PHOPHODIESTERASE 10A INHIBITORS TO AMPLIFY THE ACTION OF GLP1-MIMETICS OR DPP-IV INHIBITORS IN DIABETES

摘要

The present invention relates to a new method for prevention and treatment of type 2 diabetes based on administration of inhibitors of phosphodiesterase 10A (PDE l0A) expression or PDEl0A activity in combination with agents that enhance or mimic GLP-1 signalling in the beta cell, long-acting GLP-1 analogs like exendin-4 or inhibitors of GLP-1 breakdown (DPP-­IV inhibitors). The invention is based upon the original findings that the cAMP­phosphodiesterase (PDE) isoform 10A, an enzyme that degrades cAMP with high affinity and that so far was mainly associated with brain function is not only expressed in brain but also in endocrine cells like pancreatic islets of Langerhans, the site of insulin secretion, as well as in pancreatic beta cell lines (MIN6 and INS 1). This expression was detected both at the Mrna level (real-time quantitative RT-PCR or microarray analysis), and protein as evidenced by Western blots with an affinity-purified rabbit polyclonal antibody. The high abundance of PDEl0A in neuro-endocrine cell types (brain, adrenal gland, pituitary, islets of Langerhans) which demonstrates a clear role for PDElOA in hormone secretion. Furthermore it was found that PDElOA is induced by food intake in mouse islets and severely (70%) lowered by overnight fasting. As PDE l0A was specifically down-regulated (mRNA-level) in genetically modified mice that do not express functional GLP-1 or GIP receptors in beta cells (DIRKO mice), we claim in~retin receptors induce the mRNA in beta cells. This was further demonstrated in INS1 cells, where PDEl0A is induced by 6-24 exposure to agents that raise cAMP in the cells, such as forskolin, IBMX and GLP-l. Based on these observation a combination medicament has been developed combining the PDEl0A inhibitor, Dipyridamole or derivatives thereof or the PDE10 inhibitor, papaverine, to remarka~ y enhance the effect of agents that enhance or mimic GLP-1 signalling in the beta cell, Long­acting GLP-1 analogs like exendin-4 or inhibitors of GLP-1 breakdown (DPP-IV inhibitors) to treat a disorder of impaired insulin secretion such as type 2 diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (MT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X and more particularly type 2 diabetes.