title: Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.
abstract: We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and β-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet.
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Mei
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Haihua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Huailan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Longying
authors.initials: L
authors.lastname: Zha
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Junwei
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USA.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27559, USADepartment of Nutrition and Food HygieneTongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of ChinaDepartment of Preventive MedicineHubei University of Medicine, Shiyan, Hubei 442000, People's Republic of ChinaDepartment of Nutrition and Food HygieneSchool of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, ChinaDepartment of MedicineTai He Hospital, Hubei University of Medicine, Shiyan, Hubai 442000, ChinaDepartment of Medicine (Endocrinology)University of Virginia Health System, Charlottesville, Virginia 22908, USADepartment of Medicine (Endocrinology and Metabolism)Duke University School of Medicine, Durham, North Carolina 27705, USADepartment of NutritionGillings School of Global Public Health, Nutrition Research Institute (NRI) at Kannapolis, The Univ
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D004032:Diet; D005223:Fats / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity; D000069036:Insulin Glargine; D007333:Insulin Resistance / Q000502:physiology*; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D005223:Fats; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D008055:Lipids; D000069036:Insulin Glargine; D002784:Cholesterol
keywords: T2DM; cholesterol synthesis; diabetes; glargine; insulin; insulin resistance
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