New Horizons in Care

Development of new diabetes treatments is a fast moving area and we’ve come a long way in recent years. While there is still no cure for diabetes, the research is making steady progress on improving the drugs and devices that people with both type 1 diabetes and type 2 diabetes use.

In type 1 diabetes the body’s immune system attacks the pancreas and stops it from working properly. The main functions of the pancreas are to produce the hormones insulin and glucagon. Insulin comes from the beta cell; and glucagon from the alpha or A cell. In someone without diabetes, insulin and glucagon work together to maintain normal blood glucose levels. When their blood glucose goes down, the pancreas:
• Reduces insulin levels
• Increases glucagon levels.
When their blood glucose goes up, the pancreas:
• Increases insulin levels
• Reduces glucagon levels.
Together the two hormones insulin and glucagon keep blood glucose levels within a safe range. But of course this does not happen in someone with type 1 diabetes.

Insulin discovery
It is only about 90 years since insulin became available. Until then, most people who developed type 1 diabetes died. “We’ve come a long way since that time. Our approach to replacing insulin in type 1 diabetes mostly involves insulin injections,” Prof Seamus Sreenan, Consultant Endocrinologist, Connolly Hospital, Blanchardstown, told a recent Diabetes Ireland public meeting.
Long-acting basal insulin
Basal or slow-release insulin: This replaces the slow trickle of insulin and keeps blood glucose controlled overnight and between meals – it provides 40-50% of daily needs.
Fast-acting bolus insulin
One of the main changes in insulin treatment in the past 20 years has been the development of insulin analogues to produce fast-acting insulin.
Bolus insulin or mealtime insulin:
• Controls blood glucose after meals
• Provides an immediate rise in insulin which peaks after one hour – it provides 10-20% of total daily insulin needs at each meal.
Ultra long-acting insulin
An ultra long-acting insulin called degludec is in development and will probably be available within a year or two. “The idea is that a single injection will lead to a very flat insulin profile over 24 hours. If you have a flatter insulin profile with less peaks there is less likelihood of  hypoglycaemia,” said Professor Sreenan. Trials of degludec have shown that the overall numbers of hypos are the same, but that people have 25% less night-time hypos.

Insulin pumps
Of course, some people use an insulin pump instead of the standard daily four injections. Pumps are probably the best way of delivering insulin for a lot of people, but they are not suitable for everyone. “There is a downside to everything. If you’ve got something stuck under the skin for 24-72 hours it can get infected if
you don’t look after it very well. “If there is a problem with the pump, the rapid-acting insulin it delivers wears off very quickly and blood glucose will start to rise. You have to very closely monitor your glucose levels when you are using a pump,” said Professor Sreenan. The buttons on the pump can be used to programme a bolus to be taken with each meal. People who use an insulin pump usually have better blood glucose control over 24 hours than those using injections.

Glucose sensors

While insulin pumps have been around for a number of years, a newer piece of equipment is the glucose sensor, which can be added on to the pumps. The sensor is usually inserted in the abdomen for about three days. There are different types of sensors and most of the diabetes centres now have one of these. They provide a glucose reading every five minutes and are useful for people with erratic glucose levels or hypos. Closed loop or artificial pancreas The closed loop is also known as the artificial pancreas. In a closed loop, an insulin pump is linked up with a glucose sensor:
• The sensor continuously measures the blood glucose
• It uses bluetooth technology (wireless) to relay this information to a device (eventually this will be something like a mobile phone)
• The device uses a mathematical formula to work out how much insulin you need and transmits this information to the insulin pump.
The mathematical formula must take account of the fact that the insulin takes a little time to affect your blood glucose level. So it needs to anticipate this delay and calculate the dose accordingly.

“These closed loops have been shown in experiments to work very well in the short term. But there are greater improvements required in the technology to make them safe and more user friendly for general use,” said Professor Sreenan.

Pump delivering insulin and glucagon
In someone without diabetes, as blood glucose drops, the pancreas produces glucagon to stabilise levels. A new pump that delivers both insulin and glucagon is now being studied. “The idea will be that you can switch off the insulin and switch on the glucagon and help people recover more quickly from hypoglycaemic events,” said Professor Sreenan. A study showed that, compared to an insulin-only pump, the combined insulin glucagon pump increased the amount of time when glucose were in the target range.

