4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway

Furostanolic saponins from Trigonella foenum‐graecum alleviate diet‐induced glucose intolerance and hepatic fat accumulation

“…Previous studies have demonstrated that fenugreek attenuated body‐weight gain and improved insulin sensitivity . These beneficial effects of fenugreek have been attributed to the presence of an unusual amino acid 4‐hydroxyisoleucine . Our studies indicate that a water‐soluble furostanolic saponin free of 4‐hydroxyisoleucine contributes to the insulin‐sensitizing properties of the fenugreek.…”

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

“…Additionally, the isoleucine analog 4‐hydroxyisoleucine (4HIL) isolated form the seeds of Trigonella foenum‐graecum has been shown to induce transcript expression of lipolytic genes in L6 myotubes. Specifically, PPARα, PPARγ, carnitine palmitoyl transferase 1 (CPT1), and AMPK were upregulated using treatment concentrations of 10μM for 12 hours . 4HIL also increased expression of several genes that regulate lipolysis, mitochondrial biogenesis, and glucose uptake in both liver and skeletal muscle including PGC‐1α, PGC‐1β, NRF1, TFAM, and mitofusion1/2 (MFN1/2) in addition to several others in both skeletal muscle and liver of diabetic rats .…”

“…Specifically, PPARα, PPARγ, carnitine palmitoyl transferase 1 (CPT1), and AMPK were upregulated using treatment concentrations of 10μM for 12 hours . 4HIL also increased expression of several genes that regulate lipolysis, mitochondrial biogenesis, and glucose uptake in both liver and skeletal muscle including PGC‐1α, PGC‐1β, NRF1, TFAM, and mitofusion1/2 (MFN1/2) in addition to several others in both skeletal muscle and liver of diabetic rats . Isoleucine derivatives illicit similar effects in L6‐glucose transporter 4 (L6‐GLUT4myc) myotubes treated with 4HIL at 5–25μM for 16 hours with increased glucose uptake, likely a byproduct of increased GLUT4 .…”

“…Oral leucine or isoleucine supplementation in vivo at 1.5 g/kg (without concurrent glucose) significantly enhanced SD rat skeletal muscle GLUT4 translocation, although glycogen synthase activity was only enhanced in leucine‐treated rats in a mTOR‐dependent fashion . Others have also shown isoleucine increases GLUT4 content and translocation both in vitro (L6 myotubes) and in vivo (Wistar rats) . Likewise, studies have shown oral gavage with isoleucine lowers blood glucose at 60 and 120 minutes in‐part through reduced hepatic gluconeogenesis via AMPK activation, and possibly through suppressed glucose‐alanine cycle activity, suggesting leucine and isoleucine may function in‐part through different mechanisms (given leucine's unique ability to also enhance insulin secretion) .…”

Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

“…Insulin resistance (IR) is a pathological condition in which cells fail to respond to the normal physiological dose of insulin, and plays important roles in the pathogenesis of metabolic syndrome such as obesity and type 2 diabetes mellitus (T2DM) [1]. Accumulating studies have demonstrated that consumption of high-energy diets lead to the glycometabolic disorder and impairment of insulin sensitivity, which increased the risk of the development of metabolic abnormalities [2]. The current clinical drugs for treatment of diabetes and insulin resistance, including sulfonylureas, metformin and thiazolidinediones, always have some side effects such as weight gain and hypoglycemia [3][4][5].…”