ESPE 2014 Highlights: Day Three
The final day of ESPE 2014 shone the spotlight on obesity, starting with the first of the day’s plenary lectures given by Donal O’Shea (St Vincent’s University Hospital, Dublin, Ireland).
Prevention better than cure
O’Shea described obesity as “an epidemic that has come disguised as progress and development”. He likened the current state of treatment to that for hypertension in the 1960s, with minimally effective drugs and surgical procedures he believes will “probably be called barbaric in 20 years’ time”.
With current treatments, most patients only lose around 10% of their weight, or 30% with surgery, which he said “has to inform the need for prevention”. However, he noted that there are significant health benefits to be gained from a 10% reduction in bodyweight.
Obesity in children, he said, is driven partly by consumption of sugar-sweetened drinks, associated with low socioeconomic status, discrimination and increased cardiovascular risk, and strongly predicts obesity in adulthood. Thus, we have increasing experience with bariatric surgery in children “and it doesn’t really get much worse than that”.
O’Shea then outlined his team’s research into immune function in obese adults. Natural killer T (NKT) cells, the “foot soldiers” of the immune system, were reduced both in number and in function, he reported, as were levels of innate (i)NKT cells – the “generals” of the immune system. However, iNKT cell levels recovered after patients underwent bariatric surgery. Mice that lacked iNKT cells became twice as fat as control mice when fed a high-fat diet, but replacing their iNKT cells reversed this effect, and was dependent on interleukin-4 and -10.
This led the team to conclude that, although weight-related factors affect the immune system, the reverse is also true. Further evidence for this came from a psoriasis patient with diabetes. She was given glucagon-like peptide (GLP)-1, which is naturally secreted in response to the presence of food in the small intestine to stimulate insulin release, with the surprising result that her psoriasis markedly improved. Following this, the team discovered that GLP-1 regulates iNKT cells, which play a crucial role in psoriasis.
The immune effects of obesity were not confined to adults, however, with O’Shea’s team finding reduced iNKT cell numbers and function in obese children aged an average of 12 years. Of equal concern was their epigenetic findings; the children had switched off genes involved in defence against cancer and switched on genes involved in fatty acid metabolism and insulin signalling, which are associated with heart disease and diabetes in adulthood.
“That means that at an epigenetic level we are already delivering the 30% of people who will have Type 2 diabetes in 2050,” said O’Shea. He noted the reported correlation between obesity and prevalence of fast-food outlets and observed that “we need a public health revolution, but we’re not capable of delivering it”.
Looking to the future, he suggested that novel treatments based on GLP-1 pathways will be used in combination with the intestinal liner, adding that bile salts and faecal transplantation may also play a part. However, noting that obesity frequently makes children unhappy, he stressed that prevention is much better, and cheaper, than any type of cure.
Fat but fit?
In an afternoon session devoted to the management of obese children, Dénes Molnár (University of Pécs, Hungary) opened with a look at the concept of the metabolically healthy obese patient. His conclusion, however, was that “as a clinical entity, it may be questionable”.
He showed that good metabolic health in obese patients is likely transient, with metabolic risk factors accumulating along with the duration of obesity. He also noted that definitions of metabolically healthy obesity vary widely, with many definitions allowing patients to have at least one metabolic impairment.
Furthermore, a number of studies have shown that, although obese patients classed as metabolically healthy have better outcomes than those classed as unhealthy, their outcomes are still significantly worse than those of normal-weight patients. This suggests that metabolically healthy obesity “is not an innocent, benign condition”, said Molnár.
Obese patients who are metabolically healthy are distinguished from those who are metabolically unhealthy by factors including a smaller waist circumference, a less sedentary lifestyle and “much less” visceral fat. Because of this last factor, Molnár favours a model in which metabolic health in obesity depends on a patient’s ability to expand subcutaneous fat deposits. Those who cannot do so accumulate ectopic fat, such as visceral fat, leading to poor metabolic health.
Molnár then drew attention to the recently published IDEFICS study, which included about 16 thousand European children. It has set out two definitions for the metabolic syndrome in children: one that requires monitoring and one that requires intervention. The two definitions are distinguished by thresholds of adiposity, blood pressure, and lipid and glucose levels.
Following Molnár’s presentation, Ram Weiss (Hebrew University, Jerusalem, Israel) summarised the evidence on how doctors can predict which children will respond to obesity interventions. He noted that a positive response depends very much on the definition; however, he said predictors of success include a short duration of intervention, comparison with untreated controls rather than baseline and a lower baseline body mass index: “The less you need the intervention, the more likely you will benefit.”
Predictors of failure include male gender and an unfavourable genotype, he added.
The final presentation, by Thomas Reinehr (University of Witten/Herdecke, Germany), explored the surprising changes in insulin sensitivity seen around the time of puberty. A number of studies have shown that up to three-quarters of obese children with impaired glucose tolerance will later have normal insulin sensitivity, with only 2% converting to Type 2 diabetes. One important part of the reason, said Reinehr, is changes during puberty; recent data from his group show that moving from prepuberty to puberty doubled the risk of developing at least one cardiometabolic risk factor, whereas moving from mid to late puberty tripled the likelihood that the children would become metabolically healthy.
Reinehr stressed that studies of obese children need to account for these changes during puberty – but often do not. Indeed, unexpected results from several studies may be explained by the children moving through pubertal stages. He also highlighted that, even if impaired glucose tolerance does not predict diabetes in children, it is still a cardiovascular risk factor and could conceivably predict diabetes in adulthood.
Also among today’s sessions were the late-breaking trials. These included presentations on a once-weekly human growth hormone treatment and new global consensus recommendations for managing nutritional rickets, and will be covered in more detail in our forthcoming newsletter.