Obesity, bacteria and genes hold clues

Rapidly increasing levels of obesity are associated with a worldwide surge in Type 2 diabetes. An international study published in the Lancet, the medical magazine, last year found 347 million adults had the disease, more than twice the number in 1980.

Although diabetes is clearly linked with obesity, it is not clear whether resistance to insulin — the defining characteristic of Type 2 — is caused directly by obesity or whether some underlying factor, associated with unhealthy diet and lifestyle, causes obesity and diabetes. Or both.

Whatever the underlying reason, there is evidence that excessive fat cells accumulating to cause obesity may have a toxic effect on the body’s response to insulin, the most important metabolic hormone, at least partly by triggering a damaging inflammatory response.

But, this cannot be the whole story because non-obese people sometimes develop Type 2 diabetes too.

High-powered genetic studies, using the latest DNA sequencing technology, are proliferating through medical journals. Most are so-called genome-wide association studies, finding different mutations in people who do and do not have the disease.

These studies are just beginning to shed some light on the causes of Type 2 diabetes and are unlikely to lead to treatments any time soon.

Matthew Hobbs, head of research at Diabetes UK, says: “About 60 genes have been linked to Type 2 diabetes and there are undoubtedly more to find. There is no consensus on how the genes interact and how they are affected by the environment. “I think new drugs for Type 2 will come from this research but a lot more work will be needed.”

Beyond genetics, one of the most intriguing recent research findings came in an early-stage clinical trial at Newcastle University in the United Kingdom, which showed that Type 2 diabetes could be reversed by an extremely low-calorie diet without drugs.

Eleven people who cut their food consumption to just 600 calories per day — just above starvation — for two months became completely free of diabetes, and seven of them were still healthy three months after returning to a normal diet.

Dr Hobbs says: “We’re hoping to fund some follow-up work on calorie-restricted diets, to find out whether they could be provided through the NHS [National Health Service]. We also want to know whether the weight loss on the extreme diet or the calorie restriction itself is having the effect.”

Related research is showing that bariatric surgery, which reduces the size of the stomach, can relieve diabetic symptoms.

For example a study of 43 patients in Hyderabad, India, found that 20 of them no longer had Type 2 diabetes 20 months after surgery and the other 23 needed smaller doses of medication. It seems that bypassing part of the stomach and gut had a beneficial effect even before the patients lost weight, perhaps because the operation affected the cellular signalling system.

One of the main themes of metabolic research this year has been growing recognition of the role played by gut bacteria in disease. A healthy adult has about 1.5 kilograms of bacteria in his or her intestine. These microbes normally live in healthy harmony with their host but if the equilibrium is disrupted disease may follow.

A Danish-Chinese collaboration between the University of Copenhagen and the Beijing Genomics Institute examined the intestinal bacteria of 345 people, half of whom had Type 2 diabetes. They found clear evidence that diabetes sufferers had a more hostile bacterial environment, with more pathogens than the healthy controls.

But as usual with this sort of study it is important to distinguish between correlation and causation.

Karsten Kristiansen of University of Copenhagen says: “The big question now is whether the changes in gut bacteria can affect the development of Type 2 diabetes or whether the changes simply reflect that the person is suffering from Type 2 diabetes.”

Parallels with other diseases are also important for understanding diabetes. One is cystic fibrosis.

Almost half of CF patients develop diabetes by the age of 30. It seems that the chloride channel protein, which is defective in CF, leads to a failure of insulin-producing cells in the pancreas.

There is also a potential link with Alzheimer’s disease, possibly through a common inflammatory mechanism. The Alzheimer’s Society is funding a study to see whether diabetes drugs help treat dementia, while Diabetes UK is supporting research from the opposite direction, on the effect of Alzheimer’s drugs on diabetes.

–Financial Times

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Nipping Type 1 diabetes in the bud

While the increasing incidence of Type 2 diabetes is linked to changing diet and rising levels of obesity, type 1 diabetes is also becoming more common — up by 3 to 5 per cent per year — and here the reasons are much less clear.

In type 1 diabetes the insulin producing cells are destroyed by an autoimmune reaction, usually in childhood or young adulthood. No one knows what is triggering this self-destructive process in more and more people, though in the broadest terms, environmental changes must be responsible because human genetics cannot change so fast.

Viral and/or bacterial infection may be an important factor. The “hygiene hypothesis” holds that, because modern life in advanced industrial societies is so clean compared with the conditions in which humans evolved, infants are not exposed to all the germs and dirt required to prime the immune system to work well later.

Then when the modern child does encounter pathogens, these may set off an autoimmune disease such as diabetes or asthma (which is also far more common than in the pre-industrial world).

Whatever the cause, diabetologists hope that medical engineering, in the form of an artificial pancreas, will help type 1 patients. The artificial pancreas is a device that measures blood glucose levels continuously and transmits the readings to an insulin pump that releases exactly the right amount of hormone into the patient, as and when needed.

Although both monitor and pump work well in patients separately, no one has yet put the two together into a robust and reliable system that patients can use routinely at home.

Early clinical trials of artificial pancreas prototypes are, however, giving promising results.

Diabetes UK, for example, is supporting two projects at Cambridge University. One is aimed initially at pregnant women who are at particular risk of birth complications if their insulin and blood sugar levels are poorly controlled.

“The system works better in the lab than a glucose sensor and insulin pump working individually,” says Dr Matthew Hobbs, head of research at Diabetes UK.

“The next stage is to move it out of the lab or hospital and show how it works when people are leading normal lives.”

A more biological approach is to transplant insulin-producing islet cells into patients whose own pancreas has stopped working. This is already carried out successfully on a small scale, using islet cells from deceased organ donors but, since every patient needs the cells from three donors, transplantation is never going to become a routine treatment.

And there is the serious drawback that the recipient must stay on immunosuppressant drugs to prevent rejection.

The long-term solution may lie in islet cells or even a new pancreas generated from stem cells but Dr Hobbs warns against excessive expectations. “Stem cell therapy for diabetes is at least 20 years away,” he says.

A preventive approach may be more successful: to detect that the autoimmune process has begun at an early stage before symptoms appear, and then intervene to stop it and keep the pancreas working.

Several research projects are under way to achieve this, for example by manipulating the immune system in time to save the pancreas, but again it is too soon to tell which, if any, will lead to a useful clinical procedure.

–Financial Times