Prof. Milan HOLEČEK
Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic
Title: Perturbations of Amino Acid Metabolism in Diabetes Mellitus
Abstract:
The most frequent alterations in plasma
amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine
and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine)
levels. The likely cause of L-serine deficiency is decreased synthesis of
3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired
glycolysis. The BCAA levels increase due to decreased supply of pyruvate and
oxaloacetate from glycolysis, enhanced supply of NADH+H+ from
beta-oxidation, and subsequent decrease in the flux through the citric acid
cycle in muscles. These alterations decrease the supply of α-ketoglutarate for
BCAA transamination and activity of branched-chain keto acid dehydrogenase, the
rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to
impaired synthesis of sphingolipids and increased synthesis of
deoxysphinganines, which play a role in pathogenesis of diabetic neuropathy,
impaired homocysteine disposal via methionine cycle and transsulfuration
pathway resulting in hyperhomocysteinemia, and glycine deficiency due to the
adaptive increase in glycine utilization for L-serine synthesis. Enhanced BCAA
levels contribute to increased levels of aromatic amino acids (phenylalanine,
tyrosine, and tryptophan), insulin resistance, and accumulation of various
metabolites whose influence on the progression of diabetes has not been
clarified. Due to positive effects of BCAA on protein balance, it is not clear
whether their increased levels in diabetes are beneficial or harmful. It is
concluded that:
· Plasma amino acid concentrations
should be monitored in all patients with diabetes. In the case of the decrease
in serine and glycine levels, their supplementation should be recommended.
· The ratio between BCAA and
L-serine levels could be a better prognostic indicator of insulin deficiency or
resistance than BCAA alone.
· Better understanding of the
consequences of perturbations in BCAA metabolism is essential for making
decisions regarding their dietary recommendations in patients with diabetes.
Keywords:
branched-chain amino acids; serine; glycine; insulin resistance.
Financial Support: Charles University,
the Cooperatio Program, research area METD.
Biography:
Milan Holeček obtained M.D. degree in 1981 from Charles University
in Prague. He completed his Ph.D. degree in physiology in 1985 studying the
possibilities of nutritional modulation of liver regeneration. In 1991 he was
awarded the fellowship which took him to the laboratory of Professor Adibi in
the Department of Clinical Nutrition at the University of Pittsburgh, PA, USA.
Here he began investigation of metabolism of amino acids in catabolic states.
This work has continued to date. In 2009
he was appointed to Professor of Physiology. He has published more than 100
papers in reputed journals. Successfully supervised 4 Ph.D. students. H-index = 27.