Insulin promotes proliferation and fibrosing responses in activated pancreatic stellate cells.
Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses. We found that compared with normal, pancreata from T2DM patients displayed extensive collagen deposition and activated PaSC in islet and peri-islet exocrine pancreas. Mice fed a high-fat diet for up to 12 mo similarly displayed increasing peri-islet fibrosis compared with mice fed control diet. Both quiescent and activated PaSC coexpress insulin (IR; mainly A type) and IGF (IGF-1R) receptors, and both insulin and glucose modulate receptor expression. In cultured PaSC, insulin induced rapid tyrosine autophosphorylation of IR/IGF-1R at specific kinase domain activation loop sites, activated Akt/mTOR/p70S6K signaling, and inactivated FoxO1, a transcription factor that restrains cell growth. Insulin did not promote activation of quiescent PaSC in either 5 mM or 25 mM glucose containing media. However, in activated PaSC, insulin enhanced cell proliferation and augmented production of extracellular matrix proteins, and these effects were abolished by specific inhibition of mTORC1 and mTORC2. In conclusion, our data support the concept that increased local glucose and insulin concentrations associated with obesity and T2DM promote PaSC growth and fibrosing responses.
Department of Endocrinology, Zhongda Hospital Southeast University, China; Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
Jiayue
J
Yang
Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
Richard T
RT
Waldron
Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
Hsin-Yuan
HY
Su
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
Aune
A
Moro
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
Hui-Hua
HH
Chang
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
Guido
G
Eibl
Department of Translational Research & Cellular Therapeutics, City of Hope, Duarte, California.
Kevin
K
Ferreri
Department of Translational Research & Cellular Therapeutics, City of Hope, Duarte, California.
Fouad R
FR
Kandeel
Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
Aurelia
A
Lugea
Department of Endocrinology, Zhongda Hospital Southeast University, China.
Ling
L
Li
Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; and Stephen.Pandol@cshs.org.
Stephen J
SJ
Pandol
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D059305:Diet, High-Fat; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism
D007328:Insulin; D003094:Collagen; D017526:Receptor, IGF Type 1; D005947:Glucose
diabetes; insulin; obesity; pancreatic fibrosis; pancreatic stellate cells