</month> <fpage>285</fpage> <lpage>311</lpage> <volume>45</volume> <issue>3</issue> <object-id pub-id-type="doi" specific-use="metadata">10.4093/dmj.2020.0250</object-id></element-citation></ref><ref id="cit38"><element-citation><name><surname>Crofts</surname> <given-names>Catherine Anne Price</given-names> </name> <article-title>Hyperinsulinemia: A unifying theory of chronic disease?</article-title> <source>Diabesity</source> <year>2015</year> <month>11</month> <fpage>34</fpage> <volume>1</volume> <issue>4</issue> <object-id pub-id-type="doi" specific-use="metadata">10.15562/diabesity.2015.19</object-id></element-citation></ref><ref id="cit39"><element-citation><name><surname>Holt</surname> <given-names>S H</given-names> </name> <name><surname>Miller</surname> <given-names>J C</given-names> </name> <name><surname>Petocz</surname> <given-names>P</given-names> </name> <article-title>An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods</article-title> <source>The American Journal of Clinical Nutrition</source> <year>2018</year> <month>01</month> <fpage>1264</fpage> <lpage>1276</lpage> <volume>66</volume> <issue>5</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1093/ajcn/66.5.1264</object-id></element-citation></ref><ref id="cit40"><element-citation><name><surname>Van Cauter</surname> <given-names>E.</given-names> </name> <name><surname>Shapiro</surname> <given-names>E. T.</given-names> </name> <name><surname>Tillil</surname> <given-names>H.</given-names> </name> <name><surname>Polonsky</surname> <given-names>K. S.</given-names> </name> <article-title>Circadian modulation of glucose and insulin responses to meals: relationship to cortisol rhythm</article-title> <source>American Journal of Physiology-Endocrinology and Metabolism</source> <year>2017</year> <month>12</month> <fpage>E467</fpage> <lpage>E475</lpage> <volume>262</volume> <issue>4</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1152/ajpendo.1992.262.4.e467</object-id></element-citation></ref><ref id="cit41"><element-citation><name><surname>Jakubowicz</surname> <given-names>Daniela</given-names> </name> <name><surname>Barnea</surname> <given-names>Maayan</given-names> </name> <name><surname>Wainstein</surname> <given-names>Julio</given-names> </name> <name><surname>Froy</surname> <given-names>Oren</given-names> </name> <article-title>High Caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women</article-title> <source>Obesity</source> <year>2013</year> <month>03</month> <fpage>2504</fpage> <lpage>2512</lpage> <volume>21</volume> <issue>12</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1002/oby.20460</object-id></element-citation></ref><ref id="cit42"><element-citation><name><surname>Gugliucci</surname> <given-names>Alejandro</given-names> </name> <article-title>Fructose at the crossroads of the metabolic syndrome and obesity epidemics</article-title> <source>Frontiers in Bioscience</source> <year>2018</year> <month>11</month> <fpage>186</fpage> <lpage>211</lpage> <volume>24</volume> <issue>2</issue> <object-id pub-id-type="doi" specific-use="metadata">10.2741/4713</object-id></element-citation></ref><ref id="cit43"><mixed-citation publication-type="commun" publication-format="web"><name><surname>Weir</surname> <given-names>GC</given-names></name>, <name><surname>Bonner-Weir</surname> <given-names>S.</given-names></name> <article-title>Five stages of evolving beta-cell dysfunction during progression to diabetes.</article-title> <source>Diabetes.</source> <year>2004</year>;<issue>53(3)</issue>:<fpage>S16</fpage>-<lpage>S21</lpage>.</mixed-citation></ref><ref id="cit44"><element-citation><name><surname>Stumvoll</surname> <given-names>Michael</given-names> </name> <name><surname>Jacob</surname> <given-names>Stephan</given-names> </name> <name><surname>Wahl</surname> <given-names>Hans Günther</given-names> </name> <name><surname>Hauer</surname> <given-names>Bastian</given-names> </name> <name><surname>Löblein</surname> <given-names>Klaus</given-names> </name> <name><surname>Grauer</surname> <given-names>Peter</given-names> </name> <name><surname>Becker</surname> <given-names>Regine</given-names> </name> <name><surname>Nielsen</surname> <given-names>Mette</given-names> </name> <name><surname>Renn</surname> <given-names>Walter</given-names> </name> <name><surname>Häring</surname> <given-names>Hans</given-names> </name> <article-title>Suppression of Systemic, Intramuscular, and Subcutaneous Adipose Tissue Lipolysis by Insulin in Humans<sup>1</sup></article-title> <source>The Journal of Clinical Endocrinology &amp; Metabolism</source> <year>2014</year> <month>01</month> <fpage>3740</fpage> <lpage>3745</lpage> <volume>85</volume> <issue>10</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1210/jcem.85.10.6898</object-id></element-citation></ref><ref id="cit45"><element-citation><name><surname>Tobias</surname> <given-names>Deirdre K</given-names> </name> <name><surname>Chen</surname> <given-names>Mu</given-names> </name> <name><surname>Manson</surname> <given-names>JoAnn E</given-names> </name> <name><surname>Ludwig</surname> <given-names>David S</given-names> </name> <name><surname>Willett</surname> <given-names>Walter</given-names> </name> <name><surname>Hu</surname> <given-names>Frank B</given-names> </name> <article-title>Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis</article-title> <source>The