The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice.
Pancreatic beta-cell apoptosis is important in the pathogenesis and potential treatment of type 1 diabetes mellitus. We investigated whether Humanin, a recently described survival factor for neurons, could improve the survival of beta-cells and delay or treat diabetes in the nonobese diabetic (NOD) model. Humanin reduced apoptosis induced by serum starvation in NIT-1 cells and decreased apoptosis induced by cytokine treatment. Humanin induced signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation over a 24-hour time course. Specific inhibition of signal transducer and activator of transcription 3 resulted in nullifying the protective effect of Humanin. Humanin normalized glucose tolerance in NOD mice treated for 6 weeks, and their pancreata revealed decreased lymphocyte infiltration and severity. In addition, Humanin delayed/prevented the onset of diabetes in NOD mice treated for 20 weeks. In summary, Humanin treatment decreases cytokine-induced apoptosis in beta-cells in vitro and improved glucose tolerance and onset of diabetes in NOD mice in vivo. This indicates that Humanin may be useful for islet protection and survival in a spectrum of diabetes-related therapeutics.
Hoang
Phuong T
PT
Division of Pediatric Endocrinology, Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Park
Patricia
P
Cobb
Laura J
LJ
Paharkova-Vatchkova
Valdislava
V
Hakimi
Michael
M
Cohen
Pinchas
P
Lee
Kuk-Wha
KW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D009474:Neurons / Q000187:drug effects; D009490:Neurosecretory Systems / Q000166:cytology / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C427211:humanin; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases