Biologic Platform for Early Detection, Prevention and Treatment of Type 1 Diabetes

Type 1 diabetes (T1D) is caused by a strong reduction in number of insulin-producing beta cells following an attack by the patient’s own immune system. The failure in insulin provision requires lifelong insulin therapy. This hormonal substitution succeeds in controlling blood glucose levels, but cannot avoid risks for acute and chronic complications, nor threats on life expectancy and quality. Novel therapies are thus needed which, depending on the disease state, either (1) prevent the onset of beta cell mass depletion, or (2) replace this functional mass durably in case of partial or complete loss. Our Diabetes Research Center-DRC has provided proof-of-principle for beneficial effects of both interventions. Our clinical trials also indicated shortcomings in protocols and in their outcome as well as differences related to the biological characteristics of the patients. The present project uses a biologic platform to prepare for novel therapies according to the disease stage and personal characteristics.
The path to prevention of beta cell depletion (Goal 1), will use
(1) validated models for prediction of risk for T1D and its progression through distinct disease stages; interactions between established genetic and immune markers and genetic risk markers outside the HLA system will be determined and further analyzed by an innovative statistical approach in a large cohort of high-risk relatives of T1D patients; models will be confirmed in two independent cohorts in the perspective of a population screening for T1D risk;
(2) minimally invasive methods for early diagnosis of a poorly functional beta cell mass; for this purpose, the utility of continuous glucose measurements-CGM will be investigated in conjunction with plasma proinsulin and C-peptide levels; markers will be defined for discriminating rapid and slow progressors to clinical onset in a cohort of relatives with immune risk markers; predictive criteria will be established by using an innovative statistical approach for repeated measures;
The path to beta cell replacement protocols (Goal 2) will explore the strategy of developing beta cell implants derived from stem cell lines obtained from a T1D patient with defined disease markers, and destined to be received by the same patient (autograft). Methods have been developed for laboratory production of beta cell preparations from blood cells of T1D patients. These preparations will be investigated for
(1) their cellular composition and in vitro properties;
(2) their capacity to establish and maintain metabolically-adequate implants in mice;
(3) their induction of processes potentially leading to disease when implanted in nude rats;
(4) the significance of findings in test tubes and in animals for the autograft strategy in beta cell
replacement.