Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry

Sawada, Yuko; Izumida, Yoshihiko; Takeuchi, Yoshinori; Aita, Yuichi; Wada, Nobuhiro; Li, EnXu; Murayama, Yuki; Piao, Xianying; Shikama, Akito; Masuda, Yukari; Nishi-Tatsumi, Makiko; Kubota, Midori; Sekiya, Motohiro; Matsuzaka, Takashi; Nakagawa, Yoshimi; Sugano, Yoko; Iwasaki, Hitoshi; Kobayashi, Kazuto; Yatoh, Shigeru; Suzuki, Hiroaki; Yagyu, Hiroaki; Kawakami, Yasushi; Kadowaki, Takashi; Shimano, Hitoshi; Yahagi, Naoya

doi:10.1016/j.bbrc.2017.09.081

Cited by 25 publications

(19 citation statements)

References 34 publications

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“…An experimentally-increased amount of glycogen in the liver by itself induced hepatic insulin resistance and inhibited new glycogen synthesis in healthy dogs [ 38 ]. Interestingly, novel classes of glucose-lowering drugs, SGLT2 inhibitors and dual GLP1/glucagon agonists, are also known to reduce liver glycogen storage [ 39 – 41 ]. In addition, clenbuterol could also affect insulin sensitivity through a reduction in inflammation, since these two conditions are closely associated (reviewed in [ 42 , 43 ]).…”

Section: Discussionmentioning

confidence: 99%

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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Aims/hypothesis Chronic stimulation of β 2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β 2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β 2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg −1 day −1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and Anastasia Kalinovich and Nodi Dehvari contributed equally to this study.

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Section: Discussionmentioning

confidence: 99%

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

et al. 2020

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“…Chronic shifts in metabolic substrate utilisation and ketogenesis Depletion of liver glycogen [18,19], and other signals that increase HGP following SGLT2 inhibition ( Fig. 1), modulates the uptake and utilisation of glucose in peripheral tissues.…”

Section: Acute Changes In Glucagon Glycogen and Gluconeogenesismentioning

confidence: 99%

The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure

2018

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Inhibition of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA of 7-10 mmol/mol (0.6-0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.

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“…8 However, due to the availability of inadequate studies elucidating the pathway of SGLT-2i action in CNS or influence the sympathetic nervous system, the rationale behind SGLT-2i causing a decrease in BP (systolic BP: 5mmHg, diastolic BP: 2mmHg on average) 9 without a change in the heart rate remains unknown. [10][11][12] Nonetheless, in the past few years, researchers asserted that besides its role in glucose reabsorption, SGLT may exhibit other distinct functions in CNS. [13][14][15] Unfortunately, the definite localization of the SGLT family and their functions in CNS, specifically SGLT-2 have not been comprehensively established.…”

Section: Introductionmentioning

confidence: 99%

<p>Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice</p>

Nguyen

Gong

et al. 2020

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This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity. Material and Methods: Thirty-four normal male C57BL/6 mice were randomly assigned to 2 groups to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos, a neural activator. The distributional relationships of SGLT-2 and c-Fos were examined by immunofluorescence. Results: Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin. Conclusion: This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.

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Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry

Cited by 25 publications

References 34 publications

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure

<p>Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice</p>

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