Abstract
The limited efficacy of current treatment methods and increased type 2 diabetes mellitus (T2DM) incidence constitute an incentive for investigating how metabolic homeostasis is maintained, to improve treatment efficacy and identify novel treatment methods. We analyzed a three-generation family of Chinese origin with the common feature of T2DM attacks and fatty pancreas (FP), alongside 19 unrelated patients with FP and 58 cases with T2DM for genetic variations in Enho, serum adropin, and relative Treg amounts. Functional studies with adropin knockout (AdrKO) in C57BL/6J mice were also performed. It showed serum adropin levels were significantly lower in FP and T2DM patients than in healthy subjects; relative Treg amounts were also significantly decreased in FP and T2DM patients, and positively associated with adropin (r=0.7220, P=0.0001). Sequencing revealed that the patients shared a Cys56Trp mutation in Enho. In vivo, adropin-deficiency was associated with increased severity of glucose homeostasis impairment and fat metabolism disorder. AdrKO mice exhibited reduced endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1177), impaired glycosphingolipid biosynthesis, adipocytes infiltrating, and loss of Treg, and developed FP and T2DM. Adropin-deficiency contributed to loss of Treg and the development of FP disease and T2DM.
Highlights
Obesity arises from a sustained positive energy balance that triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2DM and pancreatic steatosis.[1]
We found that almost all patients with pancreatic steatosis were diagnosed with diabetes; in addition, Energy Homeostasis Associated gene (Enho) mutations were found in a three-generation family of Chinese origin with the common feature of T2DM attacks and fatty pancreas (FP)
Our results showed that adropin levels were inversely associated with insulin (INS) (r = − 0.3945, P = 0.0693, n = 22) (Figure 3d), as reflected by INS immunohistochemistry, which showed apparently increased islet size in AdrKO mice compared with WT mice (Figure 3e)
Summary
Obesity arises from a sustained positive energy balance that triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2DM (type 2 diabetes mellitus) and pancreatic steatosis.[1]. Excess FFAs in turn activate inflammatory pathways and impair normal cell signaling within immune cells and adipose tissue, as well as the liver and muscle, causing cellular dysfunction.[6] metabolic disorders such as insulin resistance and type 2 diabetes can develop. Adropin is a peptide hormone that was originally described as a secreted peptide, with residues 1-33 encoding a secretory signal peptide sequence It plays a role in energy homeostasis as well as glucose and fatty acid metabolism. Adropin may play a role in the pathogeneses of FP and T2DM
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