NV15-26746A – The effect of glycaemia normalisation after pancreas transplantation on advanced diabetic retinopathy
Diabetic retinopathy (DR) is a feared and common complication that depends on the severity and duration of hyperglycaemia. The renewal of glucose tolerance through pancreas transplantation may slow down its progression. As indicated by experimental data, inhibition of the mammalian target of rapamycin (mTOR) attenuates the proliferation of retinal vessels and the development of macular oedema. The purpose of the project is to test the hypothesis that system therapy using everolimus, an mTOR inhibitor authorised as an immunosuppressive drug, improves further progression of advanced DR after the transplantation. A prospective controlled non-commercial clinical study will include 60 patients with diabetic nephropathy in its terminal stage based on type 1 diabetes, undergoing combined pancreas and kidney transplantation, randomised to everolimus or mycophenolic acid as an addition to tacrolimus therapy. We will monitor a composite eye indicator and a number of partial eye and metabolic parameters for 2 years. The results published in impacted transplantation and diabetology journals will not only be important for transplantation medicine, but also for the treatment of diabetes in general.
TA04010038 – Collagenase for isolation of the islets of Langerhans
The purpose of the project is to develop a collagenase-based product with high tryptic activity and standard properties that will be primarily intended for the splitting of collagen of the pancreas upon isolation of the islets of Langerhans. Absence of a product providing standard activity is one of the main factors that currently prevent better utilisation of available pancreata from brain-dead organ donors and wider implementation of the transplantation of the islets of Langerhans in the treatment of type 1 diabetes. A partial goal is to determine, based on experiments, a suitable composition of the product (rates of various isoenzymes and additional proteases), to develop a procedure for reproducible production, to elaborate its use in the process of isolating the islets of Langerhans from animals and, finally, to demonstrate its safety in preclinical studies in terms of the morphology and function of insulin-producing beta cells. The efficacy and safety of the product will also be tested in a preclinical model of experimental diabetes treatment by transplanting the isolated islets under the renal capsule and in the liver via vena portae. Suitability of the product in the dissociation of other tissue types where commercial application can also be expected will further be verified. The product developed in the final phase of the project will be offered for testing to prime world laboratories that perform isolation of the islets of Langerhans, which have already displayed an interest in the new product.
GA13-06666S – Morphology and function of pancreatic ß-cell mitochondria in the pathogenesis of type 2 diabetes
An insufficient function of pancreatic beta-cell mitochondria apparently plays a role in the development of their dysfunction in type 2 diabetes. Therefore we explore any alterations of the mitochondria in beta-cells of the pancreatic islets from early stages up to the phase of full development of T2DM in insulin-deficient Goto-Kakizaki, insulin-resistant Zucker and hypertriglycemic HHTg rats compared to appropriate control rats. In vivo and in vitro secretion of insulin, sensitivity to insulin and bioenergetics will be studied with respect to functional changes of the mitochondria, alterations in their morphology (using 3D super-resolution Biplane FPALM microscopy), intensity of mitophagy and the level of oxidative and nitrosative stress. We will focus on possible prevention / reversing of pathological alterations in the structure and function of the β-cell mitochondria through the regeneration of the autocrine effect of insulin through its direct administration or transplantation of the pancreas or the islets themselves.