Research Unit of Diabetes and Endocrine Diseases, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
PLoS One. 2013 Jul 22;8(7):e70159. doi: 10.1371/journal.pone.0070159. Print 2013.
Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p<0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu.
胰岛素作用受损在 2 型糖尿病的发病机制中起主要作用，2 型糖尿病是一种慢性代谢紊乱疾病，给全球的发病率和死亡率带来了巨大负担。阐明胰岛素抵抗的分子机制将有助于制定 2 型糖尿病的预防和治疗策略。UDP-N-乙酰-α-D-半乳糖胺多肽 N-乙酰半乳糖胺基转移酶-2（ppGalNAc-T2）的下调会导致培养的人肝细胞中胰岛素信号和作用受损。此外，自发性胰岛素抵抗、糖尿病 Goto-Kakizaki 大鼠的肝组织中 GALNT2mRNA 水平下调。为了研究 GALNT2 在人类高血糖中的作用，我们测量了 84 名非肥胖和 46 名非肥胖非糖尿病个体以及 98 名肥胖 2 型糖尿病患者外周全血细胞中的 GALNT2mRNA 表达水平。我们还测量了在不同葡萄糖浓度下培养的人 U937 细胞中的 GALNT2mRNA 表达。体内研究表明，GALNT2mRNA 水平从非肥胖对照组到非肥胖非糖尿病组再到肥胖糖尿病组显著降低（p<0.001）。体外研究表明，与暴露于低葡萄糖浓度（即 5.5mmol/l 葡萄糖+19.5mmol/l 甘露醇）的细胞相比，暴露于高葡萄糖浓度（即 25mmol/l 葡萄糖）的 U937 细胞中的 GALNT2mRNA 水平降低。总之，我们的数据表明，2 型糖尿病患者的 GALNT2 下调，并表明这种关联至少部分是继发于高血糖。需要进一步研究以了解 GALNT2 的下调是否在维持和/或加重糖尿病环境中的代谢异常中起致病作用。
