Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance

Connelly, Margery A.; Wolak-Dinsmore, Justyna; Dullaart, Robin

doi:10.1089/met.2016.0145

Cited by 56 publications

(54 citation statements)

References 23 publications

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“…Plasma concentrations of both glucagon and nonBCCAs (e.g. alanine) during an OGTT were affected by increasing HOMA-IR; the BCAAs were also affected but in the opposite direction, as previously reported [24][25][26]. These observations support our hypothesis that impaired hepatic glucagon signalling, potentially due to fat accumulation in the liver and resulting hepatic insulin resistance [14], impairs glucagon's ability to lower plasma levels of non-BCAAs.…”

Section: Discussionsupporting

confidence: 90%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

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Aims/hypothesis The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon. Methods To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance. Results Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. Conclusions/interpretation This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

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Section: Discussionsupporting

confidence: 90%

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

et al. 2018

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“…6,7 The BCAA, valine, leucine and isoleucine, are essential amino acids that not only regulate protein production and catabolism but are also involved in glucose metabolism. 33,34,40,52,53 BCAA may be implicated in the development of insulin resistance by enhancing mitochondrial stress. On the other hand, insulin resistance itself could elicit higher fasting BCAA levels.…”

Section: Discussionmentioning

confidence: 99%

“…26,28 Details for the quantification of the BCAA have been previously reported. 34,40 The inter-assay CVs for the BCAA measurements are 3.1% for valine, 5.9% for leucine 14.1% for isoleucine and 3.2% for total BCAA. 34 Plasma aldosterone was assayed with a competitive fixed-time solid-phase Radioimmunoassay (RIA) as described (Coat-a-Count®;…”

Section: Laboratory Methodsmentioning

confidence: 99%

Primary aldosteronism is associated with decreased low‐density and high‐density lipoprotein particle concentrations and increased GlycA, a pro‐inflammatory glycoprotein biomarker

Berends

Buitenwerf

Gruppen

et al. 2018

Clinical Endocrinology

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Background: Primary aldosteronism (PA) may confer increased cardiovascular risk beyond effects on systemic blood pressure, but contributing mechanisms remain incompletely understood. We compared plasma (apo)lipoproteins and lipoprotein particle characteristics, GlycA, a pro-inflammatory glycoprotein biomarker of enhanced chronic inflammation, and plasma total branched-chain amino acids (BCAA), measured using nuclear magnetic resonance (NMR) spectroscopy, between patients with PA, control subjects without hypertension, subjects with untreated hypertension and subjects with treated hypertension. Methods: Twenty PA patients were individually matched with 2819 control subjects without hypertension, 501 subjects with untreated hypertension and 878 subjects with treated hypertension participating in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort study with respect to age, sex, body mass index, smoking and statin use. The Vantera® Clinical Analyzer was used to determine NMRbased laboratory parameters.Results: Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) B, apolipoprotein A-I (apoA-I), LDL particle and HDL particle concentrations were all decreased in PA subjects vs control subjects and subjects with untreated hypertension (P < 0.016). Triglycerides (TG) and triglyceride-rich lipoprotein (TRL) concentrations were lower in PA subjects vs subjects with (untreated) hypertension. GlycA was increased in PA vs the three comparator groups (P < 0.016). Total BCAA concentrations were unaltered in PA. Conclusions: Primary aldosteronism is associated with lower concentrations of LDLand HDL particles and to some extent also with lower TG and TRL particle concentrations. PA is also characterized by increased GlycA levels, indicating enhanced lowgrade chronic inflammation. Low HDL particle concentrations and increased GlycA could contribute to accelerated cardiovascular disease development in PA.

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“…Thus it is quite natural that plasma levels of BCAAs increase in patients of type 2 diabetes [4][5][6][7] because the metabolism of such amino acids are impaired.…”

Section: Discussionmentioning

confidence: 99%

“…Branched-chain amino acids concentrations have been shown to be elevated in response to overnutrition and can affect insulin sensitivity and secretion [3]. Number of human studies have consistently indicated that concentrations of BCAAs in plasma and urine are associated with insulin resistance [4][5][6][7]. We recently examined relationship between various foods uptakes and body mass index (BMI) and various plasma parameters in Japanese young and old men and women [8].…”

Section: Introductionmentioning

confidence: 99%

Plasma levels of various amino acids and their changes upon protein uptakes in Japanese young and old men and women

Shimizu¹,

Ishii²,

Ogawa³

et al. 2017

Integr Food Nutr Metab

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MethodsWe asked men and women older than 50 years old and men and women college students to participate in the experiments. checked their health carefully and recruited them if there were no health problems such as diabetes, hypertension nor serious diseases experienced in the past. They did not smoke in the past. We also excluded people who took drugs for dyslipidemia, hyperglycemia, or hypertension.Participants were asked not to eat anything after 21.00 PM the previous evening. We took blood samples between 9.00 AM and 11.00 AM. Plasma specimens were collected for assays of blood parameters. We obtained an informed consent prior to conducting the protocol which had been approved by the Ethical Committee of Showa Women's University and Saiseikai Shibuya Satellite Clinic.Plasma levels of various amino acids and their changes upon protein uptakes in Japanese young and old men and women

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Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance

Abstract: Insulin resistance was associated with BCAA. This association remained after adjusting for age, sex, T2DM, BMI, as well as leptin and adiponectin. It is unlikely that the relationship of insulin resistance with BCAA is to a major extent attributable to effects of leptin and adiponectin.

Cited by 56 publications

References 23 publications

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

Primary aldosteronism is associated with decreased low‐density and high‐density lipoprotein particle concentrations and increased GlycA, a pro‐inflammatory glycoprotein biomarker

Plasma levels of various amino acids and their changes upon protein uptakes in Japanese young and old men and women

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