REBECCA is 11 years old and has just been diagnosed with diabetes. Nothing unusual in that, as diabetes is now one of the fastest-growing diseases of childhood. But Rebecca’s doctors are confused: what kind of diabetes does she have? Some of her symptoms clearly point to type 1, suggesting she will need insulin injections for the rest of her life. But others look like type 2 diabetes, meaning a regime of diet and exercise would be enough to keep the disease under control.
Rebecca is one of a growing number of people visiting their doctor with a mixture of symptoms somewhere between type 1 and type 2 diabetes, informally known as “type 1.5 diabetes”. It’s not just a problem in children either. Increasing numbers of adults are also presenting with mixed symptoms, and some are being diagnosed with both forms of diabetes simultaneously – a condition recently dubbed “double diabetes” ().
There are no firm figures on type 1.5 and double diabetes yet, but experts are beginning to take notice. To many, the trend is an inevitable consequence of modern lifestyles. Others read more into it. They argue that the apparent existence of mixed forms of diabetes exposes a fundamental flaw in the way we classify and treat the disease.
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If they are right, the categorical distinction between type 1 and type 2 diabetes, which was established in 1980, is artificial, and diabetes is actually a spectrum disorder with type 1 at one end and type 2 at the other. In this view, what is being called type 1.5 or double diabetes is actually just a point on that spectrum. It is a controversial idea in diabetes circles, but even those not prepared to embrace it accept that the orthodox classification is looking frayed around the edges.
All over the world, both forms of diabetes are on the up. Type 2 – the one associated with obesity, where the body becomes resistant to insulin – has reached epidemic proportions in the west and parts of Asia. Type 1, in which insulin-producing cells are obliterated in an autoimmune attack, is now among the most common chronic diseases of childhood, for reasons that are not clear (see “Typing diabetes”, for more details).
Most cases of mixed diabetes are in people originally diagnosed with type 1, who go on to develop symptoms of type 2 as well. This can be explained fairly easily within the existing understanding of diabetes, says Francine Kaufman of the Childrens Hospital Los Angeles in California. In today’s obesogenic environment, people with type 1 diabetes are just as likely as anyone else to become overweight and develop type 2 diabetes as a result. “The genes that predispose us to each of the types of diabetes are relatively common, so it is possible to carry both,” says Kaufmann.
“171m Cases of diabetes worldwide in 2000”
Double diabetes is hard to manage and has serious implications for long-term health. “There are going to be complications associated with both type 1 and type 2,” says Paolo Pozzilli, a diabetes specialist at Queen Mary, University of London. This means damage to the small blood vessels in the retina and kidney, which is typical of type 1, plus the cardiovascular disease and raised blood lipids typical of type 2.
The mainstream view of double diabetes is that it is one disease overlying another. Not all cases fit that description, however. Type 1 usually starts in childhood and is rarely diagnosed in people over 30, yet some middle-aged adults with type 2 diabetes have been found to have signs of immune attack on the pancreas, which is diagnostic of type 1. “We think that around 10 per cent of people with type 2 also have autoantibodies,” says Kaufman. This suggests that, contrary to current models, autoimmune attack can play a part in type 2.
Rebecca’s case is similarly confusing. She has signs of autoimmune attack on her pancreas and has ketones in her urine, both of which are diagnostic of type 1. But she doesn’t have any of the other classic type 1 symptoms, such as fatigue, thirst and weight loss. In fact, she is gaining weight, not losing it.
Cases like these have led many researchers to conclude that we need to look again at how diabetes is classified. One of them is Edwin Gale at the University of Bristol, UK. “The current classification is a mental construct that assumes the existence of two forms of diabetes and confirms this by circular reasoning,” he argues. Gale isn’t calling for the existing classification to be scrapped – yet. “Given that we do not know what causes either form of diabetes, our current classification is still evolving. It’s not necessarily wrong to use type 1 and type 2 as labels of convenience, but it is bad science to pretend that they represent two distinct diseases.”
Terence Wilkin of the Peninsula Medical School in Plymouth, UK, goes further. He argues that type 1 and type 2 are actually the same disease, differing only in the tempo at which they progress.
