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

ABSTRACT: 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. 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. 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. 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.

SUBMITTER: Sato M

PROVIDER: S-EPMC8472728 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Sato Motonori M Tamura Yoshifumi Y Kaga Hideyoshi H Yamasaki Nozomu N Kiya Mai M Kadowaki Satoshi S Sugimoto Daisuke D Funayama Takashi T Someya Yuki Y Kakehi Saori S Nojiri Shuko S Satoh Hiroaki H Kawamori Ryuzo R Watada Hirotaka H

Biomedicines 20210903 9

<h4>Background</h4>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 ...[more]

PMID: 34572340

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Project description:BackgroundUsing immunomodulatory methods to address the challenging issue of craniofacial bone repair may be a potentially effective approach. The protease inhibitor saquinavir has been shown to inhibit the inflammatory response by targeting the toll-like receptor 4/myeloid differentiation primary response complex. Independently, inhibition of toll-like receptor 4 or myeloid differentiation primary response led to enhanced skull bone repair. Therefore, the authors aimed to investigate the effects of saquinavir on skull bone healing.MethodsThe effects of saquinavir on skull bone healing were assessed by means of gene expression, histology, immunohistochemistry, and tomography in a mouse calvarial defect model. Subsequently, the role of saquinavir in cell viability, migration, and osteogenic and osteoclastogenic differentiation was also evaluated in vitro.ResultsOne-week saquinavir administration improved skull bone healing based on micro-computed tomographic and histomorphometric analyses. Compared to the vehicle control, 1-week saquinavir treatment (1) enhanced osteoclast infiltration (tartrate-resistant acid phosphatase staining) at day 7, but not at days 14 and 28; (2) induced more CD206 + M2 macrophage infiltration, but not F4/80 + M0 macrophages at days 7, 14, and 28; and (3) elevated osteoclastogenic gene RANKL (quantitative polymerase chain reaction) expression and other osteogenic and cytokine expression. Furthermore, in vitro data showed that saquinavir administration did not influence MC3T3-E1 cell migration or mineralization, whereas higher concentrations of saquinavir inhibited cell viability. Saquinavir treatment also enhanced the osteoclastic differentiation of bone marrow-derived precursors, and partially reversed high-mobility group box 1-driven osteoclastogenesis inhibition and elevated proinflammatory cytokine expression.ConclusionThe improved skull bone repair following short-term saquinavir treatment may involve enhanced osteoclastogenesis and modulated inflammatory response following skull injury.Clinical relevance statementThe authors' work demonstrates improved skull bone healing by short-term application of saquinavir, a drug traditionally used in the treatment of acquired immunodeficiency syndrome. As such, saquinavir may be repurposed for skeletal repair.

Project description:BackgroundWhile the kidney-protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes.MethodsUsing a nationwide claims database, we studied 6354 older adults (≥60 years of age) who had diabetes and were newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in estimated glomerular filtration rate (eGFR) between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decrease in the rate of eGFR, which was obtained using a linear mixed-effects model with an unstructured covariance.ResultsFollowing propensity score matching, 6354 individuals including 1271 SGLT2 inhibitor users and 5083 DPP4 inhibitor users {median age 68 years [interquartile range (IQR) 65-70], male 60.4%, median eGFR 69.0 ml/min/1.73 m2 [IQR 59.1-79.0], median haemoglobin A1c [HbA1c] 6.9% [IQR 6.5-7.4]} were analysed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users [-0.97 ml/min/1.73 m2/year (95% CI -1.24 to -0.70) versus -1.83 ml/min/1.73 m2/year (95% CI -1.97 to -1.69); P for interaction <.001]. This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use and baseline eGFR. Additionally, the risk of a ≥20%, ≥30% and ≥40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than in DPP4 inhibitor users.ConclusionsOur analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decrease in eGFR was slower in individuals ≥60 years of age with diabetes who were prescribed SGLT2 inhibitors compared with those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

Dataset Information

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

Publications

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

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