Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance.
Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion and/or beta-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy.
Kaneto
Hideaki
H
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan. kaneto@medone.med.osaka
Nakatani
Yoshihisa
Y
Kawamori
Dan
D
Miyatsuka
Takeshi
T
Matsuoka
Taka-aki
TA
Matsuhisa
Munehide
M
Yamasaki
Yoshimitsu
Y
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology*; D011506:Proteins / Q000627:therapeutic use; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D011506:Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C050087:oxygen-regulated proteins; D048031:JNK Mitogen-Activated Protein Kinases