Increased Incretin But Not Insulin Response after Oral versus Intravenous Branched Chain Amino Acids

Abstract

Background/Aims: Branched chain amino acids (BCAAs) are known to exert an insulinotropic effect. Whether this effect is mediated by incretins (glucagon like peptide 1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) is not known. The aim of this study was to show whether an equivalent dose of BCAA elicits a greater insulin and incretin response when administered orally than intravenously (IV). Methods: Eighteen healthy, male subjects participated in 3 tests: IV application of BCAA solution, oral ingestion of BCAA and placebo in an equivalent dose (30.7 ± 1.1 g). Glucose, insulin, C-peptide, glucagon, GLP-1, GIP, valine, leucine and isoleucine concentrations were measured. Results: Rise in serum BCAA was achieved in both BCAA tests, with incremental areas under the curve (iAUC) being 2.1 times greater for IV BCAA compared with those of the oral BCAA test (p < 0.0001). Oral and IV BCAA induced comparable insulin response greater than placebo (240 min insulin iAUC: oral 3,411 ± 577 vs. IV 2,361 ± 384 vs. placebo 961.2 ± 175 pmol/L, p = 0.0006). Oral BCAA induced higher GLP-1 (p < 0.0001) and GIP response (p < 0.0001) compared with the IV or placebo. Glucose levels declined significantly (p < 0.001) in the same pattern during both BCAA tests with no change in the placebo group. Conclusions: An equivalent dose of BCAA elicited a comparable insulin and greater incretin response when administered orally and not when administered through IV. We conclude that insulinotropic effects of BCAA are partially incretin dependent.

Diabetes and branched‐chain amino acids: What is the link?

“…The metabolism of BCAA involves two processes: (i) a reversible process catalysed by a branched‐chain aminotransferase (BCAT), either cytosolic or mitochondrial, requiring pyridoxal to function as an amino group carrier, by which the BCAA with 2‐ketoglutarate produce a branched‐chain keto acid plus glutamate; and (ii) the irreversible mitochondrial process catalysed by branched‐chain keto acid dehydrogenase (BCKDH) leading to formation of acetyl‐coenzyme A (CoA), propionyl‐CoA, and 2‐methylbutyryl‐CoA from leucine, valine, and isoleucine, respectively, which enter the tricarboxylic acid (Krebs) cycle as acetyl‐CoA, propionyl‐CoA, and 2‐methylbutyryl‐CoA, respectively, leading to ATP formation . The BCAA stimulate secretion of both insulin and glucagon and, when given orally, of both glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), with oral administration leading to greater and more prolonged insulin and glucagon secretion . Insulin may particularly reduce BCAA turnover to a greater extent than that of other amino acids, and decreases the appearance and increases the uptake of amino acids .…”

The Impact of Amino Acids on Postprandial Glucose and Insulin Kinetics in Humans: A Quantitative Overview

“…The time series data and the calculated kinetic parameters are visualized in Supplemental Figure S10 . The effect of oral BCAA ingestion (mixtures containing leucine, isoleucine, and valine) has been investigated in healthy individuals only [ 62 , 63 ] ( Supplemental Figure S10A ). Both studies (excluding the low dose, 1 g, BCAA dose intervention [ 62 ]), showed that oral BCAA ingestion increased insulin (iAUC range, 0.47 to 1.51 µU/mL/min), and decreased glucose concentrations (iAUC, −9.22 to −3.67 mg/dL/min) from baseline and the control group (iAUC, −0.29 µU/mL/min, −0.30 mg/dL/min).…”

“…Furthermore, the 5 g BCAA dose resulted in a higher insulin peak concentration (8.5 µU/mL) than the 1 g BCAA dose (7.3 µU/mL) [ 62 ]. The highest insulin response was observed in the study that had the largest BCAA dose [ 63 ].…”

“…The effect of intravenous BCAA infusion (mixtures containing leucine, isoleucine, and valine) has also been investigated in healthy individuals [ 63 , 64 , 65 ] ( Supplemental Figure S10C ). Two out of the three studies showed increased insulin (iAUC range, 0.18 to 0.50 µU/mL/min) [ 63 , 64 ]. Glucose concentrations consistently decreased from baseline in these studies (iAUC, range, −12.05 to −8.37 mg/dL/min).…”

Is the Response of Tumours Dependent on Dietary Input of Some Amino Acids or on the Ratios Among Essential and Non-Essential Amino Acids? All That Glisters is Not Gold

“…We may also observe that in humans, one double blind controlled study on long term therapy with BCAA supplementation in diabetic patients, that found positive results on glucose tolerance and on a typical feature of insulin resistance, liver steatosis [ 30 ] , and also another study showing that acute ingestion of BCAA elicits efficient insulin response and consequently hypoglycemia [ 31 ], were also not considered and discussed. To further clarify the item, a very well designed study showed that leucine supplementation in high fat diets would have different effects on glucose tolerance and insulin resistance if studied on short or long term, when beneficial effects are unequivocally evident.…”