Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Abstract

Aims The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). Methods We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. Results Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. Conclusion SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases

“…SGLT2 inhibitors have been suggested to prevent kidney fibrosis, podocyte injury and apoptosis of glomerular cells by increasing protective adipokine expression, such as adropin, irisin and apelin, which act directly through the activation of Akt/STAT3 and tyrosine protein kinase JAK2 (JAK2)/signal transducer pathways. 34,45,48,51,52 Finally, SGLT2 inhibitors adapt metabolic homeostasis by mediating the activity of NADPH oxidase and transcription factors (nuclear factor-κB and nuclear factor erythroid 2-related factor 2) preventing advanced glycation and autophagy. 51,52 These effects are considered to be crucial in the treatment of patients with either T2DM- or non-T2DM-related CKD who have HF.…”

“…34,45,48,51,52 Finally, SGLT2 inhibitors adapt metabolic homeostasis by mediating the activity of NADPH oxidase and transcription factors (nuclear factor-κB and nuclear factor erythroid 2-related factor 2) preventing advanced glycation and autophagy. 51,52 These effects are considered to be crucial in the treatment of patients with either T2DM- or non-T2DM-related CKD who have HF. 53,54 Yet, SGLT2 inhibitors have been postulated, through their capability to change ketogenetic energy, to suppress inflammation and oxidative stress, enabling the mediation of several modalities of endogenous tissue protection, which include the enhancement of mitochondrial function and reduction of reactive oxygen species production.…”

Hepatic lipid accumulation is associated with multiple metabolic pathway alterations but not dyslipidemia and insulin resistance in central bearded dragons (Pogona vitticeps)

“…An increase in BAIBA in plasma or urine is also associated with fatty liver disease in other species, such as geese, and type 2 diabetes in humans. [28][29][30][31] BAIBA is mainly secreted by skeletal muscles, but levels are regulated by hepatic mitochondrial enzymes and are associated with important effects on carbohydrate and lipid metabolism. 31 An increase in BAIBA may also be related to alterations in other amino acid metabolic pathways.…”

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

“…Metabolomics is an emerging systems biology technology that can be utilized to explore new biomarkers for disease detection and identify metabolic pathways associated with disease etiology [20]. Prior research has indicated that SGLT2 inhibitors can significantly affect the level of circulating metabolites, especially those related to lipids, amino acids, and ketone bodies [21][22][23]. Besides, mutations resulting in SGLT1 dysfunction may modify intestinal homeostasis and promote favorable metabolic outcomes [24,25].…”