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Metformin Increases Protein Phosphatase 2A Activity in Primary Human Skeletal Muscle Cells Derived from Lean Healthy Participants
Journal of Diabetes Research ( IF 3.6 ) Pub Date : 2021-07-29 , DOI: 10.1155/2021/9979234
Aktham Mestareehi 1 , Xiangmin Zhang 1 , Berhane Seyoum 2 , Zaher Msallaty 2 , Abdullah Mallisho 2 , Kyle Jon Burghardt 3 , Anjaneyulu Kowluru 1, 4 , Zhengping Yi 1
Affiliation  

Context. Skeletal muscle insulin resistance is one of the primary contributors of type 2 diabetes (T2D). Metformin is the first-line drug for the treatment of T2D. The primary effects of metformin include decreasing glucose production in the liver and decreasing insulin resistance in the skeletal muscle. However, the molecular mechanism of metformin’s action in skeletal muscle is not well understood. Protein phosphatase 2A (PP2A), a major serine/threonine protein phosphatase, plays a pivotal role in cellular processes, such as signal transduction, cell proliferation, and apoptosis, and acts through dephosphorylating key signaling molecules such as AKT and AMPK. However, whether PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells remains to be elucidated. Objective. To investigate if PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells. Participants. Eight lean insulin-sensitive nondiabetic participants (4 females and 4 males; age: years; BMI: ; 2-hour OGTT: ; HbA1c: ; fasting plasma glucose: ; value; ). Design. A hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in human subjects, and skeletal muscle biopsy samples were obtained. Primary human skeletal muscle cells (shown to retain metabolic characteristics of donors) were cultured from these muscle biopsies that included 8 lean insulin-sensitive participants. Cultured cells were expanded, differentiated into myotubes, and treated with 50 μM metformin for 24 hours before harvesting. PP2Ac activity was measured by a phosphatase activity assay kit (Millipore) according to the manufacturer’s protocol. Results. The results indicated that metformin significantly increased the activity of PP2A in the myotubes for all 8 lean insulin-sensitive nondiabetic participants, and the average fold increase is (). Conclusions. These results provided the first evidence that metformin can activate PP2A in human skeletal muscle cells derived from lean healthy insulin-sensitive participants and may help to understand metformin’s action in skeletal muscle in humans.

中文翻译:

二甲双胍可增加源自瘦健康参与者的原代人类骨骼肌细胞中的蛋白磷酸酶 2A 活性

上下文。骨骼肌胰岛素抵抗是 2 型糖尿病 (T2D) 的主要原因之一。二甲双胍是治疗T2D的一线药物。二甲双胍的主要作用包括减少肝脏中的葡萄糖产生和减少骨骼肌中的胰岛素抵抗。然而,二甲双胍在骨骼肌中作用的分子机制尚不清楚。蛋白磷酸酶 2A (PP2A) 是一种主要的丝氨酸/苏氨酸蛋白磷酸酶,在信号转导、细胞增殖和凋亡等细胞过程中发挥着关键作用,并通过 AKT 和 AMPK 等关键信号分子去磷酸化发挥作用。然而,PP2A 是否在二甲双胍诱导的人类骨骼肌细胞胰岛素敏感性改善中发挥作用仍有待阐明。客观。研究 PP2A 是否在二甲双胍诱导的人类骨骼肌细胞胰岛素敏感性改善中发挥作用。参加者。八名瘦型胰岛素敏感型非糖尿病参与者(4 名女性和 4 名男性;年龄:年; 体重指数:; 2 小时 OGTT:; 糖化血红蛋白:; 空腹血糖:; 价值;)。 设计。采用高胰岛素-正常血糖钳夹法评估人类受试者的胰岛素敏感性,并获得骨骼肌活检样本。原代人类骨骼肌细胞(显示保留了供体的​​代谢特征)是从这些肌肉活检中培养出来的,其中包括 8 名瘦的胰岛素敏感参与者。将培养的细胞扩增、分化为肌管,并在收获前用50μM二甲双胍处理 24小时。PP2Ac活性通过磷酸酶活性测定试剂盒(Millipore)根据制造商的方案进行测量。结果。结果表明,二甲双胍显着增加了所有 8 名胰岛素敏感的非糖尿病瘦参与者肌管中 PP2A 的活性,平均增加倍数为)。 结论。这些结果提供了第一个证据,表明二甲双胍可以激活来自瘦健康胰岛素敏感参与者的人类骨骼肌细胞中的 PP2A,并可能有助于了解二甲双胍在人类骨骼肌中的作用。
更新日期:2021-07-29
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