1,5-anhydroglucitol is a good predictor for the treatment effect of the Sodium-Glucose cotransporter 2 inhibitor in Japanese patients with type 2 diabetes mellitus

Usui, Masahiro; Tanaka, Munehiko; Takahashi, Hironori

doi:10.1016/j.jcte.2020.100233

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…We therefore investigated whether reduced 1,5-AG in HFD + E mice may contribute to increased cardiac glucose utilization by relieving inhibition of hexokinase. Consistent with previous reports regarding the effects of renal tubular glycemia on 1,5-AG levels in plasma [31][32][33], we found that cardiac concentrations of 1,5-AG were signi cantly reduced in HFD compared with LFD mice, and that 1,5-AG levels were also signi cantly reduced in HFD + E mice compared with both LFD and HFD mice (Fig. 7A; P < 0.0001).…”

Section: Resultssupporting

confidence: 92%

“…The metabolite 1,5-anhydroglucitol (1,5-AG) competes with glucose for reabsorption by the kidney such that SGLT2 inhibitor therapy, which raises renal tubular glucose concentrations, reduces plasma 1,5-AG levels by promoting 1,5-AG urinary excretion [31][32][33]. Phosphorylation of 1,5-AG produces 1,5-AG-6phosphate (1,5-AG-6P), which inhibits hexokinase and in turn glycolysis [34,35].…”

Section: Resultsmentioning

confidence: 99%

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Empagliflozin Restores Cardiac Metabolic Flexibility in Diet-induced Obese C57BL6/J Mice

Xie

Ramirez

Mills

et al. 2021

Preprint

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BackgroundSodium-glucose co-transporter type 2 (SGLT2) inhibitor therapy to treat type 2 diabetes unexpectedly reduced all-cause mortality and hospitalization due to heart failure in several large-scale clinical trials, and has since been shown to produce similar cardiovascular disease-protective effects in patients without diabetes. How SGLT2 inhibitor therapy improves cardiovascular disease outcomes remains incompletely understood. Metabolic flexibility refers to the ability of a cell or organ to adjust its use of metabolic substrates, such as glucose or fatty acids, in response to physiological or pathophysiological conditions, and is a feature of a healthy heart that may be lost during diabetic cardiomyopathy and in the failing heart. While several studies have addressed metabolic changes in hearts in response to SGLT2 inhibitor therapy, none have specifically assessed metabolic flexibility in an in vivo system. We therefore undertook the described studies to determine the effects of SGLT2 inhibitor therapy on cardiac metabolic flexibility in vivo in obese, insulin resistant mice.MethodsDiet-induced obese mice were treated with the SGLT2 inhibitor empagliflozin (EMPA; 10 mg/kg/d) for four weeks prior to study and compared with untreated obese and lean controls. We assessed changes in body weight and composition, plasma metabolites in response to fasting/re-feeding, cardiac hypertrophy by echocardiography, the response to ischemic stress following coronary artery ligation, as well as cardiac-specific rates of relative glucose and fatty acid utilization using a [U13C]-glucose infusion during fasting and hyperinsulinemic euglycemic clamp.ResultsEMPA-treated mice presented with reduced cardiac hypertrophy and protection from ischemic stress compared with obese controls. In the fasted state, relative rates of cardiac glucose and fatty acid utilization were similar in control and EMPA-treated mice. During the hyperinsulinemic euglycemic clamp, rates of cardiac glucose utilization and metabolic flexibility were reduced in obese compared with lean mice, and EMPA-treatment partially restored both features. ConclusionsSGLT2 inhibitor therapy restored cardiac metabolic flexibility in obese, insulin resistant mice, and was associated with reduced cardiac hypertrophy and protection from ischemia. These observations suggest that the cardiovascular disease-protective effects of SGLT2 inhibitors may in part be explained by beneficial effects on cardiac metabolic substrate selection.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Empagliflozin Restores Cardiac Metabolic Flexibility in Diet-induced Obese C57BL6/J Mice

Xie

Ramirez

Mills

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…It was proposed that such a reabsorption is competitively inhibited by glucose when glycemia exceeds the renal threshold for glucosuria (> 10 mmol/L), promoting 1,5-AG urinary excretion and lowering of its circulating levels (14). Of note, low blood 1,5-AG was identified as the most reliable indicator to identify T2D patients being responsive to treatment with SLC5A2/SGLT2 inhibitors and efficient HbA1c reduction, regardless of the estimated glomerular filtration rate (42). This is in line with our observation (ie, a close association between 1,5-AG levels and poor glucose control in patients with established T2D), although not in nondiabetic subjects.…”

Section: Discussionmentioning

confidence: 99%

Circulating 1,5-Anhydroglucitol as a Biomarker of ß-cell Mass Independent of a Diabetes Phenotype in Human Subjects

Jiménez‐Sánchez

Mezza

Sinturel

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context During an asymptomatic pre-diabetic state, the functional ß-cell mass decreases up to a critical threshold triggering diabetes and related symptoms. To date, there are no reliable readouts able to capture in vivo a potential drop of the ß-cell mass. Objective Beside its use as a short-term marker of glycemic control, the deoxyhexose 1,5-anhydroglucitol was identified in rodents as a circulating biomarker of the functional ß-cell mass already in the asymptomatic prediabetic stage. The present study investigated the putative corresponding relevance of circulating 1,5-anhydroglucitol in different human cohorts. Methods We analyzed clinical and blood parameters in patients with established type 2 diabetes and subjects considered at high risk of developing diabetes, as well as patients with no history of diabetes scheduled for pancreaticoduodenectomy. Results Circulating 1,5-anhydroglucitol was reduced in type 2 diabetic patients, negatively correlating with fasting plasma glucose (p<0.0001) and HbA1c (p<0.0001). In healthy subjects, 1,5-AG levels positively correlated with body mass index (p=0.004) and HOMA%S (p<0.03) and was particularly high in nondiabetic obese individuals, potential accounting for compensatory ß-cell expansion. Patients with no history of diabetes undergoing pancreaticoduodenectomy exhibited a 50% reduction of circulating 1,5-anhydroglucitol levels following surgery leading to an acute loss of their ß-cell mass (p=0.002), regardless their glucose tolerance status. Conclusion In summary, plasma concentration of 1,5-anhydroglucitol follows the ß-cell mass and its non-invasive monitoring may alert about the loss of ß-cells in subjects at risk for diabetes, an event that cannot be captured by other clinical parameters of glycemic control.

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Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans

et al. 2022

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Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes associated metabolites, we leveraged a method that measures 305 targeted or “known” and 2,342 nontargeted or “unknown” compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)—a community cohort of self-identified African Americans (AAs), who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate (FDR) <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose (FPG). Of these, 144 and 68 associations, respectively, replicated in a multi-ethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ=0.29) and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.

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1,5-anhydroglucitol is a good predictor for the treatment effect of the Sodium-Glucose cotransporter 2 inhibitor in Japanese patients with type 2 diabetes mellitus

Cited by 4 publications

References 25 publications

Empagliflozin Restores Cardiac Metabolic Flexibility in Diet-induced Obese C57BL6/J Mice

Empagliflozin Restores Cardiac Metabolic Flexibility in Diet-induced Obese C57BL6/J Mice

Circulating 1,5-Anhydroglucitol as a Biomarker of ß-cell Mass Independent of a Diabetes Phenotype in Human Subjects

Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans

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