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현재 페이지 위치 : 이식외과분과 > RESEARCH > Diabetes

Diabetes

Diabetes is a group of diseases described by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both.  This disease can cause serious complications and premature death, but persons with diabetes can take measures to reduce the likelihood of such occurrences.
There are two types of diabete : Type 1 diabete, Type2 diabete. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), results from an autoimmunemediated destruction of the insulin-secreting β cells in the islets of Langerhans of the pancreas (Fig. 1) and is a disease of the young, by definition occurring below 40 years. By contrast, type 2 diabetes, or non-insulin-dependent diabetes mellius (NIDDM), is a disease of the older population, with an onset generally over the age of 40 years, and occurring from nonimmune mechanisms. Both types of diabetes require insulin therapy to greater or lesser extent, in order to prevent death from the hyperglycaemia that results from loss of insulin secretion.

Diabetes
 

Figure 1. Location of human β cells in the islets of the pancreas. (a) The pancreas is located in the upper abdomen, close to the liver and behind the stomach. (b) The pancreas secretes digestive enzymes via its duct into the duodenum. (c) An islet is a collection of endocrine cells supplied by capillaries. A thin fibrous capsule separates them from the surrounding (d) exocrine cells, which produce and secrete zymogen. The endocrine cells include: (e) β cells, which synthesise proinsulin, which is cleaved into insulin (stored in granules) and C peptide; (f) α cells, which secrete glucagon; and (g) δ cells, which secrete somatostatin.

Both types of diabetes require insulin therapy to greater or lesser extent, in order to prevent death from the hyperglycaemia that results from loss of insulin secretion. But, it is becoming increasingly clear that the discovery of insulin, though remarkable, was incomplete because the importance of a homeostatic delivery system for this insulin was not recognized until relatively recently. As a result, what are known as ‘insulin-dependent diabetes’ and ‘complications of diabetes’ are really the features and consequences of the failure of current treatment to provide the homeostatic control mechanisms that are lost during this autoimmune disease. When looked at from both these points of view, it seems logical to transplant the islet tissue itself, either by transplantation of the whole pancreas or by transplantation of pancreatic islets, rather than just replacing the insulin that has been lost.
Recently islet transplantation (TPx) has achieved remarkable results while it is not yet the ultimate solution. A major problem with islet transplantation is length of islet graft survival. The death and non-function of transplanted islets could be the result of several factors: (1) transplanting an inadequate number of islets; (2) technical factors that reduce the viability and function of islets, such as warm or cold ischaemia arising from poor retrieval techniques ; (3) nonspecific inflammation damaging the transplanted islets; or (4) immune-mediated destruction (Fig. 2).

a

b

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Figure 2. Mechanisms of rejection of transplanted islets. (a) Nonspecific inflammatory damage. Transplantation of islets will cause some local trauma, resulting in local chemokine release from inflammatorycells. This will attract to the transplant sites migratory macrophages, or liver macrophages (Kupffer cells) if the transplant site is via the portal vein. These macrophages release cytokines such as interleukin 1 (IL-1), tumour necrosis α (TNF-α) and interferon γ (IFN-γ), which attract and activate further immune cells. These cells also release several molecules that are directly toxic to islet cells, including cytotoxic aldehydes, oxygen radicals (O2) and nitric oxide (NO). (b) Direct presentation. After transplantation, dendritic cells derived from the donor graft can migrate out of the islets and into the host lymph nodes, where they can present antigenic peptide on the donor (‘wrong’) major histocompatibility complex (MHC) to the T-cell receptors (TCRs) of host T cells. The activated T cells then target back to the graft and destroy it. (c) Indirect presentation. After transplantation, dendritic cells from the host can migrate into the transplanted islets, where they can take up peptides and proteins from islet cells, including donor MHC and β-cell-specific antigens. The host dendritic cells then travel to host lymph nodes, where they present peptides to host T cells on host (‘correct’) MHC. Again, the activated T cells then target back to the graft and destroy it.

Some of the approaches that might solve these problems are then examined: (1) immune modulation to reduce or prevent immune attack by the recipient’s immune system; (2) immunoisolation to prevent recognition of the islet graft; (3)induction of tolerance; (4) xenotransplantation using islets derived from animals; and (5) gene therapy.
 The aims of our team are to investigate various methods for increasing transplanted islet survival in the Streptozotocin(STZ)-induced mouse diabete model. Preventing and reducing the immune-mediated destruction of transplanted islet is our ongoing study. Recently, we demonstrate that 15-deoxyspergualin (DSG) with the two-signal (CD154, CD45RB) blockade improves the recipient’s glucose levels in Xenotranasplantation model. And, DSG/anti-CD154/anti-CD45RB treatment blocks effectively inflammatory infiltrates at the site of transplantation. Also, we are trying to study the effects of virally transfected- vascularisation promoting substance on the survival of transplanted islet in the STZ-diabete model. 

참고자료

2. Titus, T., Badet, L., and Gray, D. W. R. 2000. Expert reviews in molecular medicine.
 Islet cell transplantation for insulin-dependent diabetes mellitus: perspectives from the present
 and prospects for the future.