RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

Abstract

Aims/hypothesis Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a highfat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal.Materials and methods Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/ immunoblotting were performed. Results HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulininduced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. Conclusions/interpretation Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.

Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis

“…Here, in livers of WSD-fed mice, mRNA expression of Insr, Irs1, and Irs2 was similar to controls, suggesting that insulin signaling was not yet altered. In contrast and in line with the findings of other groups (28), supplementation of Gln markedly affected Insr, Irs1, and Irs2 expressions in the liver. Furthermore, in livers of WSD-fed mice supplemented with Gln, the expression of Insr, Irs1, and Irs2 was significantly higher than in their respective controls.…”

“…Indeed, we and others previously showed that protection of the liver from the development of NAFLD was associated with an induction of Insr and Insr-dependent signaling cascades (4,29). Furthermore, Prada et al (28) also showed that oral supplementation of Gln in rodents in settings of liver damage was associated with induction of the insulin signaling cascade in the liver. Taken together, these data suggest that oral supplementation of Gln attenuated the development of NASH in mice fed a fructose-rich WSD.…”

Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes?

“…It is thought to inhibit lipolysis in fasting dogs [7] and postabsorptive human volunteers [8], and is a potent stimulus of glucagon-like peptide (GLP)-1 secretion in healthy individuals [9], and adults with type 2 diabetes [10]. It has been suggested that GLN improves glucose tolerance, insulin sensitivity, or both in various settings, including in critically ill patients [11], trauma patients [12], children with cystic fibrosis treated with recombinant growth hormone [13], and experimental animals [14]. GLN also enhanced glycogen storage after exercise in healthy individuals [6].…”

A Systems Biology Approach Using Transcriptomic Data Reveals Genes and Pathways in Porcine Skeletal Muscle Affected by Dietary Lysine

“…Similarly, dietary arginine supplementation increased the activity of mTOR signaling in skeletal muscle of neonatal pigs [10]. Glutamine may prevent protein hypercatabolism via inhibition of myostatin hyperexpression [11], and supplementation of glutamine to a high-fat diet improved insulin signaling in the muscle of rats [12]. In terms of lysine, however, which signaling pathways related to muscle protein accretion and carcass characteristics are regulated by its dietary supply is still unknown.…”