Pancreas transplant
There is a pancreas transplant service in Beaumont Hospital. “It is a very effective treatment for some people with type 1 diabetes. After a year if you’ve had a pancreas transplant and kidney transplant, 95% of those transplants are still working. With pancreas-only transplant, which is less commonly performed, it’s 75%,” said Professor Sreenan. “Most of these people will have no requirement for insulin or a significantly reduced requirement for insulin. The downside is the anti-rejection drugs the person has to take. “So certainly for people who have severe difficulty in controlling their blood glucose and have complications, this can be a very effective treatment,” said Professor Sreenan.

Islet transplants
This involves removing the islets from one pancreas and implanting them in the recipient. The islets are injected into the liver and they work from there. “They work in the normal way in that they respond to blood glucose levels going up in the way that the islets would in the pancreas,” said Professor Sreenan.
“There is no islet transplant service in Ireland. But we are working with colleagues in Beaumont Hospital and DCU to develop a National Transplant Programme here,” said Professor Sreenan. “The availability of islets is a significant limitation.”

Stem cells

The shortage of pancreas islets has led to the research into stem cells. “We have a really long way to go before we have stem cells available. The idea of stem cells is to take a cell that is not normally a beta cell or an insulin-making cell and to try and make it one. There is a lot of work going on but it is still very preliminary,” said Professor Sreenan.

Treatment for type 2
The body reacts differently to sugar received by eating and sugar injected into a vein. When you eat sugar, something in your gut stimulates the production of extra insulin. “This is what we call the ‘incretin effect’. We know now that this is caused by a hormone called GLP-1,” said Professor Sreenan. The protein enzyme that makes GLP-1 work properly is called Dipeptidyl Peptidase 4 (DPP4). People with type 2 diabetes produce less GLP-1 than normal. GLP-1 not only stimulates the production of extra insulin, but it also reduces the release of glucagon.
For a number of years, the treatment of people with type 2 diabetes has included either:
• Directly taking GLP-1, or
• Blocking the protein enzyme that breaks down GLP-1.
The effect of either treatment is the same. Sometimes people with type 2 diabetes take injections of GLP-1. “Anybody with type 2 diabetes may be familiar with these GLP-1s. The commonly used ones are Byetta and Victoza. They increase insulin and they cause weight loss in a lot of people. So they are a good choice for people who have type 2 diabetes and are overweight,” said Professor Sreenan. The drugs used to block the protein enzyme, Dipeptidyl Peptidase 4 (DPP4),include: sitagliptin, vildagliptin, saxagliptin and linagliptin.

Type 2 treatment may benefit type 1 A recent study involved giving people with type 1 diabetes Victoza – the GLP-1 that promotes production of insulin. They found that taking the GLP-1 meant the people with type 1 diabetes needed to take less insulin. There is an Irish trial studying this effect too. The generic name for Victoza is liraglutide.

Pumps augmented with glucose sensors
Trials have been carried out of an insulin pump augmented with a glucose sensor. It gives off an alarm if glucose levels go too low, however, during the trial at night time people often slept through the alarm. The trial showed that compared with insulin injections, people using the glucose-sensor-augmented pumps reduced their A1c (long term blood glucose) levels. “The overall hypoglycaemia rate wasn’t obliterated because they still had hypos but the time spent having hypoglycaemia was less,” said Professor Sreenan. Pump with threshold suspend “The latest development is to have a pump where not only have you got a sensor, but you’ve got a facility that the pump will suspend the insulin for a period of time if the glucose level is starting to drop. These pumps are now available,” said Professor Sreenan.
A trial last year compared:
• A sensor-augmented insulin pump, to
• A sensor-augmented insulin pump with a threshold suspend. The pump with threshold suspend cuts off the supply of insulin when glucose levels fall to a certain level. However, the insulin already under the skin will continue to be absorbed for a period of time.
The sensor-augmented insulin pump with a threshold suspend eliminated severe hypos. “It doesn’t immediately stop a hypo but it can certainly reduce the time spent with hypoglycaemia. So it’ll shorten the hypos rather than completely obliterating them,” said Professor Sreenan.