Abstract
Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice. The homeostatic model assessment of insulin resistance scores of NAG-1 Tg mice were lower than those of WT mice. Hematoxylin and eosin staining revealed a smaller lipid droplet size in the adipose tissues, lower lipid accumulation in the hepatocytes, and larger beta cell area in the pancreas of NAG-1 Tg mice than in those of WT mice. Immunohistochemical analysis revealed downregulated expression of cleaved caspase-3, an apoptosis marker, in the beta cells of NAG-1 Tg mice. Adiponectin and leptin mRNA levels were upregulated and downregulated in NAG-1 Tg mice, respectively. Additionally, the expression of IRS1/PI3K/AKT signaling pathway components, especially Foxo1, which regulates gluconeogenesis in the muscle and white adipose tissue, was downregulated in NAG-1 Tg mice. Furthermore, NAG-1 overexpression promoted the expression of As160 in both muscles and adipocytes, and the mRNA levels of the NLRP3 pathway members were downregulated in NAG-1 Tg mice. Our findings suggest that NAG-1 expression alleviates diabetes in mice.
Highlights
Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), known as growth differentiation factor 15 (GDF15), is a member of the TGF-β superfamily
These results suggest that glucose upregulates serum Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) levels in patients with diabetes, indicating that serum NAG-1 could be a potential marker for identifying individuals who are at risk for developing diabetes and obesity
Metformin has been reported to upregulate the expression of NAG-1/GDF1512, which indicates that the mechanism of action of metformin involves the induction of NAG-1 expression
Summary
Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), known as growth differentiation factor 15 (GDF15), is a member of the TGF-β superfamily. In a study examining the correlation between NAG-1 and beta cell function, serum NAG-1 levels were upregulated in the prediabetes and diabetes groups. The upregulated serum NAG-1 levels were correlated with HbA1c, glucose, insulin, baseline, and dynamic indices of insulin sensitivity[9]. These results suggest that glucose upregulates serum NAG-1 levels in patients with diabetes, indicating that serum NAG-1 could be a potential marker for identifying individuals who are at risk for developing diabetes and obesity. NAG-1 Tg mice exhibit increased energy metabolism, decreased body weight, and improved glucose and insulin responses[10]. The downregulation of NLRP3 inflammasome activity in NAG-1 Tg mice may confer resistance against diet-induced obesity and improve insulin s ensitivity[14]. NLRP3 may be a novel therapeutic target to alleviate inflammasome hyperactivation in patients with diabetes
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