Accelerated Generation of Extra-Islet Insulin-Producing Cells in Diabetic Rats, Treated with Sodium Phthalhydrazide

Abstract

β-cells dysfunction plays an important role in the pathogenesis of type 2 diabetes (T2D), partially may be compensated by the generation of extra-islet insulin-producing cells (IPCs) in pancreatic acini and ducts. Pdx1 expression and inflammatory level are suggested to be involved in the generation of extra-islet IPCs, but the exact reasons and mechanisms of it are unclear. Macrophages are key inflammatory mediators in T2D. We studied changes in mass and characteristics of extra-islet IPCs in rats with a streptozotocin-nicotinamide model of T2D and after i.m. administration of 20 daily doses of 2 mg/kg b.w. sodium aminophthalhydrazide (APH). Previously, we found that APH modulates macrophage production and increases the proliferative activity of pancreatic β-cells. Expressions of insulin and Pdx1, as well as F4/80 (macrophage marker), were detected at the protein level by immunohistochemistry analysis, the concentration of pro- and anti-inflammatory cytokines in blood and pancreas—by ELISA. Diabetic rats treated with APH showed an increasing mass of extra-islet IPCs and the content of insulin in them. The presence of Pdx1+ cells in the exocrine pancreas also increased. F4/80+ cell reduction was accompanied by increasing TGF-β1 content. Interestingly, during the development of diabetes, the mass of β-cells decreased faster than the mass of extra-islet IPCs, and extra-islet IPCs reacted to experimental T2D differently depending on their acinar or ductal location.

Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently

“…It is likely that this mediator can be activated by inflammation. This is consistent with the previous investigations [ 17 , 35 , 52 ].…”

“…Inflammation is able to induce cell transition during regeneration [ 34 ]. Early we revealed, that at the 30 days of experimental T2D the mass of solitary IPCs in pancreatic acinar increases [ 35 ].…”

Macrophage Polarization: Learning to Manage It

“…This study investigated the effect of sodium aminophthalhydrazide (APH) on the generation of extra-islet insulin-producing cells (IPC) in acini and pancreatic ducts in rats with or without diabetes. The results indicated that APH modulates the functional activity of macrophages, shifting them to a reparative anti-inflammatory phenotype and decreasing macrophage infiltration and inflammation in the pancreas [11].…”

“…Modulation of macrophage phenotypes has been suggested as a novel strategy for the treatment of inflammatory pathologies. The paper of Abidov and colleagues published in the Special Issue addressed T2D pathology with an in vivo study [11] (Figure 2G). Chronic inflammation, generated by T2D progression, increases tissue damage with the involvement of macrophage-produced mediators in both tissue injury and tissue repair.…”

“…(F) Bempedoic acid (BA) increased phagocytic activity of Mφ[10]. (G) Sodium aminophthalhydrazide (APH) increased anti-inflammatory phenotype in the pancreas[11].…”