3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism

Abstract

Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB-forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtypespecific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.

A Dual Systems Genetics Approach Identifies Common Genes, Networks, and Pathways for Type 1 and 2 Diabetes in Human Islets

“…ASCC2 is involved in ubiquitin binding activity which might be responsible for commonly regulating β-cell function in human islets and contributing to both T1D and T2D (López-Avalos et al, 2006), which deserves further investigation in future studies. HIBADH (3-hydroxyisobutyrate dehydrogenase) has been previously implicated in insulin resistance and risk of incident type 2 diabetes and gestational diabetes mellitus (Nilsen et al, 2020). Although the selection of genes based on their regulation by cytokines and/or palmitate does not necessarily identify causal genes, but merely identifies genes whose expression level correlate with cytokine/palmitate exposure.…”

Plasma BCAA concentrations during exercise of varied intensities in young healthy men—the impact of endurance training

“…It is well known that regular exercise exerts beneficial effects on the human general health including an improvement of insulin sensitivity (Holloszy, 2005). Since skeletal muscle accounts for about 60-80% of postprandial insulin-mediated glucose uptake (Meyer et al, 2002;Soulage et al, 2018), muscle insulin resistance play a key role in the disturbances in glucose homeostasis. Considering the role of BCAA in the insulin resistance and taking into account that skeletal muscles is a major tissue that utilizes BCAA, BCAA oxidation during exercise might have an important impact on the maintaining glucose homeostasis.…”

Molecular Signature of HFpEF

“…However, of those, we noted a reduction in creatine and free phosphate accompanied by an increase in AMP ( Figures 6C and 6D ), suggesting an energetic deficit. An increase in 3-hydroxyisobutyrate, a catabolic intermediate of valine metabolism and a strong marker of systemic and muscle insulin resistance ( 40 , 41 ), was also increased in abundance. Assessment of skeletal muscle mitochondrial function revealed reduced complex I and complex II state 3 respiratory rates ( Figures 6E , 6F , 6G , 6H , 6I , and 6J ), suggesting early cardiac remodeling is sufficient to promote peripheral tissue remodeling.…”