{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:11:34Z","timestamp":1788498694329,"version":"build-2803163510"},"reference-count":68,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,1,28]],"date-time":"2017-01-28T00:00:00Z","timestamp":1485561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of the liver and the endocrine pancreas in development of hyperinsulinemia in different types of obesity remains unclear. Sedentary rats (160 g) were fed a low-fat-diet (LFD, chow 13% kcal fat), high-fat-diet (HFD, 35% fat), or HFD+ 30% ethanol+ 30% fructose (HF-EFr, 22% fat). Overnight-fasted rats were culled after one, four or eight weeks. Pancreatic and hepatic mRNAs were isolated for subsequent RT-PCR analysis. After eight weeks, body weights increased three-fold in the LFD group, 2.8-fold in the HFD group, and 2.4-fold in the HF-EFr (p &lt; 0.01). HF-EFr-fed rats had the greatest liver weights and consumed less food during Weeks 4\u20138 (p &lt; 0.05). Hepatic-triglyceride content increased progressively in all groups. At Week 8, HOMA-IR values, fasting serum glucose, C-peptide, and triglycerides levels were significantly increased in LFD-fed rats compared to that at earlier time points. The greatest plasma levels of glucose, triglycerides and leptin were observed in the HF-EFr at Week 8. Gene expression of pancreatic-insulin was significantly greater in the HFD and HF-EFr groups versus the LFD. Nevertheless, insulin: C-peptide ratios and HOMA-IR values were substantially higher in HF-EFr. Hepatic gene-expression of insulin-receptor-substrate-1\/2 was downregulated in the HF-EFr. The expression of phospho-ERK-1\/2 and inflammatory-mediators were greatest in the HF-EFr-fed rats. Chronic intake of both LFD and HFD induced obesity, MetS, and intrahepatic-fat accumulation. The hyperinsulinemia is the strongest in rats with the lowest body weights, but having the highest liver weights. This accompanies the strongest increase of pancreatic insulin production and the maximal decrease of hepatic insulin signaling, which is possibly secondary to hepatic fat deposition, inflammation and other factors.<\/jats:p>","DOI":"10.3390\/ijms18020285","type":"journal-article","created":{"date-parts":[[2017,1,30]],"date-time":"2017-01-30T11:36:30Z","timestamp":1485776190000},"page":"285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome"],"prefix":"10.3390","volume":"18","author":[{"given":"Salamah","family":"Alwahsh","sequence":"first","affiliation":[{"name":"Clinic for Gastroenterology and Endocrinology, University Medical Center, Georg-August-University Goettingen, Goettingen D-37075, Germany"},{"name":"MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Dwyer","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shareen","family":"Forbes","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, University\/BHF Centre for Cardiovascular Science, Queen\u2019s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Van Thiel","sequence":"additional","affiliation":[{"name":"Advanced Liver and Gastrointestinal Disease Center, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Starkey Lewis","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Ramadori","sequence":"additional","affiliation":[{"name":"Clinic for Gastroenterology and Endocrinology, University Medical Center, Georg-August-University Goettingen, Goettingen D-37075, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.2174\/1574887109666141216111143","article-title":"Non alcoholic fatty liver: epidemiology and natural history","volume":"9","author":"Masarone","year":"2014","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/ajg.2009.67","article-title":"NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: An eleven-year follow-up study","volume":"104","author":"Adams","year":"2009","journal-title":"Am. J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1038\/ajg.2015.235","article-title":"Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy","volume":"110","author":"Wei","year":"2015","journal-title":"Am. J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1478-3231.2008.01718.x","article-title":"Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus","volume":"29","author":"Leite","year":"2009","journal-title":"Liver Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e161971","DOI":"10.1001\/jamapediatrics.2016.1971","article-title":"Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease","volume":"170","author":"Newton","year":"2016","journal-title":"JAMA Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/ajg.2012.20","article-title":"What should we recommend to our patients with NAFLD regarding alcohol use?","volume":"107","author":"Liangpunsakul","year":"2012","journal-title":"Am. