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

这份年度报告中描述的工作都来自哥伦比亚大学Paul Harris博士的观察，他使用差异基因表达研究，注意到β细胞（比其他胰腺细胞更大程度）表达水泡单胺转运蛋白-2 （VMAT-2）。Harris博士及其同事继续使用VMAT-2放射性标记配体11c -二氢四苯那嗪（11C-DTBZ）作为T1DM大鼠模型正电子发射断层扫描（PET）研究的显像剂进行研究，结果表明，在自身免疫过程中，随着β细胞质量下降，11C-DTBZ-PET胰腺信号也随之下降。的确，在那个模型中，PET信号似乎能够预测糖尿病的发病。着眼于开发用于临床介入试验的技术，招募有T1DM风险的人，我们启动了几项临床前研究，在工作单位编号DK055114-01的年度报告中描述。我们临床前研究的早期有希望的结果，加上11C-DTBZ-PET在密歇根大学进行的帕金森病患者多巴胺能神经元细胞团的临床研究中被证实的安全记录，鼓励我们在三个研究组中启动11C-DTBZ-PET产生的胰腺信号的相关性研究：(1)正常对照受试者；(2)长期患有T1DM且内源性胰岛素产生能力很少或没有的受试者；(3)有T1DM病史且早几年接受胰腺移植成功治疗的受试者。

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.