Assessing a PET-based technique for characterizing beta cell mass in vivo

评估基于 PET 的体内 β 细胞质量表征技术

• 批准号: 7734211
• 负责人: David Harlan
• 金额: $ 24.85万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734211
• 关键词: Annual Reports; Autoimmune Process; Beta Cell; Binding; Blood Glucose; C-Peptide; Cell physiology; Cells; Clinical; Clinical Research; Condition; Cooperative Research and Development Agreement; Coupled; Diabetes Mellitus; Disease; Enrollment; Eye; Functional disorder; Glucose; Goals; Human; Image; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Ligands; Manuscripts; Measures; Mediating; Metabolic; Michigan; Modeling; Names; Neurons; Normal Range; Numbers; OGTT; Pancreas; Parkinson Disease; Patients; Positron-Emission Tomography; Purpose; Radiolabeled; Rattus; Recording of previous events; Reporting; Research Ethics Committees; Research Personnel; Resistance; Risk; Role playing therapy; Safety; Secondary to; Signal Transduction; T-Lymphocyte; Techniques; Testing; Tissue-Specific Gene Expression; Transplantation; Universities; Work; base; cell type; diabetic; dihydrotetrabenazine; enantiomer; falls; in vivo; non-diabetic; pancreas allograft; preclinical study; radiotracer; therapy design; uptake; vesicular monoamine transporter 2

The work described in this annual report all emanated from observations made by Dr. Paul Harris at Columbia University who, using differential gene expression studies, noted that beta cells (to a much greater degree than other pancreatic cells) express the vesicular monoamine transporter-2 (VMAT-2). Dr. Harris and colleagues went on to perform studies using a VMAT-2 radiolabeled ligand named 11C-dihydrotetrabenazine (11C-DTBZ) as an imaging agent for positron-emission tomography (PET) studies in a rat model for T1DM with results suggesting that as beta cell mass fell during the autoimmune process, so did the 11C-DTBZ-PET pancreatic signal. Indeed, in that model the PET signal seemed able to predict diabetes onset. With an eye toward developing the technique for application in clinical interventional trials enrolling humans at risk for T1DM, we initiated several pre-clinical studies described in the annual report for work unit number DK055114-01. Early promising results from our pre-clinical studies, coupled with 11C-DTBZ-PETs proven safety record in clinical studies performed at the University of Michigan to follow dopaminergic neuronal cell mass in subjects with Parkinsons disease, encouraged us to initiate studies correlating 11C-DTBZ-PET generated pancreatic signals in three study groups: (1) normal control subjects, (2) subjects with long-standing T1DM and little to no endogenous insulin producing capacity and (3) subjects with a history of T1DM successfully treated years earlier with a pancreas transplant. After appropriate Institutional Review Board approval, we first evaluated 5 subjects with normal glycemia control as evidenced by normal oral glucose tolerance tests (OGTT). The 11C-DTBZ-PET generated pancreatic signal from all 5 subjects was strong with little inter-individual variability. We next obtained 11C-DTBZ-PET images from 5 subjects with a T1DM history successfully treated with a pancreas transplant (subjects also described in the annual report for work unit number DK055111-01) reasoning that such individuals have two pancreases under identical metabolic conditions, i.e. their original pancreas secreting very little insulin and therefore expected to contain few beta cells, and the transplanted pancreas with sufficient beta cell function to maintain the patients' blood glucose in the normal range (again by OGTT). The 11C-DTBZ-PET scans from these 5 subjects revealed little to no signal intensity over the native pancreas, with much stronger signals over the pancreas allograft (albeit slightly less intense than the non-diabetic subjects pancreatic signals). The third group consisted of subjects with long-standing T1DM. The subjects in this group made little to no C-peptide reflecting their expected severely reduced beta cell mass, but contrary to prediction, each of the 12 subjects displayed quite strong 11C-DTBZ-PET generated pancreatic signals. In fact, in two subjects with T1DM, the 11C-DTBZ-PET generated pancreatic signal was as great as or even greater than the signal observed in our non-diabetic control subjects. In order to evaluate whether the diabetic subjects pancreatic PET signals might be confounded by unusually high non-specific 11C-DTBZ binding, we took advantage of the fact that only the positive 11C-DTBZ enantiomer binds to VMAT2. We repeated DTBZ-PET scans in one subject with normal glycemia, and in one subject with long-standing T1DM. In both cases, we compared PET signals generated with the positive and negative 11C-DTBZ enantiomers. If the strong pancreatic signals observed in the subjects with T1DM were secondary to non-specific DTBZ uptake, we expected to observe comparable signals in the subject with T1DM regardless the DTBZ enantiomer, while for the normal control subject, we expected the positive DTBZ enantiomer to generate a bright pancreatic signal, and the negative enantiomer to generate a much weaker signal. To our surprise, for both the normal control subject and the subject with long-standing T1DM, the pancreatic PET signal generated by the negative 11C-DTBZ enantiomer was at least as bright as the signal generated by the positive 11C-DTBZ enantiomer. We conclude that despite the promise displayed in pre-clinical studies, 11C-DTBZ-PET generated pancreatic signals do not correlate well with BCM. We have prepared a manuscript to report these disappointing observations. As a result of our reported observations, we were approached to pursue similar studies with Eli Lilly, Inc using other imaging approaches. We established a CRADA for that purpose during this fiscal year.

