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Monday, 18 August 2003
Page: 18726

Dr WASHER (4:03 PM) —Type 1, or insulin dependent, diabetes accounts for approximately 10 per cent of all diabetes mellitus and hyperglycaemia—high blood sugar—from defects in insulin secretion and/or insulin action. Abnormalities in fat and protein metabolism are also present and are of vital importance in treatment. Damage to organs such as the retina and the lens of the eye, kidneys, somatic and autonomic nervous systems, heart arterial systems and microcirculation has already been discussed.

Insulin is formed from pancreatic islet beta cells from a large molecule called proinsulin, which is split to form insulin and an intramolecular connecting peptide called C-peptide. Both are excreted in an equal ratio, so C-peptide is an accurate marker of beta cell function. Excess glucose damages vessels and nerves to organs by (1) formation of advanced glycated end products, correlating with levels of haemoglobin Alc—which is one of these molecules; (2) oxidative stress and dangerous free radicals; (3) sorbitol production, causing nerve damage; (4) protein kinase C, which stimulates new vessel grow-th factors, resulting in neovascularisation in the eye, collagen or scar tissue synthesis, and stimulation of apoptosis or cell death and oxidative stress—vascular endothelial grow-th factor and transforming growth factor beta are two examples of neovascularisation factors; and (5) formation of nitric oxide, which generates dangerous free radicals.

Owing to genetic differences in susceptibility to the damage of high blood sugar and the difficulty in normalising blood sugar consistently, drugs to intercept some of these five pathways are necessary. One likely gene influence which makes diabetics susceptible to nephropathy, or kidney damage, is the gene for angiotensin converting enzyme—ACE—hence the use of ACE inhibitors in diabetics to protect their kidneys.

In type 1 diabetes, destruction of 90 per cent or more of the insulin producing beta cells in the pancreatic islets of Langerhans results in permanent insulin deficiency, requiring exogenous insulin replacement. Evidence points to the destruction of the beta cells by an autoimmune process. In these individuals, HLA linked genes set in motion the autoimmune attack, stimulated by exposure to a virus or toxin resembling beta cell antigen. Alternatively, the viral antigen may accelerate the normal rate of apoptosis, or cell death, of the beta cells. This process takes place over a period of a few years, starting with reduced insulin release, progressing to total insulin absence and C-peptide absence and permanent insulin dependence. This raises the possibility of treatment with immunosuppressive agents in the early stages of the disease.

Genetic factors involving polymorphism of HLA genes in the MHC locus on chromosome 6 account for 50 per cent of the genetic risk; however, diabetes type 1 is associated with at least 15 additional loci on nine other chromosomes. Eventually, genetic identification of susceptibility to type 1 diabetes may lead to early use of immunosuppressives, early low dose insulin or vaccination for prevention. The use of recombinant DNA human insulin and some of the more rapid acting monomer as compared to hexamer type insulins, dispensing with a pump driven continuous subcutaneous infusion, implantable pumps and nasal, inhalational or oral insulins are being investigated.

In my remaining time I would like to briefly cover pancreatic transplant graft survival, which is at 82 per cent with kidney transplant compared with only 62 per cent when done alone. Successful grafts require lifelong immunosuppressive therapy. Masking and removing cell surface antigens may soon allow transplantation with little or no immunosuppression. Treatment using islet cells placed in semipermeable hollow tubes allowing glucose to enter and insulin to leave while shielding the cells from inflammatory reaction to a foreign body is showing promise.

Finally, I would like to acknowledge the work done by Associate Professor Phillip O'Connell with pig islet cell xenotransplantation at Westmead Hospital, Sydney. This was jointly funded by the Juvenile Diabetes Research Foundation and the National Health and Medical Research Council. NHMRC funded $20.75 million for diabetes related research in 2003. (Time expired)