Ignite Creation Date:
2025-12-25 @ 4:26 AM
Ignite Modification Date:
2025-12-26 @ 3:29 AM
Study NCT ID:
NCT00637520
Status:
TERMINATED
Last Update Posted:
2017-07-11
First Post:
2008-03-12
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D007333', 'term': 'Insulin Resistance'}, {'id': 'D065626', 'term': 'Non-alcoholic Fatty Liver Disease'}], 'ancestors': [{'id': 'D006946', 'term': 'Hyperinsulinism'}, {'id': 'D044882', 'term': 'Glucose Metabolism Disorders'}, {'id': 'D008659', 'term': 'Metabolic Diseases'}, {'id': 'D009750', 'term': 'Nutritional and Metabolic Diseases'}, {'id': 'D005234', 'term': 'Fatty Liver'}, {'id': 'D008107', 'term': 'Liver Diseases'}, {'id': 'D004066', 'term': 'Digestive System Diseases'}]}}, 'protocolSection': {'designModule': {'bioSpec': {'retention': 'SAMPLES_WITH_DNA', 'description': 'Frozen tissue, serum, whole blood, urine'}, 'studyType': 'OBSERVATIONAL', 'designInfo': {'timePerspective': 'CROSS_SECTIONAL', 'observationalModel': 'CASE_CONTROL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 29}, 'patientRegistry': False}, 'statusModule': {'overallStatus': 'TERMINATED', 'startDateStruct': {'date': '2007-07'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2016-09', 'completionDateStruct': {'date': '2017-04-13', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2017-07-10', 'studyFirstSubmitDate': '2008-03-12', 'studyFirstSubmitQcDate': '2008-03-17', 'lastUpdatePostDateStruct': {'date': '2017-07-11', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2008-03-18', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2013-03-29', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Measure Insulin Resistance (IR) and clearance its effects on lipid metabolism, inflammatory response, and oxidative stress using intravenous glucose tolerance testing in patients with NAFLD as compared to matched controls.', 'timeFrame': '36 months'}, {'measure': 'Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls', 'timeFrame': '36 months'}, {'measure': 'Measure the differential effects of IR and lipid metabolism on peripheral mononuclear cell (PBMC) inflammatory response and the associated hepatocyte mitochondrial ultrastructure and measures of oxidative stress.', 'timeFrame': '36 Months'}]}, 'oversightModule': {'oversightHasDmc': False}, 'conditionsModule': {'keywords': ['Nonalcoholic Fatty Liver Disease', 'Insulin Resistance', 'Lipid Metabolism'], 'conditions': ['Insulin Resistance', 'Nonalcoholic Fatty Liver Disease']}, 'referencesModule': {'references': [{'pmid': '10569299', 'type': 'BACKGROUND', 'citation': 'Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999 Nov;107(5):450-5. doi: 10.1016/s0002-9343(99)00271-5.'}, {'pmid': '10833486', 'type': 'BACKGROUND', 'citation': 'Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T. Liver fibrosis in overweight patients. Gastroenterology. 2000 Jun;118(6):1117-23. doi: 10.1016/s0016-5085(00)70364-7.'}, {'pmid': '2654841', 'type': 'BACKGROUND', 'citation': 'Silverman JF, Pories WJ, Caro JF. Liver pathology in diabetes mellitus and morbid obesity. Clinical, pathological, and biochemical considerations. Pathol Annu. 1989;24 Pt 1:275-302. No abstract available.'}, {'pmid': '4741905', 'type': 'BACKGROUND', 'citation': 'Kern WH, Heger AH, Payne JH, DeWind LT. Fatty metamorphosis of the liver in morbid obesity. Arch Pathol. 1973 Nov;96(5):342-6. No abstract available.'}, {'pmid': '11961152', 'type': 'BACKGROUND', 'citation': 'Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346(16):1221-31. doi: 10.1056/NEJMra011775. No abstract available.'}, {'pmid': '11826411', 'type': 'BACKGROUND', 'citation': 'Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, Karim R, Lin R, Samarasinghe D, Liddle C, Weltman M, George J. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002 Feb;35(2):373-9. doi: 10.1053/jhep.2002.30692.'}, {'pmid': '12668987', 'type': 'BACKGROUND', 'citation': 'Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003 Apr;37(4):917-23. doi: 10.1053/jhep.2003.50161.'}, {'pmid': '11826410', 'type': 'BACKGROUND', 'citation': 'Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, Cassader M, David E, Cavallo-Perin P, Rizzetto M. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002 Feb;35(2):367-72. doi: 10.1053/jhep.2002.30690.'