Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats

Tahara, Atsuo; Kurosaki, Eiji; Yokono, Masanori; Yamajuku, Daisuke; Kihara, Rumi; Hayashizaki, Yuka; Takasu, Toshiyuki; Imamura, Masakazu; Li, Qun; Tomiyama, Hiroshi; Kobayashi, Yoshinori; Noda, Atsushi; Sasamata, Masao; Shibasaki, Masayuki

doi:10.1111/jphp.12223

Cited by 110 publications

(73 citation statements)

References 40 publications

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“…In vitro and in vivo work has suggested that sodium glucose cotransport inhibition reduces markers of inflammation and fibrosis [18,19,[29][30][31]. Although we did not measure inflammatory markers in the present trials, future studies should assess the effect of SGLT2 inhibition on pro-inflammatory and pro-fibrotic mechanisms in diabetes and associated kidney disease.…”

Section: Discussionmentioning

confidence: 90%

“…Previous experimental work using different animal models of kidney disease have demonstrated that SGLT2 inhibition alleviates renal damage. In Akita and streptozotocin-induced animal models of insulin-deficient diabetes, SGLT2 inhibition reduced albuminuria [18][19][20]. SGLT2 inhibition has similar anti-albuminuric effects in animal models of type 2 diabetes [21], including recent evidence that empagliflozin reduced albuminuria, independent of effects on BP or hyperglycaemia, in BTBR ob/ob mouse models of type 2 diabetes [22].…”

Section: Discussionmentioning

confidence: 99%

“…The albuminuria-lowering effect of SGLT2 inhibition may be due to several mechanisms. First, SGLT2 inhibition achieved through either pharmacological blockade or genetic knockout models reduces renal hyperfiltration, which is considered to be a surrogate marker for intraglomerular pressure in humans [11,12,19,26]. Such a mechanism would be expected to reduce albuminuria independent of changes in systemic BP, similar to the effects of RAAS blockade, but through afferent vasoconstrictive effects rather than efferent vasodilatory effects.…”

Section: Discussionmentioning

confidence: 99%

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The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA 1c , systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA 1c , SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 3 0 -3 0 0 m g / g ; n = 6 3 6 ) o r m a c r o a l b u m i n u r i a (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA 1c , SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (−32% vs placebo; p < 0.001) or macroalbuminuria (−41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA 1c , SBP or weight. Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

et al. 2016

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“…25,39) We previously reported that, in addition to improving glycemic control in mouse models of diabetes, ipragliflozin reduces plasma inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1). 38,40) Such an effect by ipragliflozin on inflammatory cytokines might contribute to its beneficial effects on pancreatic β-cells observed in the present study.…”

Section: Body Weight and Total Food Intakementioning

confidence: 59%

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

Takasu

Takakura

2018

Biological & Pharmaceutical Bulletin

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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...

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“…21 Similar benefits have been reported with ipragliflozin and remogliflozin in small pilot studies. 14,22 In a recent meta-analysis of three randomized controlled trials including 178 patients, SGLT2 inhibitor use was associated with reduction in fasting blood glucose and insulin dosage, with no significant risk of urinary tract infections, genital infections or diabetic ketoacidosis (DKA). 23 In another systematic review of all studies published till March 2017, SGLT2 inhibitors led to overall reduction of HbA1c (up to 0.49%) and weight (up to 2.7 kg) and lower total daily insulin dose, with lower incidence of hypoglycemia.…”

Section: Clinical Evidence With Sodium-glucose Co-transporter-2 Inhibmentioning

confidence: 99%

Sodium-glucose Co-transporter-2 Inhibitors in Type 1 Diabetes—a Dangerous Ally

Priya¹,

Kalra²,

Bhambri³

2017

US Endocrinology

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There is an unmet need for adjunctive non-insulin-based therapies in type 1 diabetes (T1D). Weight gain, recurrent hypoglycemia and suboptimal glycemic control remain significant challenges. Sodium-glucose co-transporter-2 (SGLT2) inhibitors and dual inhibitors of sodium-glucose co-transporter-1 (SGLT1) and SGLT2 may have a potential role as an add-on therapy to insulin. The benefits include improved glycemic control, weight reduction, and reduced insulin dose requirement. However, the risk of diabetic ketoacidosis with SGLT2 inhibitors is significant and the diagnosis may be delayed due to absence of significant hyperglycemia. At present, SGLT2 inhibitors are not approved for use in T1D, and the risks should be discussed at length with the patient. We propose strategies to minimize the risk of diabetic ketoacidosis associated with off-label use of SGLT2 inhibitors in T1D.

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Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats

Cited by 110 publications

References 40 publications

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

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

Sodium-glucose Co-transporter-2 Inhibitors in Type 1 Diabetes—a Dangerous Ally

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