Expert consensus on diabetes mellitus after solid organ transplantation in adults

doi:10.3877/cma.j.issn.1674-3903.2023.04.002

Abstract

Abstract:

Post-transplant diabetes mellitus (PTDM) is a common endocrine and metabolic disorder after adult solid organ transplant (SOT), affecting 10% to 40% of recipients. PTDM has been associated with increased mortality, heightened risk of infections, graft-related complications and cardiovascular diseases, all of which seriously threaten the quality of life and long-term survival of recipients. According to recent studies and the domestic healthcare system, this consensus provides a comprehensive overview of the epidemiology, risk factors, pathogenesis, screening and diagnosis, treatments, prevention strategies, cardiovascular risk factor management and microvascular complications associated with PTDM, in order to further standardize the diagnosis and treatment of PTDM. The objective is to standardize the comprehensive management of PTDM with the aim of enhancing the long-term quality of life and clinical outcomes for SOT recipients.

Key words: Post-transplant diabetes mellitus, Solid organ transplantation, Immunosuppressors, Antidiabetics

Organ Transplantation and Rehabilitation Committee of Chinese Medical Association of Rehabilitation. Expert consensus on diabetes mellitus after solid organ transplantation in adults[J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(04): 205-220.

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免疫抑制剂	主要机制	与PTDM发生风险的关系
糖皮质激素	刺激胰高糖素分泌，增加肝糖输出，这一效应呈剂量相关性^[39]，增加胰岛素抵抗并抑制胰岛素分泌，诱导胰岛细胞凋亡^[40]	泼尼松龙逐渐减量至5 mg/d有助于改善肾移植后胰岛素敏感性^[41]，糖皮质激素减撤方案可以作为降低PTDM风险的一种优选方案^[42]
CNI(他克莫司、环孢素)	抑制钙调神经磷酸酶活性，抑制细胞质钙调神经磷酸酶-活化T细胞的核因子亚单位的去磷酸化。CNI下调胰岛素受体底物2表达^[43]，影响胰岛β细胞中胰岛素和细胞增殖基因的转录，引起血糖升高。环孢素和他克莫司还可以通过增加脂肪细胞表面的葡萄糖转运蛋白4内吞速率，降低葡萄糖转运蛋白4表达来抑制葡萄糖摄取，而不依赖于胰岛素信号传导^[44]。他克莫司减少胰岛素分泌效应更强，与环孢素相比更易导致PTDM。肾移植后使用他克莫司治疗1年的PTDM发病风险是环孢素的2.7倍^{[45,46,47,48]}	CNI减量可以作为降低PTDM风险的措施，肾移植后PTDM患者可将他克莫司调整为环孢素以减少PTDM发生^[46]
mTORi(西罗莫司、依维莫司和贝拉西普)	mTORi干扰胰岛素信号传导，加重胰岛素抵抗；同时具有抗增殖作用，抑制胰岛β细胞增殖，促进β细胞凋亡。西罗莫司促进胰岛素受体底物2的磷酸化，抑制β细胞分泌胰岛素^[47]	mTORi会增加PTDM发生风险，但较CNI略低^[48]
ATG和阿仑单抗	ATG诱导促进Treg细胞增多^[49]。阿仑单抗是靶向CD52特异性单克隆抗体，CD52富集于B和T淋巴细胞表面，阿仑单抗可诱导T和B淋巴细胞凋亡^[50]，对糖代谢无直接影响	阿仑单抗或ATG诱导不增加PTDM风险^[51]
巴利昔单抗	IL-2受体的单抗(抗CD25)，可显著抑制IL-2介导的T淋巴细胞增殖。动物实验中表明，巴利昔单抗使用后诱导Treg细胞减少，出现胰岛炎、胰岛β细胞破坏及糖尿病发生^[52]	巴利昔单抗诱导发生PTDM的风险增加^[53]
其他免疫抑制剂(麦考酚酸、硫唑嘌呤和咪唑立宾)	抑制嘌呤核苷酸的生物合成发挥抗增殖、抗代谢作用，对糖代谢无直接影响	麦考酚酸或硫唑嘌呤单独应用对PTDM无影响，联合用药目前证据尚不足^[54]；吗替麦考酚酯是常用麦考酚酸类药物，与其他免疫抑制剂联用时，减少CNI、类固醇药物等药物的剂量，间接降低实体器官移植受者PTDM的风险^[55]；咪唑立宾与PTDM的关系尚无研究报道