}, {'pmid': '7752170', 'type': 'BACKGROUND', 'citation': 'Ikai E, Ishizaki M, Suzuki Y, Ishida M, Noborizaka Y, Yamada Y. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens. 1995 Feb;9(2):101-5.'}, {'pmid': '2044434', 'type': 'BACKGROUND', 'citation': 'DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991 Mar;14(3):173-94. doi: 10.2337/diacare.14.3.173.'}, {'pmid': '11473047', 'type': 'BACKGROUND', 'citation': 'Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001 Aug;50(8):1844-50. doi: 10.2337/diabetes.50.8.1844.'}, {'pmid': '7523217', 'type': 'BACKGROUND', 'citation': 'Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994 Oct;107(4):1103-9. doi: 10.1016/0016-5085(94)90235-6.'}, {'pmid': '9538625', 'type': 'BACKGROUND', 'citation': 'Lee JH, Rhee PL, Lee JK, Lee KT, Kim JJ, Koh KC, Paik SW, Rhee JC, Choi KW. Role of hyperinsulinemia and glucose intolerance in the pathogenesis of nonalcoholic fatty liver in patients with normal body weight. Korean J Intern Med. 1998 Feb;13(1):12-4.'}, {'pmid': '11788484', 'type': 'BACKGROUND', 'citation': 'Expert Committee on the Diagnosis and Clasification of Diabetes Mellitus. American Diabetes Association: clinical practice recommendations 2002. Diabetes Care. 2002 Jan;25 Suppl 1:S1-147. doi: 10.2337/diacare.25.2007.s1. No abstract available.'}, {'pmid': '15599400', 'type': 'BACKGROUND', 'citation': 'Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004 Dec;114(12):1752-61. doi: 10.1172/JCI21625.'}, {'pmid': '4750460', 'type': 'BACKGROUND', 'citation': 'Manes JL, Taylor HB, Starkloff GB. Relationship between hepatic morphology and clinical and biochemical findings in morbidly obese patients. J Clin Pathol. 1973 Oct;26(10):776-83. doi: 10.1136/jcp.26.10.776.'}, {'pmid': '12716488', 'type': 'BACKGROUND', 'citation': 'Kaneda M, Kashiwamura S, Ueda H, Sawada K, Sugihara A, Terada N, Kimura-Shimmyo A, Fukuda Y, Shimoyama T, Okamura H. Inflammatory liver steatosis caused by IL-12 and IL-18. J Interferon Cytokine Res. 2003 Mar;23(3):155-62. doi: 10.1089/107999003321532493.'}, {'pmid': '15568287', 'type': 'BACKGROUND', 'citation': 'Khaodhiar L, Ling PR, Blackburn GL, Bistrian BR. Serum levels of interleukin-6 and C-reactive protein correlate with body mass index across the broad range of obesity. JPEN J Parenter Enteral Nutr. 2004 Nov-Dec;28(6):410-5. doi: 10.1177/0148607104028006410.'}]}, 'descriptionModule': {'briefSummary': 'We hypothesize that insulin resistance is characteristic of nonalcoholic fatty liver disease as compared to age, gender, non-diabetic BMI-matched control subjects, both healthy and those with non-cirrhotic, non-steatotic liver disease.', 'detailedDescription': "Purpose of the study:\n\nTo date, no case control study evaluating insulin resistance (IR) in nonalcoholic fatty liver disease (NALFD) has been published. We hypothesize that IR is characteristic of NAFLD as compared to age, gender, non-diabetic BMI-matched control subjects, both healthy and those with non-cirrhotic, non-steatotic liver disease. The following aims test this central hypothesis:\n\nSpecific Aim 1: Measure IR and insulin clearance using intravenous glucose tolerance testing and Bergman's Minimal Modeling in patients with NAFLD as compared to matched controls (healthy and those with non-steatotic hepatitis). This aim tests the postulate that IR is necessary for the development of hepatic steatosis as compared to healthy (non-steatotic livers). It will also test the postulate that IR is not present as a confounding factor (impaired hepatic clearance) in NAFLD as compared to those with non-steatotic forms of hepatitis.\n\nSpecific Aim 2: Determine if IR is associated with altered parameters of lipid metabolism as compared to matched controls. This aim addresses whether IR (if present) is associated with abnormal lipid parameters in NAFLD or can be observed irrespective of the presence of hepatic steatosis.