Transplantation For Diabetes Mellitus
Diabetes mellitus is characterised by high blood sugars due to insufficient insulin or insensitivity to the actions of insulin.
Type 1 diabetes is due to an autoimmune destruction of the insulin-producing beta cells. Patients typically present in child-hood or adolescence with ketoacidosis and are insulin-dependent from the outset. Autoantibodies to islet cell antigens are frequently detectable.
Type 2 diabetes is the result of insulin resistance, and typically occurs in older and more obese patients. They are usually non-ketotic at presentation and do not immediately require insulin. Initially the beta cells attempt to compensate for the insulin resistance by increasing production; however, with time, the beta cells burn out.
Other forms of diabetes: Gestational diabetes (GDM) – occurs in pregnancy, has similar features to type 2 diabetes and often resolves after delivery. Many patients with GDM will go on to develop type 2 diabetes later in life.
Maturity onset diabetes of the young (MODY) – caused by single gene mutations (e.g. HNF-1α gene) that result in abnormal beta cell function, insulin processing or insulin action.
Pancreatic pathology – pancreatitis, pancreatic cancer, cystic fibrosis, haemochromatosis and pancreatectomy may all cause diabetes.
Around 1% of the cells in the pancreas are within the islets of Langerhans; these are small clusters of hormone-secreting cells that are scattered throughout the pancreas. One of these hormone-secreting cell types is the beta cell, which secretes insulin in response to high blood glucose. The islets also contain other hormonesecreting cells, such as alpha cells producing glucagon, and delta cells producing somatostatin.
Within the beta cells insulin is produced as a precursor called proinsulin, a single polypeptide chain which folds such that the two ends of the chain become bound by two pairs of disulphide bonds. This polypeptide is then cleaved into three fragments, the A, B and C peptides. A and B form the insulin molecule, and the C peptide is released. Measurement of C peptide in the serum can be used to determine whether a potential recipient makes their own insulin (i.e. not type 1), since artificial insulin does not contain this peptide.
High concentrations of glucose entering the beta cells trigger release of insulin. This insulin is secreted directly into the portal circulation to have its initial effect on the liver, where it is required to permit entry of glucose into the cells.
The complications of diabetes
The main complication of diabetes is the development of accelerated vascular disease. This is particularly marked in patients with poor glucose control and those who smoke. Vascular complica- tions are categorised according to the size of vessels involved:
1 Coronary artery disease: angina and/or myocardial infarction.
2 Peripheral vascular disease (PVD) characterised by claudication, rest pain, ulceration and gangrene.
3 Cerebrovascular disease, manifesting with transient ischaemic attacks (TIA), amaurosis fugax or cerebrovascular accident.
Retinopathy Microvascular disease affecting the retinal vessels is classified according to severity and whether the macula is involved.
- Background – microaneurysms (dots) and microhaemorrhages (blots), hard exudates.
- Pre-proliferative – cotton wool spots (soft exudates indicative of retinal infarcts), more extensive microhaemorrhage.
- Proliferative – new vessel formation.
- Maculopathy – changes described in background or pre-proliferative retinopathy affecting the macula.
If there is significant haemorrhage then retinal detachment may occur. Diabetes is also associated with cataract formation.
Neuropathy A number of types of diabetic neuropathy occur.
Peripheral sensory neuropathy – typically in a ‘glove and stocking’ distribution. Vibration sensation is lost early. In advanced disease, sensation in the feet may be completely absent, resulting in unnoticed trauma and subsequent ulceration. In the presence of PVD, the blood supply is impaired, leading to poor healing, sometimes necessitating amputation.
Autonomic neuropathy – symptoms vary and include gustatory sweating, gastroparesis (vomiting and nausea), bladder dysfunction, erectile dysfunction and postural hypotension (due to loss of regulation of vascular tone). Of most significance is the loss of awareness of hypoglycaemia. Hypoglycaemia is normally accompanied by tremor, sweating and palpitations due to the release of adrenaline (epinephrine) in response to low brain glucose (neuroglycopaenia). This has the additional role of stimulating glycogenolysis and gluconeogenesis in the liver. This compensatory adrenaline release is lost in patients with hypoglycaemic unawareness. The net result is that blood sugar may fall dangerously low, causing significant brain damage or death.
Painful neuropathy – damage to sensory nerves may lead to a burning pain or sensitivity to touch.
Mononeuritis multiplex – may affect any peripheral nerve.
Diabetic amyotrophy – painful wasting and weakness of quadriceps.
Nephropathy Patients with type 1 diabetes frequently develop renal involvement. At least 25% of diabetics diagnosed before the age of 25 years will go onto to develop end-stage renal failure.
Diabetic nephropathy is characterised by albuminuria, which may progress to heavy proteinuria with decline in glomerular filtration rate (GFR). Histologically, there is basement membrane thickening and glomerulosclerosis, which may be diffuse or nodular (Kimmelstiel–Wilson lesions). Diabetic patients are also more susceptible to urinary tract infections, which may contribute to chronic renal damage.
In the UK, diabetes is the most common cause of ESRF requiring renal replacement therapy. Diabetics on dialysis have a very poor outlook, with a 30% 5-year survival.
Both pancreas and islet transplantation are for the treatment of diabetes mellitus. Since both require standard immunosuppression, the benefits of the procedure have to outweigh the risks, and the side effects and complications of immunosuppression. There- fore it is generally agreed that the patient should have a life-threatening complication of diabetes, such as hypoglycaemic unawareness, or that they require immunosuppression for another reason, such as a kidney transplant.