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.2337\/diabetes.51.10.3014","article-title":"Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity","volume":"51","author":"Arslanian","year":"2002","journal-title":"Diabetes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2337\/diab.39.5.570","article-title":"Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes","volume":"39","author":"Svedberg","year":"1990","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1053\/j.gastro.2008.03.021","article-title":"Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes","volume":"135","author":"Kotronen","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1210\/jcem.82.6.3979","article-title":"Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals","volume":"82","author":"Jones","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","first-page":"608","article-title":"Insulin Degradation: Progress and Potential 1","volume":"19","author":"Duckworth","year":"1998","journal-title":"Endocr. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.2169\/internalmedicine.55.5288","article-title":"Significance of Hepatic Insulin Clearance in Patients with Chronic Hepatitis C and Non-alcoholic Fatty Liver Disease","volume":"55","author":"Miyaaki","year":"2016","journal-title":"Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1194\/jlr.M054080","article-title":"ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content","volume":"56","author":"Camporez","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/nm788","article-title":"Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase","volume":"8","author":"Yamauchi","year":"2002","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/S0022-3565(25)10144-4","article-title":"Alteration of rat hepatic insulin metabolism by glyburide and glipizide","volume":"264","author":"Chen","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.2337\/diabetes.53.8.2169","article-title":"Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes","volume":"53","author":"Tiikkainen","year":"2004","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jhep.2010.06.021","article-title":"Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C","volume":"54","author":"Mayoral","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Basu, S., Yoffe, P., Hills, N., and Lustig, R.H. (2013). The relationship of sugar to population-level diabetes prevalence: An econometric analysis of repeated cross-sectional data. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057873"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12986-016-0074-1","article-title":"High-fructose and high-fat diet-induced disorders in rats: Impact on diabetes risk, hepatic and vascular complications","volume":"13","author":"Lozano","year":"2016","journal-title":"Nutr. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.3945\/ajcn.2008.27336","article-title":"Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes","volume":"89","author":"Ith","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1093\/ajcn\/80.4.1043","article-title":"Fructose, glycemic load, and quantity and quality of carbohydrate in relation to plasma C-peptide concentrations in US women","volume":"80","author":"Wu","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/alcalc\/agv048","article-title":"Beer Is Less Harmful for the Liver than Plain Ethanol: Studies in Male Mice Using a Binge-Drinking Model","volume":"50","author":"Landmann","year":"2015","journal-title":"Alcohol Alcohol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Godos, J., Federico, A., Dallio, M., and Scazzina, F. (2016). Mediterranean diet and nonalcoholic fatty liver disease: Molecular mechanisms of protection. Int. J. Food Sci. Nutr.","DOI":"10.1080\/09637486.2016.1214239"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0730-725X(97)00163-X","article-title":"Effect of ethanol and fructose on liver metabolism a dynamic 31Phosphorus magnetic resonance spectroscopy study in normal volunteers","volume":"15","author":"Boesch","year":"1997","journal-title":"Magn. Reson. Imaging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.crvi.2009.01.007","article-title":"Fructose-induced increase in ethanol metabolism and the risk of Syndrome X in man","volume":"332","author":"Uzuegbu","year":"2009","journal-title":"C. R. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Song, M., Chen, T., Prough, R.A., Cave, M.C., and McClain, C.J. (2016). Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response. Alcohol. Clin. Exp. Res.","DOI":"10.1111\/acer.12994"},{"key":"ref_27","first-page":"896","article-title":"Mitoneet mediates TNF\u03b1-induced necroptosis promoted by exposure to fructose and ethanol","volume":"127","author":"Shulga","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Alwahsh, S.M., Xu, M., Schultze, F.C., Wilting, J., Mihm, S., Raddatz, D., and Ramadori, G. (2014). Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104220"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.2337\/dc08-1085","article-title":"Dietary energy density predicts the risk of incident type 2 diabetes: the European Prospective Investigation of Cancer (EPIC)-Norfolk Study","volume":"31","author":"Wang","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"G591","DOI":"10.1152\/ajpgi.00269.2014","article-title":"Effects of obesity on severity of colitis and cytokine expression in mouse mesenteric fat. Potential role of adiponectin receptor 1","volume":"308","author":"Sideri","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1172\/JCI37385","article-title":"Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight\/obese humans","volume":"119","author":"Stanhope","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/hep.23280","article-title":"Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications","volume":"51","author":"Fabbrini","year":"2010","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/hep.1840050407","article-title":"Choline fails to prevent liver fibrosis in ethanol-fed baboons but causes toxicity","volume":"5","author":"Lieber","year":"1985","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0016-5085(85)80146-3","article-title":"Citation Pathogenesis of precirrhotic portal hypertension in alcohol-fed baboons","volume":"88","author":"Miyakawa","year":"1985","journal-title":"Gastroenterology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/hep.1840100417","article-title":"Experimental methods of ethanol administration","volume":"10","author":"Lieber","year":"1989","journal-title":"Hepatology"},{"key":"ref_36","first-page":"197","article-title":"Liquid diet technique of ethanol administration: 1989 update","volume":"24","author":"Lieber","year":"1989","journal-title":"Alcohol Alcohol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1369-1600.2009.00192.x","article-title":"Ethanol Consumption: How Should We Measure It? Achieving Consilience between Human and Animal Phenotypes","volume":"15","author":"Leeman","year":"2010","journal-title":"Addict. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.jnutbio.2015.05.011","article-title":"Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time","volume":"26","author":"Sellmann","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrgastro.2015.35","article-title":"Alcoholic liver disease: mechanisms of injury and targeted treatment","volume":"12","author":"Louvet","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_40","first-page":"631","article-title":"Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease","volume":"16","author":"Nakamuta","year":"2005","journal-title":"Int. J. Mol. Med."},{"key":"ref_41","first-page":"S17","article-title":"Pathophysiology of nonalcoholic steatohepatitis","volume":"40","author":"McCullough","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Alwahsh, S.M., and Gebhardt, R. (2016). Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). Arch. Toxicol.","DOI":"10.1007\/s00204-016-1892-7"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/hep.26594","article-title":"High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase","volume":"58","author":"Ishimoto","year":"2013","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.bbrc.2015.09.090","article-title":"Alcohol exposure increases the expression of cardiac transcription factors through ERK1\/2-mediated histone3 hyperacetylation in H9C2 cells","volume":"466","author":"Gao","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.mce.2013.05.021","article-title":"Hepatic ERK activity plays a role in energy metabolism","volume":"375","author":"Jiao","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/hmg\/10.6.605","article-title":"PTEN inhibits insulin-stimulated MEK\/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1\/Grb-2\/Sos complex formation in a breast cancer model","volume":"10","author":"Weng","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","first-page":"1","article-title":"Fructose-induced ROS generation impairs glucose utilization in L6 skeletal muscle cells","volume":"5762","author":"Jaiswal","year":"2015","journal-title":"Free Radic. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature01137","article-title":"A central role for JNK in obesity and insulin resistance","volume":"420","author":"Hirosumi","year":"2002","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1038\/ncomms3434","article-title":"Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome","volume":"4","author":"Lanaspa","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"R1380","DOI":"10.1152\/ajpregu.2001.281.5.R1380","article-title":"Hyperglycemia compensates for diet-induced insulin resistance in liver and skeletal muscle of rats","volume":"281","author":"Commerford","year":"2001","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1042\/CS20110665","article-title":"Apocynin administration prevents the changes induced by a fructose-rich diet on rat liver metabolism and the antioxidant system","volume":"123","author":"Castro","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.2119\/molmed.2012.00223","article-title":"Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response","volume":"18","author":"Spruss","year":"2012","journal-title":"Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1172\/JCI110477","article-title":"Glucose Ingestion in Dogs Alters the Hepatic Extraction of Insulin","volume":"69","author":"Jaspan","year":"1982","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"132","DOI":"10.2337\/diab.31.2.132","article-title":"Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin","volume":"31","author":"Flier","year":"1982","journal-title":"Diabetes"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1053\/j.gastro.2016.01.002","article-title":"How Safe Is Moderate Alcohol Consumption in Overweight and Obese Individuals?","volume":"150","author":"Sookoian","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s00125-008-1031-y","article-title":"Moderate alcohol consumption increases insulin sensitivity and ADIPOQ expression in postmenopausal women: A randomised, crossover trial","volume":"51","author":"Joosten","year":"2008","journal-title":"Diabetologia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s00394-015-0929-7","article-title":"Moderate alcohol consumption diminishes the development of non-alcoholic fatty liver disease (NAFLD) in ob\/ob mice","volume":"55","author":"Kanuri","year":"2016","journal-title":"Eur. J. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"10480","DOI":"10.3390\/nu7125544","article-title":"Anti-Obesity Effect of 6,8-Diprenylgenistein, an Isoflavonoid of Cudrania tricuspidata Fruits in High-Fat Diet-Induced Obese Mice","volume":"7","author":"Jo","year":"2015","journal-title":"Nutrients"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ibrahim, S.M., El Denshary, E.S., Abdallah, D.M., Popkin, B., Malik, V., Popkin, B., Bray, G., Despres, J., Willett, W., and Grundy, S. (2015). Geraniol, Alone and in Combination with Pioglitazone, Ameliorates Fructose-Induced Metabolic Syndrome in Rats via the Modulation of Both Inflammatory and Oxidative Stress Status. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117516"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/hep.22811","article-title":"Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats","volume":"49","author":"Chen","year":"2009","journal-title":"Hepatology"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Papamiltiadous, E.S., Roberts, S.K., Nicoll, A.J., Ryan, M.C., Itsiopoulos, C., Salim, A., and Tierney, A.C. (2016). A randomised controlled trial of a Mediterranean Dietary Intervention for Adults with Non Alcoholic Fatty Liver Disease (MEDINA): Study protocol. BMC Gastroenterol., 16.","DOI":"10.1186\/s12876-016-0426-3"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1089\/chi.2015.0197","article-title":"Association between Adherence to the Mediterranean Diet and Presence of Nonalcoholic Fatty Liver Disease in Children","volume":"12","author":"Cakir","year":"2016","journal-title":"Child. Obes."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Heikkinen, S., Argmann, C.A., Champy, M.-F., and Auwerx, J. (2007). Evaluation of glucose homeostasis. Curr. Protoc. Mol. Biol.","DOI":"10.1002\/0471142727.mb29b03s77"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jss.2013.12.019","article-title":"Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration","volume":"203","author":"Xu","year":"2016","journal-title":"J. Surg. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.3748\/wjg.v20.i7.1807","article-title":"Diet high in fructose leads to an overexpression of lipocalin-2 in rat fatty liver","volume":"20","author":"Alwahsh","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_67","first-page":"925","article-title":"Histological changes of liver glycogen storage in mice (Mus musculus) caused by high-protein diets","volume":"21","author":"Ulusoy","year":"2006","journal-title":"Histol. Histopathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/00007890-198510000-00018","article-title":"An improved method for isolation of mouse pancreatic islets","volume":"40","author":"Gotoh","year":"1985","journal-title":"Transplantation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/285\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:27:11Z","timestamp":1760207231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,28]]},"references-count":68,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["ijms18020285"],"URL":"https:\/\/doi.org\/10.3390\/ijms18020285","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,28]]}}}