Diabetes is a condition in which the body doesn't produce enough insulin or in which insulin is not functioning properly. Research is still in progress to discover a cure. However, advanced insulin preparations, such as genetically-engineered insulin, allow patients to lead more normal lives. Research into insulins and other anti-diabetic therapies continues.
Diabetes is a chronic disease in which the body fails to process glucose properly. It is due either to a failure in the production of insulin, which occurs naturally in the beta cells of the pancreas, or because insulin does not function properly in the organs where it should act. Glucose levels in the blood become too high and, after 5-10 years, complications often arise, with serious personal, medical and economic consequences:
(i) Blood vessels and heart: the risk of coronary heart disease is 2-4 times higher than normal and accounts for 66-75 per cent of deaths from diabetes; stroke accounts for 15 per cent of deaths in people with diabetes; blood clots in the limbs can result in amputation, which is 50-80 times more common in those with diabetes; (ii) people with diabetes have a 13 times higher chance of blindness than people who do not have diabetes; the disease is the leading cause of sight problems in the US and Europe; (iii) kidney damage/failure is a problem with prolonged illness; (iv) pain or loss of sensation can cause foot problems and ulceration that can lead to amputation; and (v) coma due to excess sugar in undiagnosed diabetes has a 50 per cent mortality rate.
There are two forms of diabetes. One has an onset at between five and 20 years of age (juvenile-onset diabetes). It is called Type 1 diabetes, or insulin-dependent diabetes mellitus and has been known since ancient times. The second form, Type 2 or non-insulin-dependent diabetes mellitus occurs mostly in people over-45 who are obese and sedentary. Type 1 accounts for 15-20 per cent of cases and Type 2 for the rest. There is some tendency for Type 2 to run in families, but the pattern of inheritance is unclear.
Around five per cent of the EU population are estimated to suffer from diabetes - about 26 million people. A further 10 million are believed to have undiagnosed diabetes. Very often, diabetes is first diagnosed only after a major event like a heart attack or kidney failure. The number of people affected is expected to rise enormously by 2025, according to projections by the International Federation of Diabetes in 2007 (see table attached).
Before the discovery of insulin in 1921, Type 1 diabetes was invariably fatal. People with Type 1 diabetes produce little or no insulin in their pancreas and depend on insulin injections for survival. Many forms of insulin have been marketed. At the beginning, they were of animal origin, but for about 20 years, human insulin has been produced by genetic engineering. There are now modified forms of human insulin in self injected pens available which are fast or long acting or mix. Careful choice of insulin type and continuing patient education and support are needed to ensure optimal therapy and to avoid accidental hypoglycaemia – low blood sugar levels. Problems with patient compliance are a major reason for failure of diabetes therapy and the development of complications.
In Type 2 diabetes, there may be a decline in insulin production, but insulin resistance is more often the cause of disease. Some people cope through lifestyle changes such as weight loss and exercise, but if this fails, medicines called oral hypoglycaemics may be needed. The most commonly used of them belong either to the sulphonylureas or to the biguanides. The former stimulate insulin release while the latter reduce glucose production in the liver.
A somewhat different treatment slows the digestion of carbohydrates when taken with a meal, indirectly reducing glucose surges in the blood. More recently introduced are the ‘glitazones’. These act by reducing glucose output from the liver and causing muscles to burn glucose preferentially, rather than using other energy sources, thus lowering blood glucose levels. Also recently launched was an oral hypoglycaemic agent that stimulates the release of insulin from pancreatic beta cells in a glucose-dependent fashion.
A considerable proportion of people with Type 2 diabetes eventually require insulin as maintenance therapy, but all have an insulin requirement rather than true insulin dependence. Though these anti-diabetic products can be life-saving, people with diabetes may slowly worsen, become insulin-resistant, or develop complications which pose further management problems. Hence there remains an urgent need for new approaches and new medicines. Intractable pain due to nerve damage (neuropathy) is a troublesome complication of late-stage diabetes and does not always respond to conventional painkillers. Among others, there is a sublingual spray containing ingredients of cannabis available for this type of neuropathic pain.
Interest in insulin now focuses on new forms that will eliminate or lessen the burden of the daily injection routine such as long-acting insulins, which overcome some of these problems and avoid the night-time fall in sugar levels. Work is going on to develop inhaled formulations of insulin; the molecule is administered either by a powder inhaler or as an aerosol spray form.
Research also continues into oral hypoglycaemic agents. A carbohydrate digestion blocker is being investigated to see whether it might be helpful in the condition called impaired glucose tolerance which may lead to diabetes. Another approach is taken in developing an orally administered inhibitor of an enzyme that regulates glucose oxidation. Of general interest are compounds, which are able to increase insulin secretion from pancreatic beta cells, reduce beta cell loss and even increase the beta cell levels. Detecting a biomarker for beta cell levels in man would be a breakthrough in the evaluation of new therapies that induce the beta cell levels in diabetic patients.
The development of oral medicines for the treatment of impaired glucose tolerance, when individuals have some degree of beta cell loss but no major symptoms of the disease, would be a new avenue in preventing type 2 diabetes. Another approach is the development of molecules which increase the body’s sensitivity to insulin. Finally, a key research area deals with the enhancement of the body’s energy consumption. A small molecule hypoglycaemic is being studied to see whether it keeps cellular insulin receptors turned on, and another new substance has entered clinical studies that is said to have a beneficial effect on blood lipids, raising high-density lipoprotein (HDL) and lowering low-density lipoproteins (LDL). Researchers are looking into an experimental treatment which combines a protein found on pancreatic cells with free fatty acids to accelerate insulin secretion. The late complications of diabetes are a major cause of morbidity and mortality and pharmaceutical companies are devoting considerable efforts to developing compounds to prevent and manage them. Anti-hypertensive ACE inhibitors and angiotensin 2 receptor blockers (ARBs) are known to be able to slow diabetes-associated kidney disease. There is research to establish whether treatment with an ARB is able to prevent the retinopathy that is commonly seen in late-stage diabetes. A small regulatory peptide and a protein kinase C beta inhibitor are being tested.
Hypertension is such an important health problem in diabetes that researches into inhibitors of the production or action of endothelin and other peptides and enzymes that may be involved in vasoconstriction are among new pathways being tested. One approach is the breaking of the glucose-protein cross-links that accumulate with age in the arteries. Research has shown that this approach could reduce arterial pulse pressure significantly, thereby restoring arterial flexibility.
Many investigators are studying risk markers for type 1 diabetes. There are also efforts ongoing to examine safe therapies for the modulation of the human immune system in order to prevent the development of type 1 diabetes. Combining immunomodulation with compounds enhancing pancreatic beta cell mass would represent a breakthrough in the therapy of type 1 diabetes.
Compounds in development hold out the promise of being able to ameliorate the increasing disease burden of diabetes. There is, however, little doubt that by far the most important means of controlling the expected explosion in diabetes lies in the dual approach of improved metabolic control and the reduction of key risk factors such as hypertension, hyperlipoproteinaemia, obesity and inactivity. While some of these are amenable to control through medicines, the last two, which are of major importance, are in the realm of behaviour modification, in which progress seems rather more elusive than in the development of medicines.