The Profile of Plasma Free Amino Acids in Type 2 Diabetes Mellitus with Insulin Resistance: Association with Microalbuminuria and Macroalbuminuria

Saleem, Tahia H.; Dahpy, Marwa A.; Ezzat, Ghada M; Abdel-Rahman, Ghada H.; Abdel-Aziz, Essam M.; Farghaly, Rania

doi:10.1007/s12010-019-02956-9

Cited by 30 publications

(24 citation statements)

References 40 publications

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“…Plasma levels of Phe are regulated by phenylalanine hydroxylase (PAH); factors such as stress, sepsis, or any causes of hepatic dysfunction may influence the activity of PAH [23,24]. In accordance with studies reporting increased plasma Phe levels in CKD patients with reduced renal PAH activity [25], we also found higher Phe levels in albuminuric patients, albeit we cannot explain why the Phe level was higher in the mau rather than in the MAU patients. Corresponding to the previous studies [11,26], we also found a significant inverse correlation between the plasma levels of Trp (cut-off value 46.75 µmol/L, sensitivity 61.8%, specificity 77.3%) and the severity of albuminuria.…”

Section: Discussionsupporting

confidence: 77%

Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease

Lin

Chiu

et al. 2020

Diagnostics

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Albuminuria is a measurement and determinant factor for diabetic kidney disease (DKD). Angiotensin receptor blocker (ARB) is recommended for albuminuria in DKD with variable response. To find surrogate markers to predict the therapeutic effect of ARB, we carried out a prospective study to correlate plasma metabolites and the progression of renal function/albuminuria in DKD patients. A total of 56 type 2 diabetic patients with various stages of chronic kidney disease and albuminuria were recruited. ARB was prescribed once albuminuria was established. Urinary albumin-to-creatinine ratio (UACR) was determined before and six months after ARB treatment, with a ≥30% reduction of UACR considered an ARB responder. Plasma levels of 145 metabolites were measured before ARB treatment; only those associated with albuminuria were selected and compared between ARB responders and non-responders. Both lower tryptophan (Trp ≤ 46.75 μmol/L) levels and a higher kynurenine/tryptophan ratio (KTR ≥ 68.5 × 10−3) were significantly associated with macroalbuminuria (MAU), but only KTR (≥54.7 × 10−3) predicts ARB responsiveness (sensitivity 90.0%, specificity 50%) in MAU. Together, these data suggest that the kynurenine/tryptophan ratio predicts angiotensin receptor blocker responsiveness in patients with diabetic kidney disease.

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Section: Discussionsupporting

confidence: 77%

Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease

Lin

Chiu

et al. 2020

Diagnostics

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“…In recent years, BCAA metabolism was found to be significantly altered in patients with several diseases including diabetes [52]. Both human and animal studies demonstrated a functional correlation between BCAA metabolism and a higher susceptibility to IR in T2DM patients [53,54,55,56,57]. Here, we showed lower levels of BCAA in T2DM patients compared to CG, raising questions regarding the mechanisms regulating BCAA metabolism in our cohort.…”

Section: Discussionmentioning

confidence: 58%

“…In this context, we speculate that IR levels and disease complications may have a major impact on this result, as corroborated by other studies that utilize functional and NMR approaches. For instance, lower plasma levels, with respect to healthy controls, of BCAAs in T2DM patients were indicated as a first sign of kidney dysfunction [56]. Further, the decreased serum levels of BCAAs that we observed in T2DM are in line with the results of Shin et al [57] who demonstrated that alteration in hypothalamic insulin signaling can decrease plasma BCAA levels by inducing the hepatic activity of branched-chain α-keto acid dehydrogenase, a rate-limiting enzyme in the BCAA degradation pathway.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of these data, the high fasting insulin level measured in diabetic subjects (Table 3) could be linked to the decreased tyrosine serum level in diabetic patients. Importantly, it has been also reported that circulating tyrosine level could be correlated with the risk of developing various major complications of diabetes [56]. Moreover, other studies described an association of a low tyrosine level with the impairment of kidney function, which itself could predict future microvascular events [63,64].…”

Section: Discussionmentioning

confidence: 99%

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NMR-Based Metabolomic Approach Tracks Potential Serum Biomarkers of Disease Progression in Patients with Type 2 Diabetes Mellitus

Coco

Vergara

Matteis

et al. 2019

JCM

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Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia associated with alterations in carbohydrate, lipid, and protein metabolism. The prognosis of T2DM patients is highly dependent on the development of complications, and therefore the identification of biomarkers of T2DM progression, with minimally invasive techniques, is a huge need. In the present study, we applied a 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomic approach coupled with multivariate data analysis to identify serum metabolite profiles associated with T2DM development and progression. To perform this, we compared the serum metabolome of non-diabetic subjects, treatment-naïve non-complicated T2DM patients, and T2DM patients with complications in insulin monotherapy. Our analysis revealed a significant reduction of alanine, glutamine, glutamate, leucine, lysine, methionine, tyrosine, and phenylalanine in T2DM patients with respect to non-diabetic subjects. Moreover, isoleucine, leucine, lysine, tyrosine, and valine levels distinguished complicated patients from patients without complications. Overall, the metabolic pathway analysis suggested that branched-chain amino acid (BCAA) metabolism is significantly compromised in T2DM patients with complications, while perturbation in the metabolism of gluconeogenic amino acids other than BCAAs characterizes both early and advanced T2DM stages. In conclusion, we identified a metabolic serum signature associated with T2DM stages. These data could be integrated with clinical characteristics to build a composite T2DM/complications risk score to be validated in a prospective cohort.

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“…These results could be attributable to a lack of Asp, which is essential for the metabolism of Citrulline to Arg. Generally, plasmatic Arg concentrations are decreased in both humans and animals with diabetes [14,26,27]. This might be partially explained by the increased plasma arginase activity in diabetes [28–30].…”

Section: Discussionmentioning

confidence: 99%

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

et al. 2020

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Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

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The Profile of Plasma Free Amino Acids in Type 2 Diabetes Mellitus with Insulin Resistance: Association with Microalbuminuria and Macroalbuminuria

Cited by 30 publications

References 40 publications

Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease

Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease

NMR-Based Metabolomic Approach Tracks Potential Serum Biomarkers of Disease Progression in Patients with Type 2 Diabetes Mellitus

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

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