Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality

Abstract

A favorable effect of an inhibitor of the sodium–glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance.

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“…These observations are consistent with the maintenance of β-pancreatic activity and insulin levels in diabetic mice after the SGLTi administration [31]. While body weight control has been observed in patients treated with SGLT2i [32,33], in our hands, long-term EMP treatment maintained body weight, as previously described in db/db cachectic mice treated with SGLTi [30].…”

“…SGLTi mechanism of action is insulin independent; however, since db/db mice are a leptin receptor functional KO model, they are severely diabetic and glucose levels cannot be normalized by EMP treatment. However, we detected that diabetic hyperinsulinemia was longer maintained after EMP treatment, in a similar trend to that previously described in SGLTi-treated db/db mice [30]. These observations are consistent with the maintenance of β-pancreatic activity and insulin levels in diabetic mice after the SGLTi administration [31].…”

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…Given the results of the trials involving SGLT2 inhibitors, that is , decreased mortality along with an increase in ketone bodies, it would be interesting to test this class of molecules in mouse models of ageing to obtain preliminary observations regarding the feasibility of inducing glucose excretion as an anti‐ageing strategy. Notably, chronic treatment with an SGLT2 inhibitor attenuates LGI and prolongs lifespan in diabetic mice fed with a high‐fat diet …”

“…Notably, chronic treatment with an SGLT2 inhibitor attenuates LGI and prolongs lifespan in diabetic mice fed with a high-fat diet. 53…”

Antioxidative potential of antidiabetic agents: A possible protective mechanism against vascular complications in diabetic patients

“…can also significantly reduce the risk of mortality among diabetic subjects (Sugizaki et al, 2017). Sugizaki et al (2017) demonstrated that treatment of diabetic animals by SGLT2 inhibitors of TA-1887 reduces diabetes-induced cachexia and death by improving beta cell function and insulin sensitivity in peripheral tissues.…”