d-chiro-Inositol Ameliorates High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance via PKCε-PI3K/AKT Pathway

Abstract

d-chiro-Inositol (DCI) is a biologically active component found in tartary buckwheat, which can reduce hyperglycemia and ameliorate insulin resistance. However, the mechanism underlying the antidiabetic effects of DCI remains largely unclear. This study investigated the effects and underlying molecular mechanisms of DCI on hepatic gluconeogenesis in mice fed a high fat diet and saturated palmitic acid-treated hepatocytes. DCI attenuated free fatty acid uptake by the liver via lipid trafficking inhibition, reduced diacylglycerol deposition, and hepatic PKCε translocation. Thus, DCI could improve insulin sensitivity by suppressing hepatic gluconeogenesis. Subsequent analyses revealed that DCI decreased hepatic glucose output and the expression levels of PEPCK and G6 Pase in insulin resistant mice through PKCε-IRS/PI3K/AKT signaling pathway. Likewise, such effects of DCI were confirmed in HepG2 cells with palmitate-induced insulin resistance. These findings indicate a novel pathway by which DCI prevents hepatic gluconeogenesis, reduces lipid deposition, and ameliorates insulin resistance via regulation of PKCε-PI3K/AKT axis.

D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome

“…According to our data, DCI was able to rescue the deficiency of AKT activity (measured as activating phosphorylation) induced by DHT. As DCI has been also described in striate muscle [ 44 , 45 ], we speculate that if present in other tissues, DCI could restore the PI3k-AKT pathway and help counteract the effects of PCOS syndrome. Interestingly, other metabolic sensors such as mTOR were not noted to play a role in this response to DCI.…”

D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: a pilot study

“…DCI activity as hypoglycemic agent was recently confirmed by a preclinical study [ 67 ] that highlighted a new mechanism of action of DCI to decrease gluconeogenesis in insulin-resistant hepatocytes. This effect occurs via PI3K/AKT/FOXO1-mediated inhibition of glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase mRNA expression [ 67 ]. In the study, DCI was able to reduce hepatic gluconeogenesis and endogenous glucose consumption, not only in human HepG2 cells but also in insulin-resistant mice.…”

“…In the study, DCI was able to reduce hepatic gluconeogenesis and endogenous glucose consumption, not only in human HepG2 cells but also in insulin-resistant mice. The decreased gluconeogenesis accounts for DCI-induced lowering of blood glucose levels and amelioration of glucose homeostasis and insulin resistance (IR) [ 67 ]. Such finding increased the number of different mechanisms through which DCI counteracts peripheral IR, observed also in other experimental models where IR was induced by glucosamine [ 68 ].…”

Direct Effects of D-Chiro-Inositol on Insulin Signaling and Glucagon Secretion of Pancreatic Alpha Cells

“…In our findings, we showed that DCI treatment was able to restore phosphorylation of the IR/IRS-1/AKT pathway in α-TC1-6 cells exposed to palmitate, ameliorating the insulin responsiveness of α-cells. Previous studies indicated that DCI can improve the insulin pathway by acting on the IR/AKT axis in hepatic and skeletal muscle tissues [ 27 , 64 , 65 ].…”