Dual Effects of Beta-Hydroxy-Beta-Methylbutyrate (HMB) on Amino Acid, Energy, and Protein Metabolism in the Liver and Muscles of Rats with Streptozotocin-Induced Type 1 Diabetes

Abstract

Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.

Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus

“…Hence, during diabetes, the flux through the CAC decreases [ 11 , 15 ]. It is very likely that these alterations have a fundamental role in impaired mitochondrial respiration and energy balance observed in the muscles, hearts, and kidneys of subjects with diabetes [ 4 , 16 , 17 , 18 , 19 , 20 ].…”

“…L-serine concentrations in plasma and tissues decrease in both T1DM [ 4 , 5 , 31 , 32 ] and T2DM [ 5 , 6 , 33 , 34 , 35 , 36 , 37 ]. The decrease in L-serine levels is probably due to two reasons.…”

“…However, alterations are not consistent for most amino acids. Most consistently increase the levels of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) and aromatic amino acids (AAA, phenylalanine, tyrosine, and tryptophan) and decrease the levels of L-serine and glycine [ 2 , 3 , 4 ]. There are inconsistent data on changes in alanine, glutamate, aspartate, and glutamine, although these amino acids play a role in BCAA catabolism reactions [ 4 , 5 , 6 , 7 ].…”

The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology

“…It has been proven repeatedly that in animal models of T1DM [ 32 , 33 , 34 ] and in patients with T1DM [ 35 , 36 ], the plasma BCAAs are significantly elevated compared to healthy controls. Untreated T1DM is characterized by hyperglycemia, increased food intake, increased fatty acid oxidation as an energy source, muscle wasting and muscle mitochondria dysfunction [ 37 , 38 ].…”

“…It is suggested that the underlying mechanism involves disruptions in glycolysis and fatty acid oxidation. In T1DM, a decreased rate of glycolysis, reduced activity of citric acid enzymes and increased NADH/NAD + ratio due to enhanced fatty acid oxidation may contribute to the impaired BCAA catabolism as a consequence of the decreased supply of amino group acceptors (2-KG, PYR, oxaloacetate) and the inhibitory effect of NADH and acyl-CoAs on BCKD [ 32 , 39 ].…”