title: Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.
abstract: Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian 116044, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Guan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Feng
authors.forename: Dezheng
authors.initials: D
authors.lastname: Gong
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Cai
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism / Q000517:prevention & control; D006949:Hyperlipidemias / Q000378:metabolism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D039823:Iridoids / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D019308:Palmitic Acid / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007004:Hypoglycemic Agents; D039823:Iridoids; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D008315:Malondialdehyde; D000255:Adenosine Triphosphate; C007834:genipin; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: 2,7-dichlorofluorescein diacetate; ATP; Aging; Akt; BCA; Genipin; H2DCFDA; IR; Insulin resistance; JNK/SAPK; MDA; MMP; Mitochondria; Oxidative stress; ROS; T2DM; TC; TG; adenosine tri-phosphate; also called protein kinase B (PKB); bicinchoninic acid; c-Jun kinases/stress-activated protein kinase; insulin resistance; intravenous insulin tolerance tests; ivITT; kITT; malondialdehyde; mitochondrial membrane potential; reactive oxygen species; the glucose decay constant rate during insulin tolerance test; total cholesterol; triacylglycerols; type 2 diabetes mellitus