According to Wilkin, all cases of diabetes start with weight gain. This makes the body increasingly resistant to insulin and causes beta cells in the pancreas to ratchet up their insulin output to meet the extra demand. This makes the beta cells susceptible to autoimmune attack, causing their destruction and, eventually, the need for injected insulin.
By this reasoning, a child diagnosed with type 1 diabetes at age 8 has undergone the whole progression from insulin resistance to insulin-injection dependence in just a few years – or even months – with the early stages going undetected. Someone diagnosed with type 2 diabetes is progressing through the same continuum much more slowly – resulting in the typical type 2 pattern of a long spell of worsening insulin resistance followed by the gradual exhaustion of the beta cells and, eventually, the need for injected insulin.
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Why might people progress through this continuum at such different rates? The key is differences in their immune response, says Wilkin. It has long been known that certain combinations of genes in the group known as the HLA complex strongly predispose people to autoimmune disease, in which the immune system attacks the tissues it is supposed to defend. About 2.5 per cent of the population have the most aggressive HLA combination. Other combinations give intermediate degrees of susceptibility, while in most of us the tendency to autoimmunity is absent altogether.
“What I think we are looking at in diabetes is a sequence of events that is squeezed together when you have got highly reactive HLA genes, much more leisurely when you have got less reactive genes, and may not occur at all when you don’t have any susceptibility genes,” Wilkin says. He has christened this idea the “accelerator hypothesis” ().
Wilkin’s team has been monitoring a cohort of 300 healthy children for the past seven years, starting at the time they entered school at about age 5, to try to catch a glimpse of the events leading up to diabetes. He says that the results back his ideas. In particular, he has found that prior to diagnosis, type 1 diabetics share many characteristics with people with early type 2: they are heavier than average and have high insulin levels, suggesting that they are insulin-resistant ().
Wilkin also points out that we have known for years that early onset of type 1 diabetes is associated with the highly reactive HLA genes (). He believes that children with these genes can be propelled rapidly through the early, or type 2-like, stages of the disease and already need insulin injections by the time they are diagnosed.
So what sets the immune system on its destructive course? Wilkin argues that the ultimate driver is weight gain. As people get fatter, their tissues become increasingly resistant to insulin. In response, beta cells crank up insulin production. As time passes, the body tissues need ever more insulin to function, and eventually the beta cells can’t keep up, blood sugar rockets and diabetes is diagnosed. This is the standard explanation for type 2.
But something else is going on too, says Wilkin. Increased insulin output is not the only consequence of beta cells going into overdrive. They also start to display an array of extra proteins on their cell surface. This, Wilkin argues, makes them a bigger target for the immune system and will trigger an autoimmune attack in susceptible people. The more reactive your HLA genes, the more intense the reaction and the quicker the progression to needing injected insulin. “The autoimmune response that we have interpreted for 30 or 40 years as a primary event [in type 1 diabetes] is a response to metabolic upregulation,” he says.
It’s a controversial idea, not least because it suggests that children develop type 1 diabetes because they are overweight. An article on the hypothesis in a magazine published by the London-based charity Diabetes UK provoked an angry reaction from some parents, who felt they were being blamed for their children’s illness. Wilkin says this is a misreading of his hypothesis. He points out that for many years, studies have shown clearly that children with type 1 diabetes are, on average, heavier than their peers, even if they are not technically overweight. “People say ‘my child was never overweight’, but even a small increase may be important,” says Wilkin. “In relation to the 1970s, the whole of the population is now many kilos heavier than it was.”
The accelerator hypothesis has a lot going for it. For one thing it explains the mixed symptoms of type 1.5 and double diabetes. It also provides a culprit for the mysterious rise in childhood type 1 diabetes: the dietary and lifestyle changes that are making those of us in the west heavier.
Even so, most diabetes researchers remain sceptical. Gale points out that recent research has robustly linked one set of genetic variations with type l diabetes and another set with type 2. The lack of genetic overlap undermines the idea that the two diseases are different manifestations of a single condition, he says. It is also unclear whether people on the way to developing type 1 really do go through a phase of insulin resistance before their beta cells pack up. Data from recent studies suggests that insulin resistance is not always a factor in the development of the disease, Gale says.
