So far, the ESTRID study has resulted in 12 scientific papers and two doctoral theses. We have studied the risk for LADA and type 2 diabetes in relation to heredity and lifestyle factors such as overweight, tobacco use, alcohol consumption and dietary factors. Below we give an overview of the results we have reached based on data collected in the study.
A six-fold increase in the risk for LADA is seen among people with a family history of type 1 diabetes, while a family history of type 2 diabetes doubles the risk. Heredity also seems to be an important factor for the risk of type 2 diabetes, where this type of diabetes in the family is associated with an almost three-fold risk to be affected (Hjort et al., 2017).
In the ESTRID study, we have looked at both birth weight and weight in adult age in relation to the risk of developing LADA and type 2 diabetes. Our results indicate that the risk for LADA and type 2 diabetes increases with overweight and obesity in adult age. Among people suffering from obesity, we saw a a three times increased risk for LADA and a 19 times increased risk for type 2 diabetes. The association between obesity and LADA was stronger among persons with a more type 2-like LADA but was also present among those with a more autoimmune, type 1-like diabetes. When we looked at overweight in combination with family history of diabetes, the risk for LADA increased 4,5 times while the risk for type 2 diabetes increased as much as 24,5 times compared to if these factors were not present (Hjort et al., 2018).
We have also seen that there seems to be an association between low birth weight and the risk of developing LADA (Hjort et al., 2015). The risk for LADA more than doubled among those with a birth weight of less than 3000 grams compared to those with a birth weight of more than 4000 grams. The same was observed for type 2 diabetes. Low birth weight in combination with overweight in adult age increased the risk for LADA three-fold while the risk for type 2 diabetes increased as much as 40 times!
There are different so-called genotypes associated with LADA and type 2 diabetes. In the ESTRID study, we have so far focused on risk variants of three genes, of which HLA is the one with the strongest association with LADA. Variants of the other two risk genes, TCF7L2 and FTO, are associated with a higher risk of type 2 diabetes and overweight/obesity respectively. We have seen that overweight in combination with a high-risk variant of HLA significantly increases the risk of developing LADA but that the risk is also increased in combinations of overweight and genotypes mainly associated with type 2 diabetes (TCF7L2) and overweight (FTO) (Hjort et al., 2019).
Alcohol and tobacco
We have seen that moderate alcohol consumption is associated with a lower risk of developing type 2 diabetes. The reason for this may be that alcohol makes the cells more sensitive to insulin. When it comes to LADA, this is a bit more complicated. Here we see that the risk for LADA with low levels of autoimmunity (more type 2-like LADA), decreases with moderate alcohol consumption, in the same way that we see for type 2 diabetes. However, this association is not seen with moderate alcohol consumption and the more autoimmune, type 1-like LADA, which is characterised by the immune system attacking the insulin producing cells (Rasouli et al., 2014).
We already know that there is an association between smoking and the risk for type 2 diabetes. In the ESTRID study we have studied whether this association also pertains for smoking and the risk for LADA (Rasouli et al., 2016). Results show that those who smoke one pack of cigarettes or more per day suffer an increased risk of developing LADA. When we looked separately at those with more or less autoimmune LADA we saw that there was only an association between smoking and the less autoimmune and more type 2-like variety of LADA. In this study we also confirmed an increased risk for type 2 diabetes in smokers. Next step is to see whether there is a genetic association between smoking and the risk for LADA and type 2 diabetes.
Regarding smokeless tabacco (snus), moist powder tobacco, we have not seen any associations with the risk for LADA or type 2 diabetes (Rasouli et al., 2017). However, more participants are required in order to obtain more reliable results. What is evident is that the results concerning tobacco and LADA are contradictory and more research is needed.
The first analyses based on data from the ESTRID study focused on dietary factors. We have seen that intake of fatty fish, such as salmon, seems to decrease the risk of developing LADA, but does not affect the risk for type 2 diabetes (Löfvenborg et al., 2014). One explanation to why intake of fatty fish may be associated with a decreased risk of LADA could be that it contains high levels of two omega-3 fatty acids, EPA and DHA, which have been proven to have positive effects on the immune system.
Earlier studies have indicated an association between coffee intake and a decreased risk for type 2 diabetes. This association has also been confirmed in the ESTRID study. In order to investigate whether this association also pertains for LADA, we have studied this in ESTRID (Löfvenborg et al., 2014). The results showed that coffee intake increased the risk for the more autoimmune and type 1-like LADA but contradictory to what might be expected, we saw no association between coffee intake and the less autoimmune, more type 2-like LADA. Since we currently don't know whether coffee intake contributes to the development of autoimmune diabetes this is an important question for the future.
Intake of sweetened beverages, such as sodas and lemonade, have been associated with an increased risk for type 2 diabetes. In the ESTRID study, we have shown that this association also seems to pertain to LADA (Löfvenborg et al., 2016). Consumption of two or more glasses of sweetened beverages per day doubled the risk for LADA compared to those who did not consume any sweetened beverages. We could see similar results for artificially sweetened beverages. We also confirmed the increased risk of type 2 diabetes when consuming sweetened beverages, including artificially sweetened beverages. .
We have also showed that the increased risk of LADA and type 2 diabetes in relation to sweetened beverage intake can be only partially explained by the intake contributing to overweight and obesity. It is likely that other mechanisms are involved in this association, of which the negative impact of sweetened beverages on insulin sensitivity might be one. Furthermore, our genes seem to be of importance for the risk of diabetes in relation to sweetened beverages. For those who were carriers of high-risk variants of genes associated with LADA and type 2, sweetened beverage intake seemed to be of less importance for the risk of diabetes than for those who were carriers of the low-risk genes. This difference was more pronounced for variants of the HLA genes, associated with autoimmunity, and the risk of LADA (Löfvenborg et al., 2019).
Earlier studies have reported an association between psychological stress such as depression or mental strain and type 2 diabetes. In the ESTRID study, we have studied short-term effects of psychological strain and the risk of developing LADA (Rasouli et al., 2017). Such stressful events include, among other things, divorce/separation, financial setbacks or illness or death in the family during the past five years. We have in this study not found any associations between such serious life events and the risk of developing LADA or type 2 diabetes.
Results in short
In conclusion, lifestyle factors seem to be of importance for the development of both LADA and type 2 diabetes. Known risk factors for type 2 diabetes, such as smoking, sweetened beverage intake, low birth weight, overweight and absence of moderate alcohol consumption, seem to increase the risk for LADA as well. At the same time, heredity is associated with LADA, just like it is associated with type 1 diabetes. More research is required in order to increase knowledge about the etiology of diabetes. Our next step is to study how lifestyle factors interact with genetics in the development of LADA and type 2 diabetes. Many lifestyle factors also remain to be investigated. New analyses on the collected data are performed continuously and we continue to recruit participants to the study. The more participants, the more detailed analyses we can perform. A larger study also enables more reliable results. Therefore, every individual who participates in the ESTRID study, case or control, is equally important and contributes to new knowledge about risk factors for LADA and type 2 diabetes.