Clinical and Scientific Significance of Non Invasive Determination of the pCell Mass in Diabetes

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A reliable method for (repeated) non-invasive quantification of p-cell mass in vivo in humans will enhance our understanding of the pathophysiology of both type 1 and type 2 diabetes (T1D, T2D). Progressive p-cell loss is characteristic for T1D, but the natural history of p-cell loss remains to be determined. p-Cell dysfunction is a hallmark of T2D, but it is not known at which stage of the disease this occurs. Individual patients show large differences regarding the relative contribution of insulin resistance or insulin deficiency to the diabetic state. Also the deterioration of p-cell function varies. Development of diabetes is thought to occur in steps [1]. At early stages, p-cell mass may even be increased [2]. Development of p-cell mass and p-cell function in the course of disease do not necessarily show a direct correlation, i.e. in particular stages of the disease, the p-cell function may be impaired while the p-cell mass is not significantly reduced or vice versa [1]. If a technique were available for non-invasive quantification of p-cell mass, it would be possible to follow the natural history of the decline of functional and afunctional p-cell mass in both T1D and T2D. A method to non-invasively measure p-cell mass in vivo in humans would also enable us to study the effects of different diabetes treatments on p-cell mass which may result in a more individually-tailored therapy, based on the principle underlying defect. Such a technique would for example enable us to monitor p-cell mass in vivo in patients receiving antidiabetic medication thought to increase p-cell mass in T2D (such as Exenatide or inhibitors of dipeptidyl peptidase IV [3]).

Quantification of p-cell mass could also be used for monitoring in patients with T1D undergoing islet transplantation which is a promising method for restoration of glucose homeostasis. To obtain a sufficient number of functioning islets, islets are typically isolated from two cadaveric donor pancreata and transplanted. As yet, it is unknown how many of these islets will contribute to glucose homeostasis directly after transplantation, i.e. how many islets survive during the first weeks after transplantation. Using a number of approximately 800,000-900,000 islets per patient, the rate of insulin-independent patients is approximately 80% after 1 year, which drops to about 65% after 2 years [4]. Monitoring of the p-cell mass after transplantation may help to optimize immunosuppressive therapy regimens and thus help to increase the rate of insulin-independent p-cell recipients.

In diabetes research, non-invasive methods for quantification of p-cell mass (including p-cell loss and p-cell neogenesis) would help to perform longitudinal studies in animal models addressing the questions related to p-cell mass mentioned above. Such methods would allow researchers to image p-cell mass in vivo by small animal imaging techniques but also to follow individual islets or subgroups of islets in vivo. This would greatly improve monitoring of new therapies in animal models, speed up their translation into clinical trials, and would help to reduce the number of animals required because longitudinal studies would no longer require immunohis-tochemical determination of p-cell mass in pancreatic specimen from killed animals. Furthermore, the effects of new drugs on individual islets (with respect to blood flow, islets biodistribution of p-cell markers, etc.) could be monitored.

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