Intermittent administration of a leucine-deprived diet is able to intervene in type 2 diabetes in db/db mice

Abstract

Continuous deficiency of leucine, a member of branched chain amino acids, is able to reduce obesity and improve insulin sensitivity in mice. Intermittent fasting has been shown to be effective in intervention of metabolic disorders including diabetes. However, it is unknown whether intermittent leucine deprivation can intervene in type 2 diabetes progression. We administered leucine-deprived food every other day in db/db mice, a type 2 diabetes model, for a total of eight weeks to investigate the interventional effect of intermittent leucine deprivation. Intermittent leucine deprivation significantly reduces hyperglycemia in db/db mice independent of body weight change, together with improvement in glucose tolerance and insulin sensitivity. The total area of pancreatic islets and β cell number are increased by intermittent leucine deprivation, accompanied by elevated proliferation of β cells. The expression level of Ngn3, a β cell progenitor marker, is also increased by leucine-deleted diet. However, leucine deficiency engenders an increase in fat mass and a decrease in lean mass. Lipid accumulation in the liver is elevated and liver function is compromised by leucine deprivation. In addition, leucine deficiency alters the composition of gut microbiota. Leucine deprivation increases the genera of Bacteroides, Alloprevotella, Rikenellaceae while reduces Lachnospiraceae and these changes are correlated with fasting blood glucose levels of the mice. Collectively, our data demonstrated that intermittent leucine deprivation can intervene in the progression of type 2 diabetes in db/db mice. However, leucine deficiency reduces lean mass and aggravates hepatic steatosis in the mouse.

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice

“…A large number of studies has illustrated that the abundance of these bacteria were lower in obese or type 2 diabetic rats or humans (Schwiertz et al, 2010; Gomez-Arango et al, 2016; Jung et al, 2016). By contrast, improvement of glucose and lipid metabolism by polyunsaturated fatty acids (Li et al, 2018), berberine fumarate (Cui et al, 2018), dietary fucoidan (Shang et al, 2017), oral hydroxysafflor yellow A (Liu et al, 2018), a leucine-deprived diet (Wei S. et al, 2018), a galacto-oligosaccharide-rich diet (Cheng et al, 2018) or a traditional Chinese medicine prescription-Xiexin Tang (Wei X. et al, 2018) were all positively correlated with the abundance of these bacterial species. SCFAs (mainly acetate and butyrate), which were produced by fermentation of indigestible dietary components by specific gut microbiota, appeared to promote epithelial restitution and have anti-inflammation activity (Sturm and Dignass, 2008).…”

Investigation of leucinuria as a marker of progression of type 2 diabetes mellitus

“…One is that elevated level of BCAA would stimulate mammalian target of rapamycin complex 1 (mTORC1), which leads to uncoupling of insulin signaling. Secondly, the mitotoxic metabolite of BCAA causes mitochondrial dysfunction of beta cells of pancreas aggravating T2DM 14,17 . It has also been shown to regulate gene transcription and protein synthesis in pancreatic islet beta cells via mammalian target of rapamycin (mTOR)-dependent pathways as well as mTOR independent pathways at physiological concentration 18,19 .…”

“…It has also been shown to regulate gene transcription and protein synthesis in pancreatic islet beta cells via mammalian target of rapamycin (mTOR)-dependent pathways as well as mTOR independent pathways at physiological concentration 18,19 . Moreover, studies in mice have shown that leucine deprived food significantly reduces hyperglycemia together with improved glucose tolerance and insulin sensitivity 17,20 .…”

Autophagy-induced degradation of Notch1, achieved through intermittent fasting, may promote beta cell neogenesis: implications for reversal of type 2 diabetes

“…It has also been noted that fasting-induced reductions in mTORC1 and protein kinase A (PKA) activity in islet cells are mediators of this phenomenon 1. With respect to autophagy, it is notable that intermittent feeding of a leucine deprived, which would be expected to induce autophagy by episodic inhibition of mTORC1 activity, has likewise been shown to increase Ngn3 expression and beta cell mass in db/db mice 6…”