Protective Effect of Ipragliflozin on Pancreatic Islet Cells in Obese Type 2 Diabetic db/db Mice

Abstract

Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion and subsequently improves hyperglycemia in patients with type 2 diabetes mellitus (T2DM). To assess the beneficial effect of ipragliflozin on the mass and function of pancreatic β-cells under diabetic conditions, obese T2DM db/db mice were treated with ipragliflozin for 5 weeks. Glucose and lipid metabolism parameters, pathological changes in pancreatic islet cells and insulin content were evaluated. Pathological examination of pancreatic islet cells comprised measuring the ratios of insulin-and glucagon-positive cells and levels of oxidative stress markers. Hemoglobin A1c, plasma glucose, non-esterified fatty acid and triglyceride levels in ipragliflozin-treated groups were reduced compared to the diabetic control (DM-control) group. Histopathological examination of pancreatic islet cells revealed strong insulin staining and reduced glucagon staining in the ipragliflozin 10 mg/kg-treated group compared with the DM-control group. The ratio of α-to β-cell mass was lower in the ipragliflozin 10 mg/kg-treated group than the DM-control group and was similar to that of the non-diabetic control group. The density of immunostaining for 4-hydroxy-2-nonenal, an oxidative stress marker, in pancreatic islets was significantly lower in the ipragliflozin 10 mg/kg-treated group than the DM-control group. Pancreatic insulin content tended to be higher in the ipragliflozin-treated groups than the DM-control group. Our findings demonstrate the benefit of ipragliflozin treatment in improving glucolipotoxicity and reducing oxidative stress in pancreatic islet cells. Treatment with ipragliflozin may protect against the progressive loss of islet β-cells in patients with T2DM.Key words ipragliflozin; sodium glucose cotransporter 2 inhibitor; anti-diabetic drug; pancreatic islet cell; type 2 diabetes mellitus Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease. The main characteristics of T2DM are insulin resistance in insulin target tissues and insufficient insulin secretion from pancreatic β-cells.1,2) Insulin resistance develops as a result of overeating, physical inactivity and as a consequence of obesity and fat accumulation in the body caused by excessive insulin secretion from pancreatic β-cells.3) In the prediabetic state, a sufficient amount of insulin is secreted from β-cells to compensate for insulin resistance.4) Subsequently, larger adipocytes accumulate in adipose tissue and secrete large amounts of free fatty acids (FFAs) and inflammatory cytokines, which leads to a deterioration in β-cell function. This process is well known as β-cell lipotoxicity.5) After the collapse of compensatory insulin secretion mechanisms, β-cells are chronically exposed to hyperglycemia, leading to a gradual deterioration in function and decrease in β-cell mass. These phenomena are well known as β-cell glucose toxicity. [6][7][8] Several studies have suggested that increased FFA concentration and hyperglycemia...

<i>In Vitro</i> Pharmacological Profile of Ipragliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

“…12) We previously conducted extensive in vivo pharmacological profiling of ipragliflozin and reported that it increased urinary glucose excretion, exhibited antihyperglycemic activity, preserved pancreatic β-cells, and prevented diabetic macrovascular and microvascular complications in T2DM mouse and rat models. 9,[13][14][15][16][17] In contrast, the sole in vitro pharmacological study of ipragliflozin has only reported its selectivity for SGLT2 over SGLT1. 9) Here, we investigated the selectivity of ipragliflozin for other hSGLTs (SGLT3, 4, 5, 6 and sodium/myo-inositol (MI) cotransporter 1 (SMIT1)), and its mode of inhibition against hSGLT2 in Chinese hamster ovary (CHO) cells overexpressing hSGLT2.…”

SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes trough mitigation of oxidative and ER stress

“…Although some studies demonstrated that treatment with SGLT2i preserved β-cell mass in ZDF rats [38], streptozotocin-induced T1D mice [32] and in db/db and ob/ob mouse models of obesity and T2D [25][26][27][28][29][30]39], the underlying mechanism of this protection remains elusive. We demonstrate here for the first time that SGLT2i therapy increased islet insulin content, and decreased proinsulin through reduction in β-cell oxidative and ER stress in mouse models of monogenic NDM and obese/T2D.…”

“…T2D individuals treated with SGLT2i demonstrate improved glycemic control, increased glucose-and incretin-stimulated insulin secretion and enhanced insulin sensitivity as well as reduced blood pressure, decreased plasma lipids and reduced risk for cardiovascular events [21][22][23][24]. Db/db and ob/ob mouse models of obesity and T2D treated with SGLT2i (luseogliflozin, ipragliflozin or dapagliflozin) demonstrated reduced blood glucose, augmented insulin and GLP-1 secretion, increased β-cell mass, β-cell self-replication and α-to β-cell conversion, and restored β-cell identity [25][26][27][28][29][30]. Moreover, db/db mice with SGLT2 deletion showed improved insulin sensitivity and increased β-cell proliferation and decreased β-cell death [31].…”

“…The copyright holder for this preprint this version posted September 17, 2021. ; https://doi.org/10.1101/2021.09.17.460837 doi: bioRxiv preprint [21][22][23][24]. Db/db and ob/ob mouse models of obesity and T2D treated with SGLT2i (luseogliflozin, ipragliflozin or dapagliflozin) demonstrated reduced blood glucose, augmented insulin and GLP-1 secretion, increased β-cell mass, β-cell self-replication and α-to β-cell conversion, and restored β-cell identity [25][26][27][28][29][30]. Moreover, db/db mice with SGLT2 deletion showed improved insulin sensitivity and increased β-cell proliferation and decreased β-cell death [31].…”

Effect of ipragliflozin on metabolic syndrome components and non-alcoholic fatty liver disease

“…Плотность иммуноокрашивания маркера окислительного стресса в островках поджелудочной железы была значительно ниже в группе, получавшей ипраглифлозин. Содержание инсулина в клетках поджелудочной железы в группе ипраглифлозина было выше, чем в контрольной группе [22].…”