Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

Matsubayashi, Yasuhiro; Yoshida, Akihiro; Suganami, Hideki; Osawa, Taeko; Furukawa, Kazuo; Sano, Hiroshi; Fujihara, Kazuya; Tanaka, Shiro; Kaku, Kohei

doi:10.1111/dom.13980

Cited by 8 publications

(11 citation statements)

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“…Previous reports have demonstrated that a surrogate marker of insulin clearance during a meal load test is higher after a single dose of an SGLT2i or chronic treatment [ 34 , 35 ]. However, it remains unclear whether SGLT2i treatment alters systemic insulin clearance as measured by a hyperinsulinemic euglycemic clamp study.…”

Section: Discussionmentioning

confidence: 99%

“…Ferrannini et al reported that single-dose or 4-week administration of empagliflozin increased insulin clearance [34]. Very recently, similar results were obtained after 24 weeks of tofogliflozin treatment [35]. The mechanisms by which insulin clearance increases after SGLT2i treatment are currently unknown.…”

Section: Introductionmentioning

confidence: 90%

“…Since decreased insulin clearance is considered a relatively upstream inducer of metabolic disease, increased insulin clearance by SGLT2i treatment could be involved, at least in part, in the mechanisms underlying those improvements. However, in previous studies, insulin clearance was calculated as the ratio of total C-peptide concentration to the insulin area under the curve during a meal load test [ 34 , 35 ], a surrogate marker of insulin clearance. Thus, it remains unclear whether SGLT2i treatment alters systemic insulin clearance measured in a hyperinsulinemic euglycemic clamp study, the gold standard for evaluating systemic insulin clearance.…”

Section: Introductionmentioning

confidence: 99%

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Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

et al. 2021

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Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

et al. 2021

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“…Furthermore, SGLT2i can improve glycemic regulation via an insulin-independent mechanism (Ferrannini and Solini, 2012). The therapeutic application of SGLT2i could lead to weight loss (Merovci et al, 2014), correction of hyperinsulinemia (Matsubayashi et al, 2020), and reduced hyperleptinemia (Vickers et al, 2014). SGLT2i could also modulate inflammation via IL-1β (Nakatsu et al, 2017) and Nlrp3 inflammasome (Sukhanov et al, 2021).…”

Section: Sglt2 Inhibitors Can Increase the Production Of β-Ohbmentioning

confidence: 99%

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021

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One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.

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“…Dapagliflozin reduces liver fat but did not affect tissue insulin sensitivity of the liver, muscle, and adipocyte (23). Recent another study also reported that SGLT2i increased hepatic insulin clearance (24). SGLT2i increases glucagon section from alpha cells (25).…”

Section: Discussionmentioning

confidence: 93%

The Effect of Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on Insulin Resistance, Hepatic Insulin Clearance, Beta-Cell Function in the Japanese Patients with type 2 Diabetes

Okura

Fujioka

Nakamura

et al. 2021

Preprint

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Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a medication for type 2 diabetes mellitus (T2DM). Some reports showed SGLT2i improved insulin resistance, however, the effect on insulin resistance is not well established. Hepatic insulin clearance (HIC) is new pathophysiology of T2DM. The effect of SGLT2i on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i on insulin resistance, insulin secretion, incretins, body composition, and hepatic insulin clearance. Materials and Methods: We conducted a meal tolerance test (MTT), and the hyperinsulinemic-euglycemic clamp in 9 T2DM patients. 50 mg/day ipragliflozin was admitted, MTT and clamp were performed after 4 months. We calculated the postprandial C-peptide AUC to insulin AUC ratio as the HIC. We also measured GLP1, GIP, and glucagon levels during MTT. Results: Body weight, HbA1c, and body composition were not significantly changed after 4 months of treatment. Postprandial glucose, fasting, and postprandial insulin were significantly decreased. The insulin resistance of the glucose clamp was not changed, but HOMA-IR and insulin sensitivity index (ISI) were significantly improved. Incretins and glucagon were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. Fib 4 index and fatty liver index were significantly reduced. HOMA-beta and insulinogenic index was not changed but the C-peptide index was significantly increased. Conclusions: Although patients’ number was small, these results suggest that SGLT2i treatment decreased hepatic insulin resistance, increased hepatic insulin clearance, and decreased hyperinsulinemia, it might protect beta-cell function.

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Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

Cited by 8 publications

References 41 publications

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

The Effect of Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on Insulin Resistance, Hepatic Insulin Clearance, Beta-Cell Function in the Japanese Patients with type 2 Diabetes

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