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Molecular and cellular basis for beta cell therapy in diabetes

Research project P5/17 (Research action P5)


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Clinical onset of diabetes occurs when the pancreatic beta cell population is no longer capable of releasing the amounts of insulin that are needed to control glucose homeostasis. According to classical concepts, the disease is either caused by a massive reduction in the number of beta cells - a characteristic of type 1 diabetes - or by severe functional impairment of these cells - a common feature of type 2 diabetes. Consequently, different strategies are followed to develop an adequate treatment, namely transplantation of insulin-producing tissue in the type 1 form, and pharmacologic stimulation of endogenous beta cells in type 2 diabetes. Neither objective has so far succeeded in correcting glucose homeostasis to a sufficient degree and duration in a significant proportion of patients. Current treatment still consists in taking measures that reduce the insulin needs, in insulin injections and/or in administration of drugs that only transiently stimulate insulin release. These methods are powerful instruments in today’s clinical practice but in many patients they do not achieve metabolic normalization and therefore do not prevent development of diverse tissue lesions as a consequence of repetitive hyperglycemia. Both type 1 and type 2 diabetes can thus lead to serious chronic complications that affect quality of life as well as life expectancy. The rise in their incidence further stresses the need for more efficient compensations for failing beta cell populations.

The overall objective of this program is to contribute to the design of more efficient therapeutic strategies. We propose that interventions are needed with the dual aim of preserving the survival as well as the secretory function of the beta cells. They should be applicable in the treatment of type 1 and of type 2 diabetes. There is indeed evidence that both types exhibit a disease process whereby beta cells are lost and others are functionally impaired. The respective contribution of these two pathogenic components varies with the type of disease, but also among patients within one type. There is also variation in the sequence and in the underlying causes. This variability is not in conflict with the objective of developing interventions that target both components. It stresses the need for distinguishing these components in the disease process and, eventually, in the follow-up of patients. In this perspective, disease markers have to be identified which will make it possible to in vivo monitor processes of beta cell death and of beta cell dysfunction. The results of the planned program should prove useful in designing ways to protect and treat pancreatic beta cells as well as in protocols of beta cell transplantation.

The specific objective of this program is to define molecular and cellular sites that can serve as marker for the disease process and as target for interventions that preserve the survival and the insulin-releasing capacity of the beta cells. Our rationale is that these sites can be identified in laboratory models that allow (extra)cellular monitoring of selected molecular processes during manipulation of beta cell survival and/or function. Our laboratories provide in vitro and in vivo models that can serve this purpose as demonstrated by previous work. Our studies have indicated pathways that might be at the cross roads of the (dys)regulation of beta cell survival and functions. Techniques are available for identifying beta cell specific processes and molecules during alterations in beta cell survival and function. We now propose to undertake the second phase in our collaborative effort with endpoints that will directly contribute to the specific objective of this program. It is our goal that progress will be measured at two levels, namely the insights into the basis for designing novel interventions and the implementation in an associated network that organizes multicenter clinical trials as JDRF Center for beta Cell Therapy.


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