Tuesday, 8 November 2011

New treatments for Type 2 Diabetes

Fresh pomegranate
I went to my second local meeting of Diabetes UK last week, and it was well worth the trip. It's an odd group - the majority of members are well over retirement age, and the primary function of the group is definitely fundraising, with regular raffles, tombolas and fundraising events. Once a month at these meetings, though, they also have a lecture - I wrote about the last one, which was all about feet. This time, we had the local diabetes consultant talking about the newest developments in treatment of Type 2 Diabetes Mellitus (T2DM).

Type 2 Diabetes

Unlike type 1, where insulin is lacking, the primary symptom in T2DM is insulin resistance. When food is consumed the carbohydrate is broken down into glucose, which circulates in the blood before being used for energy or stored. As blood glucose levels rise, insulin is secreted by beta cells in the pancreas, and insulin is what facilitates the exit of glucose from the bloodstream. (I've written a post about this before). Because people with T2DM are resistant to the action of insulin, the levels of glucose in the blood remain higher for longer, and more insulin is secreted to try and deal with it, so levels of insulin are also high.

The disease is progressive, and over time the ability of the pancreas to secrete these large amounts of insulin decreases - it actually seems to 'wear out' - and eventually insulin replacement therapy may be needed, by injection, as for a person with type 1. At that point, the main difference between type 1 and type 2 is the insulin resistance; in T2DM the amount of insulin that has to be injected is very much greater.

Historical treatments

The main pharmacological treatments historically for T2DM have been aimed at overcoming insulin resistance (metformin), and stimulating insulin production while the pancreas is still able to produce any (sulphonylureas, pioglitazone). Another treatment that can be prescribed is a glucosidase inhibitor (acarbose), which inhibits the digestion of carbohydrate in the gut so that it does not enter the bloodstream, but often produces severe flatulence.

Alongside these medicines, exercise removes glucose from the blood independently of insulin, diet can help moderate high levels of blood sugar, and both diet and exercise can produce weight loss, which independently reduces insulin resistance. The recent news report of recovery of normal blood sugar levels after eight weeks on a 600 kcal/day diet (and similar remission following gastric surgery) may be attributable to this weight loss effect. And it's clear that obesity is one of the major risk factors for type 2 diabetes, so losing weight reduces risk, incidence, and severity.


The new treatments are based on another finding - that the gut produces hormones, called incretins, which stimulate insulin secretion when carbohydrate is digested. This 'amplification' of the effect of glucose stimulating insulin secretion is smaller in people with T2DM, so injectable forms of one of these incretins (Glucagon-like peptide 1 or GLP-1) have been developed. Because the effect only happens when carbohydrate is digested, these GLP-1 agonists don't provoke hypoglycaemia (when blood glucose falls dangerously low). The two drugs currently available are exenatide (Byetta) and liraglutide (Victoza).

As well as increasing insulin production, incretins keep blood sugar levels low by suppressing glucagon secretion - glucagon stimulates the liver to release stored glucose into the blood, when fasting, for example. They slow gastric emptying so people feel fuller for longer, and they also seem to act on the brain to reduce appetite - these factors contribute to the treatment by facilitating weight loss. Animal studies have also demonstrated that incretins halt the degeneration of the insulin-secreting cells in the pancreas, which would be an added bonus if it is true for humans.

Side effects are nausea, an unpleasant feeling of fullness, and possibly an increased risk of pancreatitis. Because the drugs are not exact replicas of human GLP-1 there is also the possibility of the body's immune system generating antibodies which reduce its effectiveness. Future development work is taking place around reducing the number of injections by producing a longer-acting version, and slow release via an implantable device.

Other new treatments

Natural incretins are very short-lived, which is why the GLP-1 agonist drugs are not quite the same as the human versions - they have been designed to hang around a bit longer. GLP-1 is broken down in the body by an enzyme called DPP-4, and a class of drugs called gliptins inhibit the activity of DPP-4, thus preventing the breakdown of GLP-1 and increasing its availability in the body. Gliptins can be taken as tablets, which gives them an advantage over injectable incretins.

Another class of drugs being investigated are glucose re-uptake inhibitors. At all times our blood is being filtered through the kidneys, with unwanted components passing through to the bladder for excretion in urine, while the majority of the blood and its contents are re-absorbed back into the bloodstream. Glucose goes through this process, with nearly 100% being re-absorbed as long as blood levels are not too high. Glucose in the urine is one of the diagnostic criteria for diabetes, when there is so much glucose in the blood that it 'overflows' into the urine.

Glucose re-uptake inhibitors inhibit the channels in the kidneys that reabsorb glucose, so preventing re-uptake and forcing excretion of glucose in the urine even when blood levels are not sky-high. This will lower blood glucose levels slightly, improving blood glucose control and also leading to a small amount of weight loss (but less than with GLP-1 agonists). The down sides are potential urinary tract infections (because bacteria love sugary urine), and a dehydrating effect.

The last development that the speaker mentioned briefly were new types of insulin: ultra short acting and ultra long acting, which can help with both type 2 and type 1 diabetes.

And finally

After the lecture, I asked the consultant about his work with dietitians and any inside knowledge of whether there might be any opportunities for voluntary or unpaid work or work experience. He was moderately encouraging, and I have emailed him as we agreed, but so far have heard nothing.

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