Diabetes Mellitus Flashcards
What is the composition of an islet cell?
Alpha cells-Glucagon
Beta cells- Insulin, C-peptide
Delta cells- Somatostatin
Gamma cells- Pancreatic polypeptide
What is metabolism like in an untreated Type 1 DM patient?
Increased glucagon Gluconeogenic Breakdown of protein Switch to fat oxidation Increased ketone bodies Ketoacidosis Diabetic coma
What are the secondary complications of diabetes?
Atherosclerosis (macrovasculature)
Nephropathy and retinopathy (microvasculature)
Nuropathy (NS)
Which cells are effected in Type 1 DM and how?
Auto immune destruction of pancreatic beta cells
What is used to model T1DM in rats?
Streptozotocin (STZ)
How is vp1 possibly implicated in T1DM?
Over 60% T1DM cases had some vp1 positive islets
Expression of vp1 localises with insulin but not with glucagon
Suggestion of viral trigger
How could viral infection trigger DM?
Cytolysis
Viral persistence causing prolonged localised inflammation
Damage to beta cells by the virus induced T cell activation (bystander activation)
Molecular mimicry
Explain how immune cell infiltration has an effect on pathophysiology of DM
Infiltration of mononuclear immune cells (macs/APCs, T-lymphocytes)
Direct cell:cell killing (Fas/FasL, perforin/granzyme B)
Secretion of inflammatory mediators (cytokines, ROS)
Anti-islet autoantibodies
Describe the role of inflammatory cytokines in pathophysiology of DM
Secreted by infiltrating immune cells
Bind to cell surface receptors on islet cells
multiple and diverse effects on cellular function
Act synergistically
Species difference in susceptibility
What are the exogenous sources of reactive species?
Secretion from macrophages/APC
iNOS active duct cells
What are the endogenous sources of reactive species?
Cytokine-induced iNOS expression
MnSOD
What are the antioxidant defence mechanisms?
MnSOD
Catalase
Glutathione Peroxidase and reductase
Reduced expression in beta-cells
What is the current approach to therapy for DM?
Currently, insulin replacement the only viable option
How can insulin be delivered therapeutically?
Injection- slow/fast release, insulin pumps
Inhaled- exubera (discontinued)
Oral admin- ORMD-0801 (Phase 2 trials)
Liver-targeted- Thyroxyl insulin
What are the problems associated with islet transplantation?
Number of donor pancreas' Islet stress re-vascularisation Host rejection (alloimmune response) Glucotoxicity Recurrent autoimmunity Islet yield Blood-mediated inflammatory response
Define Allotransplantation
Transplantation between individuals of the same species
Define Autologous transplantation
Transplants between the same individual (self to self)
Define Synergic transplants
Genetically identical transplants
Define Xenotransplantation
Transplants between different species
What is the current criteria for an islet transplant?
Severe/prolonged T1DM Recurrent hypoglycaemia Hypoglycaemia unawareness Often remain on small dose of insulin Immunological considerations Require multiple donors and several transplants
How is the issue of revascularisation tackled?
Growth factor supplementation, gene based approaches (over-expression of VEGF)
How is the issue of inflammation tackled?
Drug targets
Gene based approaches: (Caspase-3 siRNA, iNOS shRNA, hIL-1RA expression, Over-express XIAP)
Encapsulation
How is the issue of poor islet cell mass tackled?
Increased beta cell proliferation in transplanted tissue
Donor availability
Improved survival/retention of grafted tissues
What are the sources for transplantation?
Cadaveric donors Differentiation of non-beta cells Mesenchymal stem cells Embryonic stem cells Induced pluripotent stem cells
What is DIABECELL?
Porcine insulin-producing islets encapsulated in alginate
What are the problem associated with DIABECELL?
Microencapsulated islets are irretrievable
Safety
Ethics
What are the pros and cons of using the intra-hepatic via the portal vein as a islet transplant site?
Pros- high success rate, near optimal O2 tension, avoid systemic hyperinsulinaemia
Cons- Inflammatory response, immunosuppressant levels, difficult to biopsy, glucotoxicity
What are the alternative sites for islet transplantation?
Kidney capsule Anterior eye chamber Subcutaneous Intramuscular Intrapancreatic
What are the features of and instant blood-mediated inflammatory response (IBMIR)?
Non-specific innate response Massive early cell loss Expression of tissue factor and vascular injury during transplantation Activation of coagulation system Activation of complement
What does IDN-6556 target?
The caspase cascade
What are the effects of IDN-6556?
Improved glucose tolerance
Improved insulin content
Reduced apoptosis
What are the types of encapsulation and some of their properties?
Macro-encapsulation
Micro-encapsulation in alginate- additional surface coat to modify properties, difficult to control the process and variable islet volume
Nano-encapsulation-conformational/surface coating
Immune evasion- cell surface coating
What are the pitfalls of encapsulation?
Biocompatibility
Immune response
Hypoxia
What gene based approaches can be used in islet transplantation?
Over-expressing a gene to promote engraftment
Over expressing genes to prevent cell loss
Expressing a construct to ‘silence’ expression of pro-apoptotic genes
Construction of Bipartite vectors
