New therapies

Diabetes was once a relatively rare condition. Although its prognosis continues to improve, the rise in its prevalence has more than cancelled out the benefit. Many believe that the disease process itself has not changed, but that people have become more susceptible to it because of increasing age and obesity. Lasting change will therefore only be achieved at a public health (primary prevention) level, and any intervention subsequent to the development of dysglycaemia is essentially a stop-gap measure designed to mitigate its consequences. At this clinical level, intervention has three possible main objectives: (1) to restore beta cell function; (2) to restore insulin sensitivity; (3) to protect against the harmful consequences of dysglycaemia by non-glycaemic interventions. The principal aim of therapy in type 1 diabetes is restoration of beta cell function, and this section will offer an overview of pancreatic or islet transplantation; further details of these are provided in the section on type 1 diabetes. Type 2 diabetes represents a greater therapeutic challenge, for there is no easily identifiable or remediable genetic or mechanistic target for therapy; instead it represents a complex, dynamic and pleiotropic process which requires multi-layered intervention.

Restoration of insulin secretion

Therapies for Type 1 diabetes mellitus are described in much greater detail in Future prospects. This section reviews pancreas and islet transplantation because of their potential interest in type 2 diabetes, although their use is currently directed towards type 1 diabetes.

Pancreatic transplantation

Despite significant advances in medical treatment, whole pancreas transplantation is still the only treatment that consistently achieves the ultimate goal of normoglycaemia without a significantly increased risk of hypoglycaemia. Whole pancreas transplantation allows also freedom from the continuous attention to blood glucose control that medical therapies require. Enthusiasm for the outcomes offered by transplantation is tempered by fear of the risks of the transplant procedure, in particular the risks associated with the need for immunosuppressive therapy. Furthermore, evidence of benefit with regard to microvascular and macrovascular complications of diabetes has been lacking. Data are now available to allow objective discussion of risks and benefits for individual patients. It is essential that this treatment is only offered to patients for whom it is likely to result in significant improvement in quality of life. Whole pancreas transplantation may be carried out as simultaneous pancreas kidney (SPK) transplantation for the patient who also requires renal replacement therapy, pancreas after kidney (PAK) transplantation for the patient with a successful kidney transplant, or solitary pancreas transplantation (PTA) for the patient with normal kidney function. See Pancreas Transplantation

Islet transplantation

The pancreas is formed by the fusion of embryological precursors of both endocrine and exocrine tissue, and the need to graft unwanted exocrine tissue into unphysiological locations represents a major limitation for the transplant surgeon, not to mention a source of post-operative complications. Rational although it is, this approach to therapy is currently limited by the vulnerability of islets obtained from human pancreas to hypoxic damage and to the physical stress involved in the isolation and transplantation procedures. Although now a viable procedure, it is very costly because of the need for fresh high quality pancreas and immunosuppressive therapy. Long term results remain disappointing, but the field is steadily inching forward. The ultimate solution would be an endless source of cultured islet cells, which could also potentially be engineered to make them less of a target to the immune system, but this remains a long-term prospect. See Islet transplantation - an overview in this section, also Islet transplantation and Stem cell therapies in the section on type 1 diabetes.

Improving insulin sensitivity

Insulin resistance has long been a tempting target for intervention in type 2 diabetes, but this approach has been limited by the multifactorial nature of its causation and the off-target effects of insulin sensitizing agents such as Biguanides and Thiazolidinediones/ PPAR agonists. Both have been used in the prevention of type 2 diabetes, although sceptics have argued that this approach has only been shown to reduce blood glucose, as might be expected from glucose-lowering agents, rather than to influence the natural history of the condition. See Prevention of T2DM: Pharmacological Interventions

Non-glycaemic Approaches

Although there has been interest in the possibility of severing the link between hyperglycaemia and its downstream consequences upon tissues and blood vessels, for example by blocking glycation of structural proteins, no viable approaches to therapy are currently in trial.

An alternative of interest is therapeutic use of C-peptide, the "lock" that holds the proinsulin molecule together as a single peptide chain. The possibility that C-peptide may exert direct physiological effects of its own was evaluated in the early 1990’s. In a series of studies involving administration of the peptide to patients with type 1 diabetes, who lack C-peptide, replacement of C-peptide in physiological concentrations resulted in significant improvements of several diabetes-induced functional abnormalities.This prompted a renewed interest in C-peptide physiology and during the past 20 years a steadily increasing number of reports on new aspects of C-peptide physiology have emerged. The information available today includes studies of the peptide's interaction with cell membranes and its intracellular signaling properties. In vivo studies in animal models of type 1 diabetes have defined a beneficial influence of C-peptide on diabetes-induced functional and structural abnormalities of the kidney and the peripheral nerves. In addition, several clinical studies describing positive effects of C-peptide replacement therapy on nerve and kidney function in type 1 diabetic subjects have been reported. The wealth of information now available supports the hypothesis that C-peptide has therapeutic potential. This view is summarized in Therapeutic potential of C-peptide.

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