Residual insulin production and pancreatic ß-cell turnover after 50 years of diabetes: Joslin Medalist Study.
Residual insulin production and pancreatic ß-cell turnover after 50 years of diabetes: Joslin Medalist Study.
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作者：
Keenan HA;Sun JK;Levine J;Doria A;Aiello LP;Eisenbarth G;Bonner-Weir S;King GL
评价大量病程≥ 50年的胰岛素依赖型糖尿病患者的胰腺β细胞功能程度（Medalists）。411名奖牌获得者的临床和生化参数以及β细胞功能的表征与9名奖牌获得者的尸检形态学发现的相关性。Medalist队列的平均病程和年龄分别为56.2 ± 5.8岁和67.2 ± 7.5岁，具有与1型糖尿病相似的临床表型（1型糖尿病）：平均值± SD发作时间为11.0 ± 6.4岁，BMI为26.0 ± 5.1 kg/m2，胰岛素剂量为0.46 ± 0.2 u/kg，DR 3和/或DR 4阳性率≥ 94%，29.5%的患者血清中存在IA 2或谷氨酸脱羧酶（GAD）自身抗体。随机血清C肽水平显示，超过67.4%的参与者的水平处于最低（0.03-0.2 nmol/l）或持续范围（≥0.2 nmol/l）。与较高随机C-肽相关的参数是较低的血红蛋白A1 C，发病年龄较大，HLA DR 3基因型频率较高，对混合餐耐量试验（MMTT）的反应性。超过一半的空腹C肽>0.17 nmol/l的奖牌获得者在MMTT中的反应是空腹的两倍或更多。对9名Medalists的胰腺进行尸检，结果显示所有胰腺均具有胰岛素+ β细胞，其中一些细胞TUNEL染色呈阳性，表明细胞凋亡。产生胰岛素的胰腺细胞的持久性和功能的证明表明，在相当数量的1型糖尿病患者中，即使对于那些慢性持续时间的患者，刺激增强内源性β细胞的稳态转换可能是一种可行的治疗方法。
To evaluate the extent of pancreatic β-cell function in a large number of insulin-dependent diabetic patients with a disease duration of 50 years or longer (Medalists). Characterization of clinical and biochemical parameters and β-cell function of 411 Medalists with correlation with postmortem morphologic findings of 9 Medalists. The Medalist cohort, with a mean ± SD disease duration and age of 56.2 ± 5.8 and 67.2 ± 7.5 years, respectively, has a clinical phenotype similar to type 1 diabetes (type 1 diabetes): mean ± SD onset at 11.0 ± 6.4 years, BMI at 26.0 ± 5.1 kg/m2, insulin dose of 0.46 ± 0.2 u/kg, ∼94% positive for DR3 and/or DR4, and 29.5% positive for either IA2 or glutamic acid decarboxylase (GAD) autoantibodies. Random serum C-peptide levels showed that more than 67.4% of the participants had levels in the minimal (0.03–0.2 nmol/l) or sustained range (≥0.2 nmol/l). Parameters associated with higher random C-peptide were lower hemoglobin A1C, older age of onset, higher frequency of HLA DR3 genotype, and responsiveness to a mixed-meal tolerance test (MMTT). Over half of the Medalists with fasting C-peptide >0.17 nmol/l responded in MMTT by a twofold or greater rise over the course of the test compared to fasting. Postmortem examination of pancreases from nine Medalists showed that all had insulin+ β-cells with some positive for TUNEL staining, indicating apoptosis. Demonstration of persistence and function of insulin-producing pancreatic cells suggests the possibility of a steady state of turnover in which stimuli to enhance endogenous β cells could be a viable therapeutic approach in a significant number of patients with type 1 diabetes, even for those with chronic duration.