Dataset Information

N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice.

ABSTRACT: Oxidative stress is associated with different pathological conditions, including glucose intolerance and type 2 diabetes (T2D), however studies had failed to prove the benefits of antioxidants in T2D. AIM:On the assumption that the failure to demonstrate such anti-diabetic effects is a result of sub-optimal or excessive antioxidant dosage, we aimed to clarify the dose-response effect of the antioxidant N-Acetyl-L-Cysteine (NAC) on the progression of T2D in-vivo. METHODS:Experiments were conducted on KK-Ay mice and HFD-fed mice given NAC at different concentrations (200-1800 and 60-600 mg/kg/day, respectively). Glucose and insulin tolerance tests were performed and plasma insulin and lipid peroxidation were measured. Insulin signaling pathway was followed in muscle and liver. Hepatic TG accumulation and mRNA expression of genes involved in glucose metabolism were measured. RESULTS:While 600-1800 mg/kg/day NAC all improved glucose tolerance in KK-Ay mice, only the 1200 mg/kg/day treatment increased insulin sensitivity. Hepatic function was not affected, however; microsteatosis rather than macrosteatosis was observed in NAC-treated mice compared to control. Glucose tolerance was improved in NAC-treated HFD-fed mice as well; the best results obtained with a dose of 400 mg NAC/kg/day. This was followed by lower weight gain and hepatic TG. Plasma lipid peroxidation was not correlated with the glucose-lowering effects of NAC in either model. CONCLUSION:Identification of the optimal dose of NAC and the population that would benefit the most from such intervention is essential in order to apply preventive and/or therapeutic use of NAC and similar agents in the future.

SUBMITTER: Falach-Malik A

PROVIDER: S-EPMC5040673 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice.

Falach-Malik Alona A Rozenfeld Hava H Chetboun Moria M Rozenberg Konstantin K Elyasiyan Uriel U Sampson Sanford R SR Rosenzweig Tovit T

American journal of translational research 20160915 9

Oxidative stress is associated with different pathological conditions, including glucose intolerance and type 2 diabetes (T2D), however studies had failed to prove the benefits of antioxidants in T2D.<h4>Aim</h4>On the assumption that the failure to demonstrate such anti-diabetic effects is a result of sub-optimal or excessive antioxidant dosage, we aimed to clarify the dose-response effect of the antioxidant N-Acetyl-L-Cysteine (NAC) on the progression of T2D in-vivo.<h4>Methods</h4>Experiments ...[more]

PMID: 27725855

Similar Datasets

Project description:Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes.

Dataset Information

N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice.

Publications

N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets