title: Novel insulin sensitizer modulates nutrient sensing pathways and maintains β-cell phenotype in human islets.
abstract: Major bottlenecks in the expansion of human β-cell mass are limited proliferation, loss of β-cell phenotype, and increased apoptosis. In our previous studies, activation of Wnt and mTOR signaling significantly enhanced human β-cell proliferation. However, isolated human islets displayed insulin signaling pathway resistance, due in part to chronic activation of mTOR/S6K1 signaling that results in negative feedback of the insulin signaling pathway and a loss of Akt phosphorylation and insulin content. We evaluated the effects of a new generation insulin sensitizer, MSDC-0160, on restoring insulin/IGF-1 sensitivity and insulin content in human β-cells. This novel TZD has low affinity for binding and activation of PPARγ and has insulin-sensitizing effects in mouse models of diabetes and ability to lower glucose in Phase 2 clinical trials. MSDC-0160 treatment of human islets increased AMPK activity and reduced mTOR activity. This was associated with the restoration of IGF-1-induced phosphorylation of Akt, GSK-3, and increased protein expression of Pdx1. Furthermore, MSDC-0160 in combination with IGF-1 and 8 mM glucose increased β-cell specific gene expression of insulin, pdx1, nkx6.1, and nkx2.2, and maintained insulin content without altering glucose-stimulated insulin secretion. Human islets were unable to simultaneously promote DNA synthesis and maintain the β-cell phenotype. Lithium-induced GSK-3 inhibition that promotes DNA synthesis blocked the ability of MSDC-0160 to maintain the β-cell phenotype. Conversely, MSDC-0160 prevented an increase in DNA synthesis by blocking β-catenin nuclear translocation. Due to the counteracting pathways involved in these processes, we employed a sequential ex vivo strategy to first induce human islet DNA synthesis, followed by MSDC-0160 to promote the β-cell phenotype and insulin content. This new generation PPARγ sparing insulin sensitizer may provide an initial tool for relieving inherent human islet insulin signaling pathway resistance that is necessary to preserve the β-cell phenotype during β-cell expansion for the treatment of diabetes.
authors: Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri, United States of America.
authors: Nidhi
authors: N
authors: Rohatgi
authors: Haytham
authors: H
authors: Aly
authors: Connie A
authors: CA
authors: Marshall
authors: William G
authors: WG
authors: McDonald
authors: Rolf F
authors: RF
authors: Kletzien
authors: Jerry R
authors: JR
authors: Colca
authors: Michael L
authors: ML
authors: McDaniel
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D009687:Nuclear Proteins; D010641:Phenotype; D010766:Phosphorylation; D045706:Proprotein Convertase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D014157:Transcription Factors; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C581095:MSDC-0160; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; C000715628:Nkx2-2 protein, rat; D009687:Nuclear Proteins; D011725:Pyridines; D045162:Thiazolidinediones; D014157:Transcription Factors; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D045706:Proprotein Convertase 2
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