The branched-chain amino acids valine and leucine predict all-cause mortality in cardiovascular disease patients independently from the presence of type 2 diabetes mellitus

Background: Milk and sugar are excessively consumed in a Western diet. There is increasing epidemiological evidence that the intake of unfermented pasteurized cow´s milk is associated with an increased risk of type 2 diabetes mellitus (T2D). It is the intention of this review to provide translational biochemical evidence for milk´s diabetogenic mode of action. Milk proteins provide the highest amounts of branched-chain amino acids (BCAAs) and thus contribute to total BCAA intake, which enhances BCAA plasma levels associated with increased risk of T2D. The consumption of pasteurized milk raises plasma levels of miRNA-29b, which is a diabetogenic miRNA promoting insulin resistance (IR). miRNA29b inhibits the activity of branched-chain-keta acid dehydrogenase, the rate limiting enzyme of BCAA catabolism, which is impaired in patients with IR and T2D. Milk consumption stimulates mTORC1 activity and increases insulin synthesis. -cell mTORC1 is overactivated in T2D patients resulting in impaired autophagy which enhances endoplasmic reticulum (ER) stress associated with a greater risk of early -cell apoptosis, the pathogenic hallmark of T2D. Chronic insulinotropic action of milk-derived BCAAs, IR-promoting mTORC1 overactivity, and miRNA-29b signaling combined with excessive glucose-mediated insulin secretion overburden -cell insulin homeostasis. Epidemiological and translational evidence identifies continued milk intake as a promoter of T2D, the most common metabolic disease of Western civilization. Keywords: Branched-chain amino acids, branched-chain-keto acid dehydrogenase, diabetes mellitus type 2, insulin resistance, milk, miRNA-29b, mechanistic target of rapamycin complex 1.

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A novel NMR-based assay to measure circulating concentrations of branched-chain amino acids: Elevation in subjects with type 2 diabetes mellitus and association with carotid intima media thickness

Clinical Biochemistry ◽

10.1016/j.clinbiochem.2018.02.001 ◽

2018 ◽

Vol 54 ◽

pp. 92-99 ◽

Cited By ~ 30

Author(s):

Justyna Wolak-Dinsmore ◽

Eke G. Gruppen ◽

Irina Shalaurova ◽

Steven P. Matyus ◽

Russell P. Grant ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Amino Acids ◽

Type 2 Diabetes Mellitus ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Branched Chain Amino Acids ◽

Media Thickness ◽

Branched Chain

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Serum Branched Chain Amino Acids Are Associated with Type 2 Diabetes Mellitus in Jordan

Korean Journal of Family Medicine ◽

10.4082/kjfm.17.0122 ◽

2018 ◽

Vol 39 (5) ◽

pp. 313-317 ◽

Cited By ~ 3

Author(s):

Mahmoud A. Alfaqih ◽

Zaina Abu-Khdair ◽

Rami Saadeh ◽

Nesreen Saadeh ◽

Ahmed Al-Dwairi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Amino Acids ◽

Type 2 Diabetes Mellitus ◽

Branched Chain Amino Acids ◽

Branched Chain

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Renal impairment and all-cause mortality in cardiovascular disease: effect modification by type 2 diabetes mellitus

European Journal of Clinical Investigation ◽

10.1111/eci.12035 ◽

2013 ◽

Vol 43 (2) ◽

pp. 198-207 ◽

Cited By ~ 11

Author(s):

Sharmini Selvarajah ◽

Cuno S. P. M. Uiterwaal ◽

Jamaiyah Haniff ◽

Yolanda van der Graaf ◽

Frank L. J. Visseren ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 2 Diabetes Mellitus ◽

Renal Impairment ◽

Effect Modification ◽

All Cause Mortality ◽

Disease Effect

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A Newly Developed Diabetes Risk Index, Based on Lipoprotein Subfractions and Branched Chain Amino Acids, is Associated with Incident Type 2 Diabetes Mellitus in the PREVEND Cohort

Journal of Clinical Medicine ◽

10.3390/jcm9092781 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2781

Author(s):

Jose L. Flores-Guerrero ◽

Eke. G. Gruppen ◽

Margery A. Connelly ◽

Irina Shalaurova ◽

James D. Otvos ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Amino Acids ◽

Risk Index ◽

Branched Chain Amino Acids ◽

Diabetes Risk ◽

Incident Type ◽

Incident Type 2 Diabetes ◽

Branched Chain

Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97–20.89, p < 0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73–5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14–1.65), p < 0.001). The Kaplan–Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank test <0.001). Conclusions: Higher DRI scores are associated with an increased risk of T2D. The association is independent of clinical risk factors for T2D including HOMA-IR, BMI and conventional lipids.

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All-Cause Mortality And Cardiovascular Events In A Spanish Nonagenarian Cohort According To Type 2 Diabetes Mellitus Status And Established Cardiovascular Disease

10.21203/rs.3.rs-457930/v1 ◽

2021 ◽

Author(s):

MA Salinero-Fort ◽

J Mostaza-Prieto ◽

C Lahoz-Rallo ◽

J Cárdenas-Valladolid ◽

JI Vicente-Díez ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 2 Diabetes Mellitus ◽

Primary Outcome ◽

P Values ◽

Group 4 ◽

All Cause Mortality

Abstract Background: To analyze all-cause mortality and cardiovascular events in nonagenarians from a Mediterranean population.Methods: Primary Health Care (265 health centres)Participants: Primary health records of all the nonagenarians living in the Community of Madrid (N=59,423). We defined 4 groups according to prevalent type 2 diabetes mellitus and established cardiovascular disease: (1) type 2 diabetes mellitus (-), cardiovascular disease (-); (2) type 2 diabetes mellitus (-), cardiovascular disease (+); (3) type 2 diabetes mellitus (+), cardiovascular disease (-); and (4) type 2 diabetes mellitus (+), cardiovascular disease (+). Follow-up time was 2.5 years. Primary outcome: Cumulative incidence and the density incidence rates of all-cause mortality, non-fatal myocardial infarction, non-fatal stroke (combined they constituted the first composite primary outcome (CPO1)), and heart failure (similarly, combined with the previous they constituted CPO2). We evaluated the adjusted effect of groups classification on all-cause mortality (Cox regression). Results. Mean age was 93.3±2.8 years; 74.2% were women. Hypertension, dyslipidemia, heart failure, albuminuria and estimated glomerular filtration rate <60 mL/min/1.73m2 were significantly more prevalent in group 4 (type 2 diabetes mellitus (+), cardiovascular disease (+)) than in the other groups (all p values <0.001). We observed significantly higher rates of cumulative incidence of all-cause mortality, CPO1 and CPO2 in participants belonging to group 4 (all p values ≤0.001). People in group 2 (type 2 diabetes mellitus (-), cardiovascular disease (+)) presented higher rates of all-cause mortality, heart failure, CPO1 and CPO2 than people in group 3 (type 2 diabetes mellitus (+), cardiovascular disease (-)) (all p values ≤0.001). In the fully-adjusted model, prevalent type 2 diabetes mellitus plus established cardiovascular disease (group 4) independently predicted all-cause mortality (HR=1.48 (95% CI, 1.40 to 1.57) as compared to reference group 1 (type 2 diabetes mellitus (-), cardiovascular disease (-)) (p <0.01). Also, cardiovascular disease and type 2 diabetes mellitus alone showed significant HRs (1.13 and 1.14, respectively; both p values <0.01)).Conclusions. In Spanish nonagenarians, established cardiovascular disease and type 2 diabetes mellitus conferred modest all-cause mortality risks. The concurrent presence of both conditions conferred the highest all-cause mortality risk.

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