免疫抑制剂	主要机制	与PTDM发生风险的关系
糖皮质激素	刺激胰高糖素分泌，增加肝糖输出，这一效应呈剂量相关性^[39]，增加胰岛素抵抗并抑制胰岛素分泌，诱导胰岛细胞凋亡^[40]	泼尼松龙逐渐减量至5 mg/d有助于改善肾移植后胰岛素敏感性^[41]，糖皮质激素减撤方案可以作为降低PTDM风险的一种优选方案^[42]
CNI(他克莫司、环孢素)	抑制钙调神经磷酸酶活性，抑制细胞质钙调神经磷酸酶-活化T细胞的核因子亚单位的去磷酸化。CNI下调胰岛素受体底物2表达^[43]，影响胰岛β细胞中胰岛素和细胞增殖基因的转录，引起血糖升高。环孢素和他克莫司还可以通过增加脂肪细胞表面的葡萄糖转运蛋白4内吞速率，降低葡萄糖转运蛋白4表达来抑制葡萄糖摄取，而不依赖于胰岛素信号传导^[44]。他克莫司减少胰岛素分泌效应更强，与环孢素相比更易导致PTDM。肾移植后使用他克莫司治疗1年的PTDM发病风险是环孢素的2.7倍^{[45,46,47,48]}	CNI减量可以作为降低PTDM风险的措施，肾移植后PTDM患者可将他克莫司调整为环孢素以减少PTDM发生^[46]
mTORi(西罗莫司、依维莫司和贝拉西普)	mTORi干扰胰岛素信号传导，加重胰岛素抵抗；同时具有抗增殖作用，抑制胰岛β细胞增殖，促进β细胞凋亡。西罗莫司促进胰岛素受体底物2的磷酸化，抑制β细胞分泌胰岛素^[47]	mTORi会增加PTDM发生风险，但较CNI略低^[48]
ATG和阿仑单抗	ATG诱导促进Treg细胞增多^[49]。阿仑单抗是靶向CD52特异性单克隆抗体，CD52富集于B和T淋巴细胞表面，阿仑单抗可诱导T和B淋巴细胞凋亡^[50]，对糖代谢无直接影响	阿仑单抗或ATG诱导不增加PTDM风险^[51]
巴利昔单抗	IL-2受体的单抗(抗CD25)，可显著抑制IL-2介导的T淋巴细胞增殖。动物实验中表明，巴利昔单抗使用后诱导Treg细胞减少，出现胰岛炎、胰岛β细胞破坏及糖尿病发生^[52]	巴利昔单抗诱导发生PTDM的风险增加^[53]
其他免疫抑制剂(麦考酚酸、硫唑嘌呤和咪唑立宾)	抑制嘌呤核苷酸的生物合成发挥抗增殖、抗代谢作用，对糖代谢无直接影响	麦考酚酸或硫唑嘌呤单独应用对PTDM无影响，联合用药目前证据尚不足^[54]；吗替麦考酚酯是常用麦考酚酸类药物，与其他免疫抑制剂联用时，减少CNI、类固醇药物等药物的剂量，间接降低实体器官移植受者PTDM的风险^[55]；咪唑立宾与PTDM的关系尚无研究报道

诊断标准	静脉血浆葡萄糖或HbA_1c水平
典型糖尿病症状
加上空腹血糖	≥ 7.0 mmol/L
或加上随机血糖	≥11.1 mmol/L
或加上OGTT 2 h血糖	≥11.1 mmol/L
或加上HbA_1c	≥ 6.5%^a
无糖尿病典型症状者，需改日复查确认

诊断标准	静脉血浆葡萄糖或HbA_1c水平
典型糖尿病症状
加上空腹血糖	≥ 7.0 mmol/L
或加上随机血糖	≥11.1 mmol/L
或加上OGTT 2 h血糖	≥11.1 mmol/L
或加上HbA_1c	≥ 6.5%^a
无糖尿病典型症状者，需改日复查确认

糖代谢状态	静脉血浆葡萄糖(mmol/L)
糖代谢状态	空腹血糖	2hPG
正常血糖	<6.1	<7.8
空腹血糖受损	6.1≤FPG<7.0	<7.8
糖耐量减低	<6.1	7.8≤2hPG<11.1
糖调节受损	<7.0	7.8≤2hPG<11.1
糖尿病	≥7.0	≥11.1

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