The aim of our study was to investigate the ability of keratinocyte growth factor (KGF; palifermin) in regulating β-cell growth in normal newborn rats and in rats with neonatal diabetes. Wistar rats were injected with streptozotocin (STZ) to induce diabetes on the dayof birth. From days 2 to 6 after birth, animals received a daily s.c. injection of KGF (STZ/KGF group) and at the dose of 3 mg/kg body weight or saline solution (STZ groups). A group of non-diabetic Wistar rats was treated either with saline (Wistar group) or with KGF from days 2 to 6 after birth at the dose of 3 mg/kg body weight (Wistar/KGF group). β-cell mass was measured at day 7 after birth in all groups. β- and ductal cells replication were measured in all groups and apoptosis was assessed in the pancreas of 2-, 4-, and 7-day-old STZ and STZ/KGF rats. The total β-cell mass of the 7-day-old KGF/STZ neonates was significantly increased compared with that of age-matched STZ rats. β-cell replication rate was decreased at day 2 in the STZ/KGF group and was similar in the 4- and 7-day-old rats from STZ and STZ/KGF groups. Duct cell replication was significantly increased in the pancreas of 2- and 4-day-old KGF/STZ neonates when compared with that of age-matched rats from STZ control group. The rate of apoptosis in the neonatal pancreases of STZ and KGF/STZ groups was not significantly different. In non-diabetic Wistar rats, KGF treatment led to a slight but significant increase in duct cell proliferation at day 2 without significant changes in the total β-cell mass in the 7-day-old rats. We provide evidence for a growth-promoting effect of KGF during β-cell regeneration in neonatal diabetic rats. KGF exerts strong mitogenic effect on the pancreatic duct cells, thus expanding the population of precursor cells that subsequently differentiate into insulin-producing β-cells.
Jamileh Movassat and Bernard Portha
Caterina Luana Pitasi, Junjun Liu, Blandine Gausserès, Gaëlle Pommier, Etienne Delangre, Mathieu Armanet, Pierre Cattan, Bruno Mégarbane, Anne-Sophie Hanak, Kamel Maouche, Danielle Bailbé, Bernard Portha and Jamileh Movassat
Islet inflammation is associated with defective β cell function and mass in type 2 diabetes (T2D). Glycogen synthase kinase 3 (GSK3) has been identified as an important regulator of inflammation in different diseased conditions. However, the role of GSK3 in islet inflammation in the context of diabetes remains unexplored. In this study, we investigated the direct implication of GSK3 in islet inflammation in vitro and tested the impact of GSK3 inhibition in vivo, on the reduction of islet inflammation, and the improvement of glucose metabolism in the Goto-Kakizaki (GK) rat, a spontaneous model of T2D. GK rats were chronically treated with infra-therapeutic doses of lithium, a widely used inhibitor of GSK3. We analyzed parameters of glucose homeostasis as well as islet inflammation and fibrosis in the endocrine pancreas. Ex vivo, we tested the impact of GSK3 inhibition on the autonomous inflammatory response of non-diabetic rat and human islets, exposed to a mix of pro-inflammatory cytokines to mimic an inflammatory environment. Treatment of young GK rats with lithium prevented the development of overt diabetes. Lithium treatment resulted in reduced expression of pro-inflammatory cytokines in the islets. It decreased islet fibrosis and partially restored the glucose-induced insulin secretion in GK rats. Studies in non-diabetic human and rat islets exposed to inflammatory environment revealed the direct implication of GSK3 in the islet autonomous inflammatory response. We show for the first time, the implication of GSK3 in islet inflammation and suggest this enzyme as a viable target to treat diabetes-associated inflammation.