Insulin promotes proliferation and fibrosing responses in activated pancreatic stellate cells

Abstract

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.

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

“…Cells that migrated to the lower compartment and adhering to the bottom surface of the membrane were stained and quantified. 19,26 Therefore, this study explored the role of physiological concentration of insulin in the malignant progression of human pancreatic duct-derived cells, as well as clarifying the underlying mechanism in vitro. The data are expressed as the mean ± SD (n = 3).…”

Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production

“…Thus, the exocrine pancreas has always been viewed as part of the gastroenterology domain, whereas the endocrine pancreas has been an area of interest for those studying diabetes. Hyperactivity of pancreatic endocrine has been reported to activate pancreatic stellate cells via insulin, leading to fibrosis response in pancreas [ 38 ]. On the other hand, insufficiency of pancreatic exocrine is associated with an impairment in insulin secretion and glucose metabolism [ [39] , [40] , [41] ].…”

Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer

“…Western-type high fat diet can result in, hyperinsulinemia, and over time lead to hyperglycemia due to insulin resistance, and particularly to elevated IGF-1 levels in the circulation. This metabolic derangement was shown to activate PaSCs that express IR-A and IGF-1 receptors [ 49 ], and to boost stromal fibrosis and also specifically fibrosis within islets, which is typically encountered in T2DM [ 50 , 51 ].…”