本年度报告中描述的工作都源于哥伦比亚大学的Paul Harris博士的观察，他使用差异基因表达研究指出，β细胞（比其他胰腺细胞更大程度地）表达囊泡单胺转运蛋白-2（VMAT-2）。 Harris博士及其同事继续使用VMAT-2放射性标记的配体11 C-DTBZ作为T1 DM大鼠模型正电子发射断层扫描（PET）研究的成像剂进行研究，结果表明，随着β细胞质量在自身免疫过程中下降，11 C-DTBZ-PET胰腺信号也是如此。 事实上，在该模型中，PET信号似乎能够预测糖尿病发作。 着眼于开发技术以应用于入组T1 DM风险人群的临床干预性试验，我们启动了工作单元编号DK 055114 -01年度报告中描述的几项临床前研究。 我们临床前研究的早期有希望的结果，加上在密歇根大学进行的跟踪帕金森病受试者多巴胺能神经元细胞质量的临床研究中证明的11 C-DTBZ-PET安全记录，鼓励我们启动与11 C-DTBZ-PET相关的研究在三个研究组中产生胰腺信号：（1）正常对照受试者，（2）具有长期T1 DM且几乎没有内源性胰岛素产生能力的受试者，和（3）具有T1 DM病史且多年前通过胰腺移植成功治疗的受试者。 在适当的机构审查委员会批准后，我们首先评估了5名口服葡萄糖耐量试验（OGTT）证明血糖控制正常的受试者。 所有5例受试者的11 C-DTBZ-PET生成的胰腺信号均较强，个体间变异性很小。 接下来，我们获得了5例成功接受胰腺移植治疗的T1 DM受试者的11 C-DTBZ-PET图像（受试者也在工作单位编号DK 055111 -01的年度报告中描述）推理这些个体在相同的代谢条件下具有两个胰腺，即他们的原始胰腺分泌非常少的胰岛素，因此预期包含很少的β细胞，并且移植的胰腺具有足够的β细胞功能以将患者的血糖维持在正常范围内（再次通过OGTT）。 这5名受试者的11 C-DTBZ-PET扫描显示，自体胰腺上几乎没有信号强度，而胰腺同种异体移植物上的信号要强得多（尽管强度略低于非糖尿病受试者的胰腺信号）。 第三组由长期T1 DM受试者组成。 该组中的受试者几乎不产生C肽，反映了他们预期的β细胞质量严重减少，但与预测相反，12名受试者中的每一名都显示出相当强的11 C-DTBZ-PET产生的胰腺信号。 事实上，在2例T1 DM受试者中，11 C-DTBZ-PET产生的胰腺信号与我们的非糖尿病对照受试者中观察到的信号一样大，甚至更大。 为了评估糖尿病受试者胰腺PET信号是否可能被异常高的非特异性11 C-DTBZ结合所混淆，我们利用了仅阳性11 C-DTBZ对映体与VMAT 2结合的事实。 我们在一名正常的糖尿病患者和一名长期存在的T1 DM患者中重复了DTBZ-PET扫描。 在这两种情况下，我们比较了正和负11 C-DTBZ对映体产生的PET信号。 如果在T1 DM受试者中观察到的强胰腺信号继发于非特异性DTBZ摄取，则我们预期在T1 DM受试者中观察到相当的信号，无论DTBZ对映体如何，而对于正常对照受试者，我们预期阳性DTBZ对映体产生明亮的胰腺信号，阴性对映体产生弱得多的信号。 令我们惊讶的是，对于正常对照受试者和长期T1 DM受试者，阴性11 C-DTBZ对映体产生的胰腺PET信号至少与阳性11 C-DTBZ对映体产生的信号一样亮。 我们的结论是，尽管在临床前研究中显示的承诺，11 C-DTBZ-PET产生的胰腺信号不相关，以及与胰腺炎。 我们准备了一份手稿来报告这些令人失望的观察结果。 由于我们报告的观察结果，我们与Eli Lilly，Inc.进行了类似的研究，使用其他成像方法。 为此，我们在本财政年度建立了一个CRADA。