Pancreas or Islets Transplantation
The final objective in the treatment of type 1 diabetes is the restoration of endogenous insulin sources. At present, only pancreas transplantation can achieve insulin independence. With the introduction of more effective and safer immunosuppressive therapy, the success of whole-organ transplantation has improved dramatically. During the last decade, patient and graft survival were 91% and 75% at one year, 88% and 72% at two years and 85% and 67% at three years, respectively. Further improvement in the risk/benefit ratio of chronic immunosuppressive therapy will be welcome as it will provide better selectivity in the prevention of graft rejection.

An alternative option to whole-organ transplant is the intra-hepatic engraftment of isolated pancreatic islets. The procedure is less invasive but remains much less used due to a lower success rate. A great deal of work and investigation is in progress to improve outcomes, taking into consideration even the newly available immunosuppressive agents and microencapsulation techniques. The latter are designed to separate the insulin-producing cells from cell-mediated rejection. However, even if this might become an efficient procedure, similar to whole pancreas transplantation, its feasibility will be heavily dependent on organ availability.

Several alternative sources of insulin-producing cells are currently being examined. This includes the use of tissues from other species (pigs represent the most suitable donor species) and engineered human non-beta cells.35

Stem Cells
Stem cells and progenitor-based approaches have become the focus of high expectations, as effective generation of beta cells might provide an unlimited source of self-tolerated insulin-producing cells. Stem cells are characterised by self-renewal capacity and the ability to differentiate into various different cell types. This includes embryonic stem (ES) and adult stem (AS) cells. The first successful differentiation of mouse ES cells into pancreatic lineage was attained through transfection of a drugresistant gene under control of the insulin promoter, followed by cell lineage selection and maturation.

After in vitro differentiation, one transgenic ES cell clone showed regulated insulin release and, after transplantation, normalised glycaemia in streptozotocin-induced diabetic mice.36 Subsequent modifications have been used to generate functional islet-like clusters.37 However, a feature of undifferentiated ES cells is their tumourigenic potential.38

AS cells are involved in the maintenance and regeneration of tissues. Moreover, they may transdifferentiate into various cell types of other lineages with much lower tumourigenic potential. Propagation and direction of multipotent AS cells into the pancreatic lineage in vitro would allow a sufficient amount of transplantable cells to be generated. A successful generation of insulinreleasing cells was reported from different 3 pancreatic sources.37 Using stem cells derived from easily accessible tissues, such as bone marrow, might provide an optimal strategy.

Normalisation of blood glucose levels through cell replacement strategies is obviously the objective of all these procedures. However, until now, there little attention has been paid to other aspects of islet function, including the regulatory roles of glucagon, somatostatin and pancreatic polypeptides in carbohydrate, protein and lipid metabolism. It is also clear that any therapeutic application of stem cells in diabetes therapy is still far away.

Artificial Pancreas
An alternative approach to beta cell replacement is the artificial pancreas, i.e. a closed-loop portable device with the capacity of continuous measurement of blood glucose concentration and appropriate delivery of insulin for maintenance of normoglycaemia (see Figure 2).39 Although components necessary to assemble an artificial pancreas (insulin pump, glucose sensor and mathematical algorithm of control) are available, further work is needed to ensure co-ordinated interaction between them and persistent reliability of blood glucose reading and insulin delivery.

Major advances have been obtained for each of these components. Thus, ‘smart pumps’ have been developed. Once supplied with information on blood glucose levels and meal carbohydrate content, the microcomputer of the pump, based on the insulin/carbohydrates ratio, the individual insulin sensitivity, glycaemic targets and residual insulin activity of previous bolus will suggest the appropriate insulin dose for the meal. However, for the purpose of closing the loop, using implantable pumps with intraperitoneal insulin delivery appears to be the best approach.

Essential in the development of a miniaturised artificial pancreas is a reliable and long-lasting glucose sensor. Continuous glucose monitoring of glycaemia can be achieved through measurement of glucose concentration in the vascular bed or interstitial fluids or by studying the effects of the glucose on tissues. Intravenous continuous glucose sensing is unlikely to be the solution, particularly in long-term glucose monitoring. The current subcutaneous fibre microdialytic or reverse iontophoresis systems, however, are handicapped by substantial lag time between glucose changes in blood and interstitial fluids. The development of systems capable of realtime glucose reading and assessment of glycaemic trends might provide the possibility for a closed-loop insulin delivery system.

Conclusions
Diabetes has always represented a formidable arena for new and modern advances in therapeutic solutions. Insulin discovery was a landmark in medical research of isolating a hormone for therapeutic use. Recombinant DNA technology has initially been used to synthesise the first ‘human’ hormone, i.e. insulin. Insulin is the first hormone to be engineered to obtain analogues with well-specified pharmacokinetic and phamacodynamic properties.

Diabetes research will continue to provide cutting-edge solutions in the attempt to achieve independence from multiple administration of insulin, recovery of physiological insulin sensitivity and secretion. Nonetheless, major research efforts and a substantial amount of time will be required to achieve these ambitious goals. In the meantime, diabetes will continue to pose a great challenge to the patient, the physician and the industry. At present, the greatest challenge is to ensure good glycaemic control and, thus, better chances of reducing the risk and the burden of diabetic complications for as many diabetic patients as possible .

With the course of time new solutions will become available and it is imperative for physicians to use all of these solutions at full capacity. This requires awareness of the importance of strict glycaemic control and the need for an uncompromising ‘treat-to-target’ approach.40