For now, the mainstream position looks set to hold. “Type 1 and type 2 are two distinctly different conditions,” says Simon O’Neill of Diabetes UK. Even so, he says, “there are still many pieces of the diabetes jigsaw missing, and we would welcome new research regarding the classification of diabetes.”
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Wilkin now wants to test his accelerator hypothesis in children who have a very high risk of developing type 1 diabetes because they have a family history of the disease, and already have antibodies to beta cells in their blood. He proposes giving the children an insulin-sensitising drug called metformin, widely used by adults with type 2. This, he suggests, would lighten the workload on their beta cells, possibly staving off autoimmune attack. It may not, however: a similar trial by Jay Skyler of the University of Miami in Florida in 2002 found that using insulin to rest the beta cells did not prevent the onset of type 1 ().
If nothing else, the controversy promises to improve the way diabetes is treated. Rather than shoehorning people into one category or the other, doctors are increasingly prepared to treat them as individuals, says Gale. “There is a growing awareness that patients should be assessed as accurately as possible and treated in the light of their capacity to secrete insulin and their level of resistance to its action,” he says. The cloud of double diabetes, it seems, could have a silver lining after all.
Typing diabetes
Type 1
Cause Failure to produce insulin as a result of autoimmune attack on beta cells in the pancreas
Onset Typically in childhood or early adulthood
Prevalence About 10 per cent of all diabetics are type 1
Symptoms Thirst, hunger, excessive urination; weight loss, vision changes, drowsiness or exhaustion. Onset can be very rapid
Treatment Injected insulin
Prevention Not possible at present
Type 2
Cause Insulin resistance brought about by overweight/obesity and physical inactivity
Onset Usually middle age but increasingly seen in younger people, even children
Prevalence About 90 per cent of all diabetics are type 2
Symptoms Similar to type 1 but initially much milder. Almost half of people with type 2 are not aware they have it
Treatment Diet, exercise, weight loss, insulin-sensitising drugs. Many type 2 diabetics progress to injected insulin after their beta cells fail
Prevention Dietary changes and physical activity can reduce the risk
Historically, diabetes was seen as a single disease. In 1936, however, Harry Himsworth of University College Hospital in London published a (vol 227, p 127) suggesting it was actually two different diseases. After lengthy debate, the WHO officially recognised two distinct types of diabetes in 1980. There have been a couple of name changes since, but the idea of duality has persisted.
In type 1 diabetes, the cells in the pancreas that produce insulin, called the beta cells, are destroyed by the immune system. Without insulin, the rest of the body’s cells can no longer take sugar from the blood, so blood sugar levels skyrocket. This leads to a circle of insatiable thirst and frequent urination as sugar spills over into the urine, dragging water with it. Meanwhile, cells are forced to burn fat for energy, causing the patient to lose weight and leaving by-products of fat metabolism called ketones in the urine and on the breath. The attack on beta cells also leaves a telltale trace of antibodies in the blood. This type of diabetes almost always begins in children or young adults. Fortunately the body still responds to insulin, and with daily insulin injections the symptoms disappear.
For reasons that are not clear, the incidence of type 1 diabetes is at around 3 per cent per year, and the average age at diagnosis is falling. The rise is too rapid to be explained by genetic changes, and is not down to improved diagnosis as the condition is unmistakable. Various explanations have been proposed, including viruses and toxins, but the main contender is the “hygiene hypothesis”. In developed countries, infants are exposed to less dirt and fewer germs than in the past, and many researchers argue that this lack of early “training” for the immune system makes them less able to deal with harmless antigens appropriately.
Type 2 diabetes is strongly linked to obesity, which, also for reasons that are not clear, makes the body resistant to insulin. Its onset is gradual and often goes undetected. Until recently the disease was confined to middle and older age, but it is now seen in children as young as 10, although this is still uncommon. In the early stages type 2 can be controlled by diet, exercise and weight loss, but most people end up needing insulin-sensitising drugs. Many eventually go on to insulin injections because their beta cells fail.
