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Diabetes treatment in the future: what can we expect?

Pat Miles
RGN ENB A05
Diabetes Nurse Specialist
The Royal Bornemouth Hospital

This is an exciting time for those of us involved in diabetes care, and a time of hope for our patients. New treatments currently in development or new to the market offer the possibility of better glucose control with less unwanted side-effects and are better targeted at the underlying causes - particularly in type 2 diabetes. Less than a hundred years after the discovery of insulin and the possibility of saving the lives of people with type 1 diabetes, we now have a large range and depth of knowledge about the condition and its effects on the body, and have the ability to tailor the treatment offered to an individual's needs.

Type 2 diabetes
Type 2 diabetes is a complex metabolic disorder resulting from a combination of insulin resistance and decreased pancreatic excretion of insulin.(1) Insulin resistance results in weight gain, hypertension, lipid abnormalities, glucose intolerance and eventually type 2 diabetes.(2) Modern treatment aims to treat all of these to reduce the risk of the main cause of death in these patients - cardiovascular disease.(3)
Sulphonylurea drugs, which stimulate insulin production from the pancreas, may hasten the decline of the pancreatic ß-cells and shorten the time between diagnosis and the need for injected insulin.(4) Sulphonylurea and insulin treatment can cause weight gain, which leads to increased insulin resistance and higher blood glucose levels.(5) Modern treatment regimens aim to reduce insulin resistance which in turn helps improve all the metabolic parameters, eg, blood pressure, lipids and weight as well as glucose levels.(6)

Incretin mimetics
Incretin hormones are produced in the gastrointestinal tract in response to food and play an important role in the maintenance of glucose homeostasis. New incretin mimetics mimic the effect of one of these hormones called glucagon-like peptide-1 (GLP-1). GLP-1 analogues stimulate insulin secretion in response to food and decrease glucose output from the liver, resulting in reduced blood glucose levels and improved insulin sensitivity. They also slow the rate of digestion inducing a feeling of fullness (satiety), which can lead to weight loss, suggesting that they may be particularly helpful in obese type 2 patients. Importantly, they can also cause regeneration of ß-cells and so have the potential to halt the progression of type 2 diabetes and normalise glucose levels.(7)
The first GLP-1 analogue to the market is Exenatide (Byetta; Eli Lilly), which was launched in the United States in 2005 and is due to be launched in the UK early in 2007. It is administered twice daily by subcutaneous injection in a fixed dose. The experience from the States so far has been very positive and it only remains to be seen what price the NHS will be asked to pay for it and if NICE (National Institute of Health and Clinical Excellence) will restrict its use. Its probable place would be as an alternative to insulin for those with suboptimal control on oral hypoglycaemic agents.

DPP IV inhibitors
Dipeptidyl peptidase IV (DPP IV) is the enzyme that activates GLP-1. As above, GLP-1 is an important mediator of blood glucose levels. By increasing active levels of GLP-1, DPP IV inhibitors have been clinically shown to provide long-term improvement in glucose control without the risk of hypoglycaemia or weight gain. They do not cause any further deterioration in pancreatic ß-cells, so also potentially prevent the steady progression of type 2 diabetes.(8) DPP IV inhibitors are currently at clinical trial stage, and are expected onto the market in the next 12 months or so.

Cannabinoid-1 receptor blockers
The endocannabinoid system plays a crucial role in the control of food intake and energy balance in humans. By blocking the signals from the cannabinoid type 1 receptor it is possible to promote significant weight loss, particularly around the waist, and a sustained improvement in blood glucose, lipid and blood pressure levels. Cannabinoid type 1 receptor blockers act on the brain, decreasing the motivation for palatable food. They act on the hypothalamus producing an anorexigenic effect and on the gastrointestinal tract, stimulating satiety signals. They also act on adipose tissue inhibiting lipogenesis on the muscle cells and increasing glucose uptake. In addition, they have an unknown beneficial effect on the liver.
Studies show a 6kg average weight loss in the first 12 months together with improved lipid profiles and decreased insulin resistance and waist circumference.(9,10) The first drug of this type to market is rimonabant (Acomplia; Sanofi Aventis), which was launched in 2006 in the UK. It is still awaiting review by NICE.

Type 1 diabetes
Type 1 diabetes is an autoimmune disorder where the immune system gradually destroys the insulin-producing cells in the pancreas leading to an inability to control blood glucose levels. People with type 1 diabetes are insulin deficient, and all treatment aims to replace insulin as physiologically as possible to normalise blood glucose levels.
The advent of analogue insulins has enabled a more physiological insulin replacement by subcutaneous injection, but it is still not perfect and many people with this condition suffer from unexpected hypoglycaemia or fluctuating control despite their best efforts.(11)
The hope of nearly all involved in type 1 diabetes is that a cure will eventually be found, but until then, improving insulin delivery to normalise glucose levels without increasing the risk of hypoglycaemia is the aim.

