Excess weight and the risk of type 1 diabetes

Yes, but in a more nuanced way than in type 2 diabetes. Type 1 diabetes is an autoimmune disease, in which the immune system destroys the beta cells in the pancreas, and weight is not the cause of this attack. Nonetheless, excess weight acts as an accelerator. It can influence both the moment when autoimmunity appears and the speed with which the disease later progresses towards the clinical form [1].

Weight thus intervenes at two different moments. First, in the child at the beginning of the autoimmune process (with a single autoantibody), where excess weight can, under certain conditions, increase the risk of developing two or more autoantibodies. In the child who already has multiple autoantibodies (stage 1), excess weight hastens the passage through the stages of the disease, from stage 1 to stage 2 and then to clinically manifest diabetes. Of all the factors that influence this disease, weight is the only one we can, at least in theory, modify.

In the child who already has a single islet autoantibody, excess weight above the 85th percentile (the definition of overweight in children) is associated with an increased risk of progressing towards multiple islet autoantibodies, that is, towards confirmed islet autoimmunity (in the absence of HLA risk genes). Data from the TrialNet cohort showed that, in children over 9 years of age with a single autoantibody and without high-risk HLA genes, excess weight increased this risk more than sevenfold. This is a magnitude comparable to that brought by the HLA risk genes themselves. In practice, in these children weight “weighs” as much as genetics [2].

It is essential, however, to understand that this effect appears only in children who do not carry HLA risk genes. In the presence of HLA risk genes, excess weight adds no further risk of autoimmunity appearing. Excess weight matters most exactly where genetics protects you. When the risk genes are absent, the metabolic factor takes over the baton, in a way.

The explanation lies in the way risk factors combine. HLA risk genes are a powerful “engine” of autoimmunity. When they are present, they push the risk so high that a milder factor, such as excess weight, has nothing significant left to add. The risk is capped [3].

By contrast, in children without HLA risk genes, this genetic “engine” is missing, and the background risk is lower. Here, excess weight becomes the factor that can make the difference and that can tip the balance towards the appearance of confirmed islet autoimmunity (the passage from a single autoantibody to multiple autoantibodies). This is the reason why studies observe the effect of weight on the appearance of autoimmunity precisely in the genetically protected subgroup. This is a clear example of an interaction between genetics and metabolism.

The accelerator hypothesis was proposed by Terence Wilkin in 2001 and provides the framework through which we understand the role of weight in the appearance of type 1 diabetes. It describes three “accelerators” that press, simultaneously, on the same beta cell and push it towards death (also called apoptosis): the genetically determined rate of apoptosis, autoimmunity (the immune attack on the beta cell) and insulin resistance, linked to obesity and to a sedentary lifestyle.

The idea is that insulin resistance, which we usually associate with type 2 diabetes, is placed directly within the mechanism by which type 1 diabetes appears. Once autoimmunity has appeared (2+ autoantibodies), excess weight accelerates the loss of beta cells against any genetic background and represents a common link between the two types of diabetes [4].

The mechanism is, in essence, metabolic. Excess weight generates insulin resistance, that is, a state in which the tissues respond more weakly to insulin. To keep blood glucose normal, the body demands more insulin, and the beta cells are forced to work “overtime”, increasing their production.

The problem is that, in type 1 diabetes, these beta cells are already under siege by the immune system. A cell that is overworked and, at the same time, under attack gives way more quickly. When the beta cells are forced to secrete more, they make more noise in the process and are thus more irritating to the immune system, which hears them better. The net result is an accelerated functional decline of the beta cell mass and an earlier clinical onset of diabetes [5]. The same destination, but with progression through the presymptomatic stages at different speeds.

No. The effect is not uniform. Viewed across the entire population of at-risk children, the association between weight and the appearance of autoimmunity can become weak or even statistically non-significant. The strong signal stimulating the appearance of autoimmunity appears in a specific subgroup. This subgroup is made up of children over 9 years of age, without high-risk HLA genes, exactly those in whom, in the absence of a powerful genetic engine, the metabolic factor becomes decisive [2].

A persistently raised body mass index is associated with a risk of progression from stage 1 to stage 3 that is roughly 63% higher, and for each kilogram per square metre of cumulative excess weight the risk increased by about 6%, independently of whether the HLA risk genes are present or not [1]. The threshold from which weight becomes risky for progression is lower in children under 12 years, and in girls the effect can appear even before a child is officially considered overweight. In other words, the harmful effect of weight can begin before the “overweight” label formally applies.

First of all, early detection of type 1 diabetes, that is, in stage 1, must be ensured. Children at risk (those who have first-degree relatives with type 1 diabetes or an increased genetic risk) should be tested for the presence of islet autoantibodies. Those with two or more positive autoantibodies should be investigated further to see whether or not their blood glucose levels are normal. Type 1 diabetes can thus be recognised long before symptoms appear [6].

Next comes maintaining a healthy weight, as an adjuvant measure, with a maximum benefit theoretically in children without high-risk HLA genes. These children with type 1 diabetes who are in the presymptomatic stages should be referred to a centre with experience in the treatment of type 1 diabetes. In a child over 8 years of age with confirmed stage 2, it is useful to discuss, in a specialised centre, the therapies that modify the course of the disease, such as teplizumab. The family doctor or paediatrician does not decide everything, but is the one who opens the door to these options [7].