Almeida Edelbert Anthonio, Mehndiratta Mohit, Madhu S V, Kar Rajarshi, Puri Dinesh
Department of Biochemistry, University College of Medical Sciences, University of Delhi, Delhi, India.
Department of Endocrinology, University College of Medical Sciences, University of Delhi, Delhi, India.
Int J Endocrinol Metab. 2022 Jul 16;20(3):e122553. doi: 10.5812/ijem-122553. eCollection 2022 Jul.
The model of obesity-induced insulin resistance has long been used to explain the development of type 2 diabetes mellitus (T2DM) in obese individuals (body mass index (BMI) > 25 kg/m), but this model failed to explain the development of the disease in lean individuals (BMI < 18.5 kg/m). Defects in the insulin signaling pathway have been postulated to play a role in these patients, particularly in suppressors of cytokine signaling (SOCS) proteins, which are involved in the downregulation of insulin transduction. The expression of is also known to be induced by cytokines such as interferon gamma (IFN-γ). It is still not clear whether these pathways operate differently in lean versus obese patients with T2DM. Therefore, this pilot study was designed to study the expression of , , and in lean and obese patients with T2DM.
The levels of IFN-γ in serum and the messenger RNA (mRNA) expression of SOCS ( and ) and genes in whole blood in lean and obese patients with T2DM.
Sixty newly diagnosed T2DM patients (not on any pharmacotherapy) were enrolled and divided into 2 groups of lean (BMI < 18.5 kg/m) and obese (BMI > 25 kg/m) patients (n = 30 per group). Serum IFN-γ was measured by enzyme-linked immunosorbent assay (ELISA), and mRNA expression of -γ, , and was measured by real-time polymerase chain reaction (PCR) using the ∆∆ Ct method.
Serum IFN-γ levels were 10.83 ± 5.81 pg/mL in the lean group and 9.35 ± 5.14 pg/mL in the obese group (P = 0.02). Fasting serum insulin levels were 16.07 ± 8.39 µIU/mL in the lean group and 27.11 ± 4 .91 µIU/mL in the obese group (P = 0.001). There was a 3.16-fold increase in mRNA expression of IFN-γ and a 1.3-fold increase in mRNA expression of SOCS1 in the lean group compared to the obese group. mRNA expression of SOCS3 was similar in both groups.
The level of IFN-γ increased at both transcriptional and translational levels, and mRNA expression of SOCS1 was higher in the lean group than in the obese group. The SOCS protein is a known negative regulator in insulin signaling pathways. Thus, our findings and available scientific literature suggest that IFN-γ might impair the insulin signaling pathway to a greater extent in lean patients than in obese patients via induction of SOCS1. This signaling pathway could be a major contributing factor to hyperglycemia in lean patients with T2DM compared with obese counterparts. This suggests that different therapeutic approaches to these groups might be of greater benefit in the treatment of T2DM.
肥胖诱导的胰岛素抵抗模型长期以来一直被用于解释肥胖个体（体重指数（BMI）>25kg/m²）中2型糖尿病（T2DM）的发病机制，但该模型无法解释瘦个体（BMI<18.5kg/m²）中该疾病的发病情况。胰岛素信号通路缺陷被认为在这些患者中起作用，特别是细胞因子信号转导抑制因子（SOCS）蛋白，其参与胰岛素转导的下调。已知干扰素γ（IFN-γ）等细胞因子可诱导SOCS的表达。目前尚不清楚这些通路在瘦型与肥胖型T2DM患者中是否有不同的作用机制。因此，本初步研究旨在研究瘦型和肥胖型T2DM患者中SOCS1、SOCS3和IFN-γ的表达情况。
测定瘦型和肥胖型T2DM患者血清中IFN-γ水平以及全血中SOCS1、SOCS3和IFN-γ基因的信使核糖核酸（mRNA）表达。
纳入60例新诊断的T2DM患者（未接受任何药物治疗），分为瘦型（BMI<18.5kg/m²）和肥胖型（BMI>25kg/m²）两组（每组n = 30）。采用酶联免疫吸附测定（ELISA）法检测血清IFN-γ水平，采用∆∆Ct法通过实时聚合酶链反应（PCR）测定IFN-γ、SOCS1和SOCS3的mRNA表达。
瘦型组血清IFN-γ水平为10.83±5.81pg/mL，肥胖型组为9.35±5.14pg/mL（P = 0.02）。瘦型组空腹血清胰岛素水平为16.07±8.39µIU/mL，肥胖型组为27.11±4.91µIU/mL（P = 0.001）。与肥胖型组相比，瘦型组IFN-γ的mRNA表达增加3.16倍，SOCS1的mRNA表达增加1.3倍。两组SOCS3的mRNA表达相似。
IFN-γ水平在转录和翻译水平均升高，且瘦型组SOCS1的mRNA表达高于肥胖型组。SOCS蛋白是胰岛素信号通路中已知的负调节因子。因此，我们的研究结果和现有科学文献表明，IFN-γ可能通过诱导SOCS1在瘦型患者中比在肥胖型患者中更严重地损害胰岛素信号通路。与肥胖型T2DM患者相比，该信号通路可能是瘦型T2DM患者高血糖的主要促成因素。这表明针对这些群体的不同治疗方法可能对T2DM的治疗更有益。
