Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging
Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging
复制标题
DOI：
10.1007/s00125-018-4624-0
复制
发表时间：
2018-12-01
期刊：
影响因子：
8.2
通讯作者：
Calle, Roberto A.
中科院分区：
文献类型：
--
作者：
Cline, Gary W.;Naganawa, Mika;Calle, Roberto A.
目的/假设β细胞功能的进行性丧失是2型糖尿病自然史的一部分。尸检研究表明，这部分是由于β细胞质量（β-cell mass）的损失，但这尚未在体内得到证实。非侵入性的方法来量化糖尿病可能有助于更好地了解2型糖尿病的病理生理和治疗策略的发展。在人类中，囊泡单胺转运蛋白2型（VMAT 2）在β细胞和胰腺多肽细胞中的定位，在其他外分泌或内分泌胰腺细胞中的表达最小，导致其发展为一种衡量胰腺炎的指标。我们使用的VMAT 2示踪剂[F-18]氟丙基-（+）-二氢丁苯那嗪，以量化在人类葡萄糖耐量受损（糖尿病前期）或2型糖尿病，并在健康肥胖志愿者（HOV）。MethodsDynamic正电子发射断层扫描（PET）数据获得4小时代谢物校正的动脉血测量16 HOV，5糖尿病前期和17型糖尿病参与者。11名参与者（6名HOV和5名2型糖尿病患者）接受了两次腹部PET/计算机断层扫描（CT）扫描，以评估重测变异性。计算胰腺亚区（头部、体部和尾部）的标准化摄取值比（SUVR），以脾脏作为参考区域，以确定3- 4 h时的非特异性示踪剂摄取。结果测量SUVR减1（SUVR-1）解释了非特异性示踪剂摄取。通过标准（精氨酸刺激试验[AST]）后的C肽释放和对葡萄糖增强AST的急性胰岛素反应（AIRargMAX）评估功能性β细胞能力。对结合变量与AST和AIRargMAX后的C肽AUC进行Pearson相关性分析。结果所有地区的绝对重测变异性（aTRV）均为15%。在所有组中测量SUVR-1的变异性和重叠; HOV和糖尿病前期和2型糖尿病参与者。SUVR-1在所有胰腺亚区（全胰腺p=0.009和胰头p=0.009;体部p=0.019和尾部p =0.023）与AIRargMAX（所有组）均显示出显著正相关性。SUVR-1与整个胰腺（p=0.033）和胰头（p=0.008）中的HbA（1c）（所有组）呈负相关。SUVR-1也与胰头诊断为2型糖尿病的时间呈负相关（p=0.049）和胰尾（p=0.035）.结论/解释观察到的胰腺和胰腺区域中VMAT 2密度与诊断2型糖尿病以来的年数的相关性，血糖控制和β细胞功能表明，β细胞的丧失导致2型糖尿病患者胰岛素分泌不足。
Aims/hypothesisThe progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [F-18]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV).MethodsDynamic positron emission tomography (PET) data were obtained for 4h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test-retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3-4h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose-enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX.ResultsAbsolute test-retest variability (aTRV) was 15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p=0.009 and pancreas head p=0.009; body p=0.019 and tail p=0.023). SUVR-1 inversely correlated with HbA(1c) (all groups) in the whole pancreas (p=0.033) and pancreas head (p=0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p=0.049) and pancreas tail (p=0.035).Conclusions/interpretationThe observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes.