ADA 2017: Type 2 highlights – by Emily Burns
If you caught our Type 1 diabetes research highlights from the American Diabetes Association’s 77th Scientific Sessions – the largest diabetes conference in the world – last week, we’re back now with our Type 2 series.
This is part one of two, with research updates on gut bacteria, the beta cell, and the latest treatment innovations.
Gut bacteria and our health
Engineering bacteria to our benefit
The microbiome – all of the organisms living inside us – are often part of the diabetes debate. It’s thought that our gut bacteria is linked to our immune system, suggesting that bacteria may play a role in Type 1 diabetes. Meanwhile, early research suggests that transplanting gut bacteria from people of a healthy weight could help to reduce weight – and therefore the risk of Type 2 – in obese people.
But Dr Sean Davies had a different take. He wanted to know if Type 2 diabetes could be treated by changing the gut microbiome using genetic engineering. He’s been investigating a type of molecule called NAPEs, which are produced inside the body when we eat food. They reduce appetite and also have anti-inflammatory properties. The amount of NAPEs our body produces is, at least in part, decided for us by our genetics.
Dr Davies’ idea was to hijack the gut bacteria, genetically engineering a type of bacteria so that they produce more NAPEs, to reduce appetite and inflammation. .
They’ve tested this in mice and have shown that the bacteria can stop obesity. When researchers stopped feeding the mice the bacteria, the effects were seen for another four weeks. So why not just give NAPE to the mice – why bother with the gut bacteria at all? Dr Davies explained that you’d need really high doses of NAPE to see any benefit, with the bacteria being much more effective.
Whether this could be used for people at risk of Type 2 diabetes in the future is another story, but it’s definitely another string in the microbiome bow.
Professor Leonie Callaway kicked off the first session at the ADA with hot-off-the-press data from the SPRING trial, testing the effects of a probiotic pill taken during pregnancy on the risk of gestational diabetes in overweight or obese women.
This isn’t the first time the benefits of probiotics have been explored. Previous clinical trials have found that probiotics have reduced the rates of gestational diabetes or improved metabolism, while a 2014 trial in Ireland found no effect.
Early findings from the SPRING trial showed that the make-up of the microbiome was more accurate at predicting problems with metabolism in pregnant women than their BMI (body mass index, calculated using weight and height). Not only that, using antibiotics during pregnancy was linked to a dramatic shift in the make-up of the baby’s microbiome.
The SPRING trial involved 433 pregnant women who took either a probiotic or placebo capsule daily. The final data is still being analysed, so Professor Callaway couldn’t reveal too much. But the bottom line was that probiotics did not prevent gestational diabetes in overweight or obese women.
The results were negative, and as Professor Callaway put it, “This is the point where grown men and women cry.” She reminded colleagues that they’re scientists, and therefore shouldn’t get attached to the results one way or another. But to be sure, the team are checking the original faeces samples to confirm that the women on the study actually took the probiotic capsules.
So why was it negative? Were the women ‘too healthy’ to start with? Is yoghurt consumption in Australia so high that it would mask an effect? Or is it simply that, as the results suggest, probiotics are not useful in preventing gestational diabetes?
We’ll have to wait for the full results to find out.
We know that having high blood glucose levels long-term can increase the risk of complications. Clinical trials that have reduced HbA1c have reduced the risk of microvascular complications (kidneys or eyes) – although the effect on macrovascular complications (the heart) is more modest.
As it turns out, controlling blood glucose levels is necessary to prevent complications, but it’s not enough. According to Dr James Galvin, we need to refresh our understanding of the underlying biology and natural course of Type 2 diabetes – and get to grips with the need to personalise treatments for different people.
Dr Galvin proposed that the shortcomings of existing treatments are based on how much more we need to learn about this complex condition. It’s much bigger than the pancreas alone, or insulin resistance. For example, many organs are involved and many genes linked to Type 2 diabetes are also linked to diabetes-related complications.
Conditions closely linked to Type 2 diabetes (such as high blood pressure) are often treated with a combination of different drugs, but Type 2 is often approached in a ‘step-wise’ manner. This means that we start with diet, then move to a single therapy, then increase the dose of that therapy, and then begin second-line treatment options. Each time a treatment option fails, people could be exposed to higher blood glucose levels again, potentially increasing their risk of complications. Metformin is a go-to Type 2 drug, but metformin’s ability to control blood glucose levels wears off over time and the drug doesn’t improve the body’s ability to respond to insulin. Type 2 diabetes is also very dynamic, with the biology changing as the condition progresses.
For all of these reasons, Dr Galvin believes that combination therapy could have many advantages, potentially reducing complications and even slowing progression. Trials have shown better reductions in HbA1c using combination therapies, but we’re yet to see evidence of improved long-term health, we don’t know how much this approach would cost and we don’t know who might (or might not) benefit.
Dr Roopa Mehta agreed that Type 2 is much more complicated that the beta cell and insulin resistance, and combination therapies could help us move beyond this one-size-fits-all approach. But at the same time, we need to avoid a ‘pill burden’, where people feel they’re taking more medications than they can cope with.
Finally, she noted that it’s important that combined drugs should work in different ways, either complementing each other or increasing the overall positive effects.
Dr Karsten Wassermann presented the results of an exciting Novo Nordisk study looking at an area of research that has remained out of reach for decades: an oral insulin pill that can be taken to control blood glucose levels.
The trial involved 50 people with Type 2 diabetes who had never taken insulin before. The participants took either oral insulin or insulin glargine for eight weeks, with the results showing that both forms of insulin improved blood glucose levels in a similar fashion.
“The results of our feasibility study show for the first time that it’s possible to develop, on a small-scale level, therapeutically meaningful insulin in an easy-to-take oral tablet.” explained Dr Wassermann.
But for now, it’s back to the drawing board for Novo Nordisk. While the results are exciting, only around 2 percent of the insulin in the pill was absorbed through the gut, making it very inefficient. Research is now focusing on the technology needed to produce the pill, to see it can be made more efficient and therefore more commercially viable.
Can effects of childhood obesity be reversed?
Researchers from Denmark think so. They looked at the Danish health records on over 60,000 men who had their height and weight measured between 7 years of age and 17-26 years. They wanted to know if changing your weight considerably between childhood and adulthood was linked to a change in Type 2 risk.
They studied four weight patterns:
- Healthy to healthy
- Healthy to overweight
- Overweight to healthy
- Overweight to overweight
They found that 5.4 percent of the boys were overweight in childhood and they had a 50 percent higher risk of developing Type 2 – with a three times higher risk in adulthood.
But boys who were overweight in childhood and lost the weight by adulthood? Their risk of Type 2 diabetes was the same as the people who were not overweight when they were children. This suggests that if the boys lost the weight before they reached adulthood, there would be no lasting impact on their risk of Type 2.
But there was a catch: if they lost the weight after the age of 13, they still had a higher risk of Type 2 diabetes in adulthood. So early childhood could be an important point.
“Our results highlight the need for normalising weight among overweight children before they reach adulthood,” explains Dr Lise Bjerregaard, the lead author of the study.
There are some limitations. Firstly, it was only looking at men in Denmark. Secondly, the data the team used was collected in the late thirties – a lot has changed since then. For one, the number of children who are obese is now much higher – just under 20 percent in the UK.
Back to basics
Professor Domenico Accili was awarded the prestigious Banting award for Scientific Achievement for his work into the beta cell.
Professor Accili described research as a continuation of clinical care: Type 2 diabetes won’t go away by its own accord. Current therapies treat the condition, but can’t reverse or modify two critical factors: when the body stops responding to insulin (insulin resistance) and when beta cells stop working. But understanding around these two factors has reached a critical mass in recent years, and Professor Accili believes that the community is now ready to develop new drugs to combat them.
Professor Accili believes that drugs could potentially be developed to turn off particular genes involved in insulin resistance, as a key to reversing it. While we’re not there yet – and Professor Accili acknowledged the challenge of translating basic research findings into actual treatments – reversing insulin resistance could be a thing of the future.
We know Type 2 diabetes is an incredibly complex condition, but in terms of the beta cell, there are three main steps. We start with a healthy, working beta cell; this beta cell is exposed to high levels of glucose and fat and start to fail; at this point, it’s thought that the beta cell starts to lose its identity. Early research suggests that the beta cells are turning into another cell type that exists in the pancreas: the alpha cell. Alpha cells produce the hormone glucagon.
If beta cells are turning into alpha cells – or any other type of cell – it means that they’re not dead. Professor Accili believes that the clinical implications of this are huge: there could be potential to turn these cells back into beta cells, restoring their function even after the onset of Type 2 diabetes.
Watch this space…