Insulin pumps
Insulin pumps are electronic devices approximately the size of a pager, which contain rapid-acting insulin delivered via cannula and tubing subcutaneously, usually into the abdominal area. The cannula site needs to be changed every two to three days.
The pump can be programmed to deliver a variable basal rate of insulin, delivered continuously and adjusted to the individual patient's requirements. There is also the facility to give a bolus of insulin from the pump every time carbohydrate is eaten. To benefit from pump therapy, patients need to commit to work hard at adjusting their basal rate and working out their carbohydrate to insulin ratios. They also need to feel confident about managing hypoglycaemia and raised glucose levels with ketonuria.
Data from our centre show improved HBA1c with reduced insulin requirements and less hypoglycaemia. Some patients with loss of hypoglycaemia warning signs have experienced a return of these as well.(12)

Continuous glucose monitoring systems
Blood glucose monitoring with meters only tells you the glucose level at the time tested, and even if someone tests seven times daily there are long periods of time where they do not know what is happening, particularly through the night. There have been continuous glucose monitoring systems (CGMS) available for several years now, but only recently have these been available for patients to use themselves.
The monitor is attached to the patient via a subcutaneous cannula that contains a sensor, which detects glucose levels in the interstitial fluid and displays the results continuously on the monitor. The sensors have to be changed every two to three days and this is still an expensive option. The potential benefits of such systems are that the monitor displays "real-time" readings and can be set to alarm if the glucose goes below or above preset levels. This could be particularly useful if people have concerns about hypoglycaemia during the night or loss of hypoglycaemia warning signs.(13)

Artificial pancreas
With pumps and CGMS available, the next logical step would be to "marry them" to produce an artificial pancreas - a device that constantly monitors blood glucose levels and feeds that information to a pump, which then delivers a preset dose of insulin depending on the blood glucose level. Trials of such systems are underway at the moment and it is hoped that a commercially available artificial pancreas will reach the market by 2011.(14)

Islet cell transplants
There was great hope that islet cell transplants would offer a cure to many people with type 1 diabetes when they were developed, but three-year data on the 36 people who received the first transplants are very disappointing, with only one being completely free from the need to inject insulin. Difficulty in obtaining sufficient donor organs and the need for immunosuppression also makes this an unlikely treatment option for many people.(15)

Stem cells
Stem cells are the basic cells from which all other cells develop. If stem cells can be stimulated to develop into insulin-producing cells, then the hope is these can be transplanted into individuals to "cure" diabetes.
There are several problems with this area of research at present. Stem cells can be obtained from embryos in the early stages of development, from the amniotic fluid around fetuses and adult cadavers. The first two sources may present ethical problems, and at the moment there is not a big enough supply available. Any transplant requires treatment with immunosuppressive drugs to prevent rejection and this carries long-term health risks for the patient. In addition, the original autoimmune response that caused the diabetes in the first place will begin destroying the new ß-cells. Cloning of cells may be a possibility, but all of this is a long way from clinical availability.(16)

Conclusion
There are many new treatments for diabetes in development or about to come onto the market. The place for these alongside current treatments has yet to be determined. Whatever new treatments promise, the need for evaluation through NICE and for long-term efficacy data may restrict their use in the UK, even if they have proved successful in other countries. As we know, even if NICE recommends a treatment, such as insulin pumps, financial constraints may make it difficult for patients to obtain that treatment from their PCT.

References

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  2. Mead M. Ten key facts on insulin resistance. Diabetes and Primary Care 2003;5:29-33
  3. Laakso M. Insulin resistance and cardiovascular disease. Br J Diabetes Vasc Dis 2002;2:s9-11.
  4. Barnett A. Emerging therapies in type 2 diabetes. Practical Diabetes Int 2001;18:s16-8.
  5. Krentz A, Bailey C. Type 2 diabetes in practice. 2nd ed. London: Royal Society of Medicine Press; 2005.
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  9. Pi-Sunyer F, Aronne L, Heshmati H, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006;295:761-74.
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  11. Barnett A. Completing the revolution - towards sustained euglycaemia in insulin therapy. Modern Diabetes Management 2002;2:2-8.
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  13. Weiss M. Continuous glucose monitoring: the facts. NiP 2005;25:36-40.
  14. JDRF. Cambridge scientists begin trials of artificial pancreas. Diabetes Breakthrough 2006;38:3.
  15. Shapiro A, Ricordi C, Herring-Berhard J, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;335:1318-30.
  16. Hampton T. Stem cells probed as diabetes treatment. JAMA 2006;296:2785-6.