DIABETES, RECONSIDERED
Type 2 study identifies new triggers
It’s been a tidy explanation for generations: Type 2 diabetes is largely driven by too much weight, too many sugary drinks and too little exercise.
But new research is challenging the notion that obesity alone can explain away much of a disease some believe is on path to becoming the biggest epidemic in human history.
Yes, lifestyle plays a part, as does genetics. But science is also unearthing new potential triggers, from the environment in the womb and the immune system living in the gut, to whether a person’s outlook on life is positive or less-than-sunny.
Worldwide, the number of people with diabetes — a condition that results when the pancreas doesn’t produce enough insulin to regulate blood sugar, or the body can’t use the insulin it does produce — has climbed from 108 million in 1980, to more than 422 million today, according to the World Health Organization. The number is expected to rise to 642 million throughout the next decade.
Diabetes heightens the risk for blindness, kidney failure, heart attacks, stroke and lower limb amputation, and kills more than 7,000 people in Canada every year. In fact, we rank among the worst OECD (Organization for Economic Co-operation and Development) countries for diabetes prevalence, with more than three million Canadians, or nine per cent of the population, living with the disease in 2014.
We also have one of the highest rates of obesity among OECD countries, weighing in fourth behind the U.S., Mexico and New Zealand, and ahead of the U.K.
And as obesity rates in children rise, a growing number are developing Type 2 diabetes, a disease once rarely seen in children. Formerly known as “adult onset” diabetes, Type 2 diabetes, which accounts for roughly 90 per cent of all diabetes, is now being diagnosed in children as young as eight.
It’s not clear why, but the story might begin in the womb, and with a youngish branch of science known as epigenetics, which looks at how the environment, including a mother’s uterus, can cause certain genes to switch on or off, affecting a person’s risk for illnesses later in life.
The science dates back to the Dutch Hunger Winter in 1944-45 in the Netherlands, then under German occupation.
Women who conceived during the famine gave birth to babies that, six decades later, had higher rates of obesity, diabetes and other chronic health problems compared to people conceived before or after the famine.
Studies on their DNA would later show that systems regulating the Hunger Winter babies’ growth genes were altered. The feeling is that a stressor in the parental generation makes the fetus more vulnerable. A stressor like under nutrition — or over nutrition — may cause specific epigenetic changes to the fetus’s genome, making the baby more vulnerable to diseases like diabetes.
What’s more, diabetes in pregnancy itself can cause epigenetic changes, says Dr. Paul Zimmet, one of Australia’s top diabetes researchers. “We know that mothers with pre-gestational diabetes and mothers with gestational diabetes are more likely to have offspring who are either obese or have diabetes,” Zimmet wrote in the journal Clinical Diabetes and Endocrinology. “And the epigenetic effect appears to be intergenerational. It means you could have a vicious cycle perpetuating the diabetes epidemic.”
Again, it brings us back to obesity. One of the major risks factors for gestational diabetes is obesity.
But what is it, exactly, about obesity that triggers diabetes? What links obesity to insulin resistance?
Twenty years ago, the question was what causes any body to become insulin resistant. “We now know that low levels of inflammation throughout the body is one of the major drivers, says Dr. Dan Winer, a scientist at Toronto General Hospital Research Institute. And visceral fat — the fat deep in the body that connects our internal organs — is one of the main sources of whole-body inflammation.
Fat inflammation causes the body to pour out cytokines, little proteins secreted by the immune system, and fatty acids shed from the fat. Inflammation jams up insulin signalling in the fat, which drives up insulin resistance, setting people up for diabetes.
“So, the question then was, what causes the fat to be inflamed? That’s when we started looking at the gut,” Winer says.
In work reported in August in Nature Communications, he and his team discovered that, during obesity, the gut produces lower levels of an immune cell that makes an antibody called IgA.
IgA antibodies are especially good at neutralizing dangerous gut bacteria that can “leak” through intestinal tissues, causing inflammation.
In a study in mice, Winer and his team found that a high-fat diet cripples the amount of IgA produced in the gut, allowing new types of harmful bacteria to flourish in the intestines.
Next, when they analyzed stool samples taken from people before, and one month after, bariatric surgery, the Toronto researchers found that IgA levels increased in 71 per cent of patients, post-surgery.
It may help explain why surgically manipulating the gut via bypass surgery, and the dietary regimen that goes with it, can reverse Type 2 diabetes, or at least park it in remission, in most people.
“Diabetes has been very pancreas-centric for many years,” says Winer. “But there are other organs in play. This work brings the immune system living inside the gut to the centre stage as a new area that really needs to be investigated further.”
At the very least, “it reinforces the idea of having a healthy, balanced diet, because it impacts the bacteria and the immune cells in the gut.”
Others are exploring whether our personalities, and not just what we eat, may put us at greater risk of diabetes.
A study published earlier this year in the journal Menopause linked positive traits like optimism to a reduced risk of diabetes, while low optimism, “high negativity” and hostility were associated with increased risk.
The study involved nearly 140,000 post-menopausal women from Women’s Health Initiative, a massive trial that has been following women since the early ’90s. During 14 years of followup, 19,240 women developed Type 2 diabetes.
Compared to the least optimistic, women who were the most optimistic had a 12-per-cent lower risk of developing diabetes. Women with the most hostile frame of mind had a 17-per-cent higher risk of diabetes. And the hostility-diabetes association was stronger in women who were not obese.
The findings held after BMI, smoking, diet, physical activity, depression, how much alcohol the women drank and other factors were taken into account.
Just what might link personality traits to diabetes isn’t clear but stress likely has a hand, says the study’s first author Dr. Juhua Luo of Indiana University’s School of Public Health.
Women with high hostility and low optimism likely also experience more emotional stress, and when chronically stressed, the body releases hormones like cortisol, which increases sugar in the blood stream, as well as those cytokines that increase inflammation. The result: Visceral fat accumulates, more free fatty acids are released and then, insulin resistance.
It’s hard to change personality traits, which are shaped at least in part by life circumstances, Luo says. But it’s not impossible. Randomized controlled trials have shown psychological interventions can increase optimism, which has also been linked with lower rates of heart attacks and stroke. And a study published in September in the Proceedings of the National Academy of Sciences is just the latest to link optimism with a longer life, with the most optimistic men and women living 11 to 15 per cent longer lifespans, on average. They also had greater odds of achieving “exceptional longevity,” meaning living to 85 or beyond.
Women (and men) might benefit from knowing how their personality might heighten their risk for diabetes, Luo and her co-authors say. But we might also want to intervene even earlier in life, by encouraging optimism and positive attitudes in our children, Luo says — and in turn potentially help break the cycle feeding the diabetes epidemic.