Investigation for the Protecting Effects of Estradiol on Glucosamine-induced Insulin Resistance

Abstract

The metabolic syndrome and type 2 diabetes mellitus (T2DM) are highly prevalent health problems in the modern era Insulin resistance (IR) is a hallmark of T2DM and metabolic syndrome Many literatures have shown that the higher prevalence of T2DM and metabolic syndrome in menopausal than premenopausal women is a powerful evidence that ovarian estrogen 17 β-estradiol (E2) has protecting effects in IR and pancreatic β-cell dysfunction Besides many menopausal women suffered from osteoarthritis and glucosamine (GlcN) is a popular nutritional supplement used to treat osteoarthritis Some studies have demonstrated that GlcN causes not only IR but also β-cell dysfunction To date no study has investigated for the protecting effect of E2 on GlcN-induced IR In our studies we found that female rats do not develop IR upon GlcN treatment except after ovariectomy (OVX) and the underlying mechanisms are relevant to decreasing the expression of glucose transport protein subtype 4 (GLUT-4) in skeletal muscle and increasing the size of pancreatic islets Besides in pancreatic islets we found either GlcN or ovariectomy alone reduced the mRNA expression and the staining intensity of insulin The combination of GlcN and OVX further synergistically reduced the mRNA expression and staining intensity of insulin GlcN alone also induced β-cell apoptosis and this adverse effect aggravated after ovariectomy In our in vitro study we found GlcN inhibited insulin secretion of β-cell via decreasing intracellular calcium (Ca2+) influx and Kir6 2 expression in MIN-6 cells GlcN also decreased MIN-6 cell viability by inducing the expression of ER stress-associated proteins including C/EBP homologous protein (CHOP) phospho-protein kinase-like endoplasmic reticulum kinase (p-PERK) phospho-eukaryotic translation initiation factor 2? (p-EIF2?) and c-Jun N-terminal kinase (JNK) E2 counteracted the GlcN-induced attenuation in intracellular calcium concentration extracellular insulin secretion expression of Kir6 2 cell viability and the expression of ER stress-associated proteins and ICI182 780 inhibited these beneficial effects of E2 In conclusion we demonstrated that E2 has the protecting effects for GlcN-induced IR and β-cell dysfunction in vivo and in vitro

Date of Award	2014 Aug 30
Original language	English
Supervisor	Meng-Hsing Wu (Supervisor)