Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
PLoS One. 2013 May 22;8(5):e63346. doi: 10.1371/journal.pone.0063346. Print 2013.
Transglutaminase type 2 (TG2) has been reported to be a candidate gene for maturity onset diabetes of the young (MODY) because three different mutations that impair TG2 transamidase activity have been found in 3 families with MODY. TG2 null (TG2(-/-)) mice have been reported to be glucose intolerant and have impaired glucose-stimulated insulin secretion (GSIS). Here we rigorously evaluated the role of TG2 in glucose metabolism using independently generated murine models of genetic TG2 disruption, which show no compensatory enhanced expression of other TGs in pancreatic islets or other tissues. First, we subjected chow- or fat-fed congenic SV129 or C57BL/6 wild type (WT) and TG2(-/-) littermates, to oral glucose gavage. Blood glucose and serum insulin levels were similar for both genotypes. Pancreatic islets isolated from these animals and analysed in vitro for GSIS and cholinergic potentiation of GSIS, showed no significant difference between genotypes. Results from intraperitoneal glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) were similar for both genotypes. Second, we directly investigated the role of TG2 transamidase activity in insulin secretion using a coisogenic model that expresses a mutant form of TG2 (TG2(R579A)), which is constitutively active for transamidase activity. Intraperitoneal GTTs and ITTs revealed no significant differences between WT and TG2(R579A/R579A) mice. Given that neither deletion nor constitutive activation of TG2 transamidase activity altered basal responses, or responses to a glucose or insulin challenge, our data indicate that glucose homeostasis in mice is TG2 independent, and question a link between TG2 and diabetes.
转谷氨酰胺酶 2（TG2）已被报道为青年发病型糖尿病（MODY）的候选基因，因为在 3 个 MODY 家族中发现了 3 种不同的突变，这些突变会损害 TG2 转酰胺酶的活性。TG2 缺失（TG2(-/-)）小鼠表现为葡萄糖不耐受和葡萄糖刺激的胰岛素分泌受损（GSIS）。在这里，我们使用独立产生的遗传 TG2 缺失的小鼠模型，严格评估了 TG2 在葡萄糖代谢中的作用，这些模型显示胰岛或其他组织中没有其他 TG 的代偿性增强表达。首先，我们用 Chow 或高脂肪喂养的同基因 SV129 或 C57BL/6 野生型（WT）和 TG2(-/-) 同窝仔鼠，进行口服葡萄糖灌胃。两种基因型的血糖和血清胰岛素水平相似。从这些动物分离的胰岛，并在体外分析 GSIS 和胆碱能增强 GSIS，两种基因型之间没有明显差异。腹腔内葡萄糖耐量试验（GTTs）和胰岛素耐量试验（ITTs）的结果在两种基因型之间相似。其次，我们使用表达 TG2 突变体（TG2(R579A)）的同基因模型，直接研究 TG2 转酰胺酶活性在胰岛素分泌中的作用，该突变体对转酰胺酶活性具有组成型活性。腹腔内 GTTs 和 ITTs 显示 WT 和 TG2(R579A/R579A) 小鼠之间没有显著差异。鉴于 TG2 转酰胺酶活性的缺失或组成型激活都没有改变基础反应，或对葡萄糖或胰岛素的挑战反应，我们的数据表明，小鼠的葡萄糖稳态与 TG2 无关，并质疑 TG2 与糖尿病之间的联系。