\n\nSpecific Aim 3: Measure the differential effects of IR and lipid metabolism on peripheral mononuclear cell (PBMC) inflammatory response and the associated hepatocyte mitochondrial ultrastructure and measures of oxidative stress. Since increased oxidative stress and bioenergetic failure have been associated with hepatic steatosis, this aim will address whether IR and/or steatosis results in impaired inflammatory response and increased oxidative stress as compared to controls. Changes in innate immune response will be determined by measuring inflammatory indices thought to correlate with obesity, IR, and/or chronic hepatitis: 1) interleukins (IL-2, IL-4, IL-6, IL-10, IL-12, IL-18) 2) C-reactive protein, 3) TNF-a and TGF-B 4) IFN-A \\& IFN-g, and 5) adiponectin. Changes in oxidative stress will be determined by measuring key indices of oxidative stress and damage. These include, a) reduced and oxidized glutathione (GSH and GSSG); oxidation/reduction status), b) malondialdehyde (MDA;lipid peroxidation), c) nitrotyrosine (NO damage), and d) 8OHdG and 8OHG (DNA damage).\n\nBackground and significance:\n\nObesity, diabetes, hypertriglyceridemia, hypertension, and coronary heart disease constitute a phenotype common to individuals with either the IR syndrome or NAFLD1-12. Furthermore, the hepatic steatosis, fibrosis, and cirrhosis characteristic of NAFLD are also frequent histologic findings in patients with IR 3-7. Together, these data beg the question whether NAFLD and IR are causally associated. Support for this notion derives from recent observations that IR may be a strong, independent predictor of NAFLD, even in the absence of glucose intolerance 13. Moreover, since NAFLD has been reported to occur in lean subjects (BMI greater than 25) with normoglycemia 14, 15, it is reasonable to postulate that NAFLD may be an early manifestation and a consequence of IR. Increased oxidative stress is an important pathogenic mechanism of obesity-associated metabolic syndrome 16. Fat accumulation correlated with systemic oxidative stress in humans and mice. However, increase oxidative stress as an instigator of the metabolic syndrome in patients with NAFLD as compared to controls has not yet been investigated. Furthermore, impaired cytokine medicated inflammatory response has been shown to correlate with body mass index across the broad range of obesity and may mediate hepatic steatosis and/or lead to mitochondrial dysfunction in hepatocytes 17, 18. Discerning whether NAFLD is attributable to increased oxidative stress and/or abnormalities in innate immune response would be imperative in identifying potentially useful therapeutic targets for obesity-associated liver disease."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '75 Years', 'minimumAge': '18 Years', 'samplingMethod': 'NON_PROBABILITY_SAMPLE', 'studyPopulation': 'Liver Clinic, Liver Transplant Clinic, Weight Loss Surgery Clinic', 'healthyVolunteers': True, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Biochemical and liver histologic features to confirm the presence of a healthy liver, fatty liver, and/or non-fatty liver with inflammation due to another etiology besides NAFLD.\n\nExclusion Criteria:\n\n* \\> 20 grams of alcohol/day\n* Impaired oral glucose tolerance test\n* Clinical or histologic evidence of cirrhosis (stage 5-6 fibrosis) or portal hypertension.\n* Chronic hepatitis C infection\n* Known diabetes mellitus or need for insulin-sensitizing agents and/or insulin therapy.\n* Pregnancy'}, 'identificationModule': {'nctId': 'NCT00637520', 'briefTitle': 'Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study', 'organization': {'class': 'OTHER', 'fullName': 'Duke University'}, 'officialTitle': 'Insulin Resistance in Nonalcoholic Fatty Liver Disease: A Case Control Study', 'orgStudyIdInfo': {'id': 'Pro00006742'}, 'secondaryIdInfos': [{'id': 'NIH K23 Award'}, {'id': '8592', 'type': 'OTHER', 'domain': 'Duke legacy protocol number'}]}, 'armsInterventionsModule': {'armGroups': [{'label': '1', 'description': 'Subjects with NAFLD'}, {'label': '2', 'description': 'Subjects without liver disease'}, {'label': '3', 'description': 'Subjects with non-steatotic hepatitis'}]}, 'contactsLocationsModule': {'locations': [{'zip': '27710', 'city': 'Durham', 'state': 'North Carolina', 'country': 'United States', 'facility': 'Duke University Medical Center', 'geoPoint': {'lat': 35.99403, 'lon': -78.89862}}], 'overallOfficials': [{'name': 'Manal F Abdelmalek, MD., MPH', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Faculty Member'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Duke University', 'class': 'OTHER'}, 'collaborators': [{'name': 'University of Florida', 'class': 'OTHER'}], 'responsibleParty': {'type': 'SPONSOR'}}}}