Insulin Resistance as a Physiological Defense Against Metabolic Stress: Implications for the Management of Subsets of Type 2 Diabetes
Insulin Resistance as a Physiological Defense Against Metabolic Stress: Implications for the Management of Subsets of Type 2 Diabetes
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DOI：
10.2337/db14-0694
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发表时间：
2015-03-01
期刊：
影响因子：
7.7
通讯作者：
Prentki, Marc
中科院分区：
文献类型：
--
作者：
Nolan, Christopher J.;Ruderman, Neil B.;Prentki, Marc
对2型糖尿病（T2D）的管理进行分层必须考虑到患者表型的显著变异性，这是由于其病理生理学的异质性、疾病过程的不同阶段以及包括合并症在内的多种其他患者因素。这里的重点是非常具有挑战性的T2D患者亚组，这些患者超重或肥胖，伴有胰岛素抵抗（IR）和最难治性高血糖症，因为无法改变生活方式以逆转正能量平衡。对于T2D患者的这一亚组，我们质疑IR主要对身体有害并应不惜一切代价抵消的教条。相反，我们认为IR，特别是在这个高危亚组中，是一种防御机制，保护心血管系统的关键组织免受营养素诱导的损伤。因此，为了降低血糖水平而过度胰岛素抵抗，特别是强化胰岛素治疗，可能是有害的。营养素卸载以降低葡萄糖的治疗更可能是有益的。IR作为一种适应性防御机制和胰岛素诱导的代谢应激的概念可能为最近T2D主要临床试验的一些意外结果提供解释。潜在的分子机制，这些概念，其分层的T2D管理的临床意义，特别是在超重和肥胖患者难以血糖控制，和未来的研究要求进行了讨论。
Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of IR as an adaptive defense mechanism and insulin-induced metabolic stress may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed.