Abstract
Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans – strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.
Introduction
Type 2 diabetes (T2D) is one of world’s most prevalent diseases, and is related to the epidemic of obesity [1]. Obesity can lead to the onset of T2D when pancreatic β-cells are no longer able to compensate higher insulin secretion for the reduced insulin sensitivity that often accompanies obesity [2]. Over the last decade, branched-chain amino acids (BCAA) catabolism has increasingly been considered to have an emerging role in the development of insulin resistance in people with obesity and T2D. In these individuals, BCAA levels are considerably elevated in plasma and tissues [3,4,5,6,7,8,9]. Furthermore, elevated BCAA levels in plasma strongly associate with insulin resistance in people with obesity and T2D [3, 4, 6,7,8, 10,11,12,13]. Although it is still unknown why these BCAA levels are elevated and why they associate with insulin resistance, a dysfunctional BCAA catabolism may be one of the underlying factors. This review aims to provide insight into the mechanisms behind elevated plasma BCAA levels in people with obesity and/or T2D and its role in the pathogenesis of insulin resistance. Furthermore, this review will overview pharmaceutical and alternative lifestyle intervention strategies in order to lower plasma BCAA levels and its effects on metabolic health.
Conclusion
Dysregulation of BCAA catabolism is closely related to obesity- and T2D related metabolic disturbances since BCAA levels plays a key role in interorgan metabolic crosstalk. Findings from animal and human studies provided evidence that dysfunctional BCAA catabolism in several tissues could be a plausible explanation for the elevated plasma BCAA levels seen in obesity and T2D, however, huge knowledge gaps exist in tissue-specific BCAA catabolism in humans. Insulin resistance can occur via dysfunctional BCAA catabolism or BCAA levels acting as signaling molecules hampering the insulin signaling pathways. Therefore, exploring intervention strategies to increase BCAA oxidation and/or lower BCAA levels is important to investigate whether this could be a new potential strategy in the treatment of metabolic diseases, including obesity and T2D.
Source: Nature
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