Lancet Diabetes &amp; Endocrinology</source> <year>2015</year> <month>11</month> <fpage>968</fpage> <lpage>979</lpage> <volume>3</volume> <issue>12</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/s2213-8587(15)00367-8</object-id></element-citation></ref><ref id="cit46"><element-citation><name><surname>Wing</surname> <given-names>Rena R</given-names> </name> <name><surname>Phelan</surname> <given-names>Suzanne</given-names> </name> <article-title>Long-term weight loss maintenance</article-title> <source>The American Journal of Clinical Nutrition</source> <year>2018</year> <month>02</month> <fpage>222S</fpage> <lpage>225S</lpage> <volume>82</volume> <issue>1</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1093/ajcn/82.1.222s</object-id></element-citation></ref><ref id="cit47"><element-citation><name><surname>Tucker</surname> <given-names>Shanna</given-names> </name> <name><surname>Bramante</surname> <given-names>Carolyn</given-names> </name> <name><surname>Conroy</surname> <given-names>Molly</given-names> </name> <name><surname>Fitch</surname> <given-names>Angela</given-names> </name> <name><surname>Gilden</surname> <given-names>Adam</given-names> </name> <name><surname>Wittleder</surname> <given-names>Sandra</given-names> </name> <name><surname>Jay</surname> <given-names>Melanie</given-names> </name> <article-title>The Most Undertreated Chronic Disease: Addressing Obesity in Primary Care Settings</article-title> <source>Current Obesity Reports</source> <year>2021</year> <month>07</month> <fpage>396</fpage> <lpage>408</lpage> <volume>10</volume> <issue>3</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1007/s13679-021-00444-y</object-id></element-citation></ref><ref id="cit48"><element-citation><name><surname>Dankner</surname> <given-names>R.</given-names> </name> <name><surname>Chetrit</surname> <given-names>A.</given-names> </name> <name><surname>Shanik</surname> <given-names>M.H.</given-names> </name> <name><surname>Raz</surname> <given-names>I.</given-names> </name> <name><surname>Roth</surname> <given-names>J.</given-names> </name> <article-title>Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up</article-title> <source>Diabetes/Metabolism Research and Reviews</source> <year>2012</year> <month>08</month> <fpage>618</fpage> <lpage>624</lpage> <volume>28</volume> <issue>7</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1002/dmrr.2322</object-id></element-citation></ref><ref id="cit49"><element-citation><name><surname>Zavaroni</surname> <given-names>I.</given-names> </name> <name><surname>Bonini</surname> <given-names>L.</given-names> </name> <name><surname>Gasparini</surname> <given-names>P.</given-names> </name> <name><surname>Barilli</surname> <given-names>A.L.</given-names> </name> <name><surname>Zuccarelli</surname> <given-names>A.</given-names> </name> <name><surname>Dall'Aglio</surname> <given-names>E.</given-names> </name> <name><surname>Delsignore</surname> <given-names>R.</given-names> </name> <name><surname>Reaven</surname> <given-names>G.M.</given-names> </name> <article-title>Hyperinsulinemia in a normal population as a predictor of non—insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The barilla factory revisited</article-title> <source>Metabolism</source> <year>2004</year> <month>09</month> <fpage>989</fpage> <lpage>994</lpage> <volume>48</volume> <issue>8</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/s0026-0495(99)90195-6</object-id></element-citation></ref><ref id="cit50"><element-citation><name><surname>Mehran</surname> <given-names>Arya E.</given-names> </name> <name><surname>Templeman</surname> <given-names>Nicole M.</given-names> </name> <name><surname>Brigidi</surname> <given-names>G. Stefano</given-names> </name> <name><surname>Lim</surname> <given-names>Gareth E.</given-names> </name> <name><surname>Chu</surname> <given-names>Kwan-Yi</given-names> </name> <name><surname>Hu</surname> <given-names>Xiaoke</given-names> </name> <name><surname>Botezelli</surname> <given-names>Jose Diego</given-names> </name> <name><surname>Asadi</surname> <given-names>Ali</given-names> </name> <name><surname>Hoffman</surname> <given-names>Bradford G.</given-names> </name> <name><surname>Kieffer</surname> <given-names>Timothy J.</given-names> </name> <name><surname>Bamji</surname> <given-names>Shernaz X.</given-names> </name> <name><surname>Clee</surname> <given-names>Susanne M.</given-names> </name> <name><surname>Johnson</surname> <given-names>James D.</given-names> </name> <article-title>Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production</article-title> <source>Cell Metabolism</source> <year>2012</year> <month>12</month> <fpage>723</fpage> <lpage>737</lpage> <volume>16</volume> <issue>6</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1016/j.cmet.2012.10.019</object-id></element-citation></ref><ref id="cit51"><element-citation><name><surname>Ludwig</surname> <given-names>David S.</given-names> </name> <name><surname>Friedman</surname> <given-names>Mark I.</given-names> </name> <article-title>Increasing Adiposity</article-title> <source>JAMA</source> <year>2014</year> <month>05</month> <fpage>2167</fpage> <volume>311</volume> <issue>21</issue> <object-id pub-id-type="doi" specific-use="metadata">10.1001/jama.2014.4133</object-id></element-citation></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
