Interplay between birthweight, family history, obesity, and genes in the development of latent autoimmune diabetes in adults (LADA) and type 2 diabetes

Diabetes is a chronic and serious public health concern affecting millions of people around the globe. For effective prevention understanding of modifiable risk factors is fundamental. For type 2 diabetes these risk factors are well-described. However, for autoimmune diabetes such as type 1 diabetes, information is essentially missing. LADA, latent autoimmune diabetes in adults is suggested to be a hybrid of type 1 and type 2 diabetes and despite being common, its risk factors are scarcely investigated. Thus, the aim of this thesis was to add new understanding to the aetiology of LADA in relation to birthweight, overweight, obesity, family history of diabetes (FHD) and genes as well as the interaction between these factors in relation to the risk of LADA and how this compares with type 2 diabetes. The analyses were based on data from two large population based studies: ESTRID, an ongoing case-control study from Sweden including incident cases of diabetes and randomly selected controls (≥35 years of age) and HUNT, a prospective study from Norway with incident cases of diabetes and 22 years of follow-up. LADA was defined by the criteria that age at initial diagnosis is at least ≥35 years old and glutamic acid decarboxylase antibody (GADA) positivity. In ESTRID LADA patients also had C-peptide levels indicating residual insulin secretion. Patients ≥35 years of age with GADA negativity were considered to have type 2 diabetes. Information on birthweight, body mass index (BMI kg/m2) and FHD was self-reported in ESTRID. In HUNT, information on BMI was collected at the baseline medical examination. Our results indicate that heredity is primarily linked to FHD of type 1 diabetes (Relative risk [RR] 5.75; 95% confidence interval [CI] 3.23-10.25) but is also associated with FHD of type 2 diabetes (RR 1.89; CI 1.45-2.47). Furthermore, our findings suggest that obesity (BMI ≥30) increases the risk of LADA 3-6 fold, although the risk was not as marked as for type 2 diabetes (10-19 fold increased risk). In line with this, the risk of LADA was greater in individuals with low GADA but present also among those with higher degree of autoimmunity. Notably, our analyses indicate that 31-56% of all LADA patients may be prevented by keeping a normal weight (BMI <25). The greatest risk of LADA was seen in those with overweight in combination with HLA genes associated with autoimmunity (RR 7.59, CI 5.27-10.93), with attributable proportion due to interaction (AP) estimated to 0.29 (CI 0.10-0.47). Additionally, type 2 diabetes risk genes interacted with overweight in relation to LADA; TCF7L2 (AP=0.31, CI 0.09-0.52) and FTO (AP=0.38, CI 0.15-0.61). Moreover, low birthweight was associated with a more than 2-fold increased risk of LADA and type 2 diabetes, with the strongest risk in those with low birthweight in combination with adult overweight; LADA, RR 3.26 (CI 1.69, 6.29); and type 2 diabetes, RR 39.93 (CI 19.27, 82.71). In conclusion, results from this thesis indicate that LADA is associated with risk factors linked to insulin resistance and type 2 diabetes while genetic susceptibility is linked foremost to genes associated with autoimmunity and type 1 diabetes. Importantly, our findings suggest that LADA in part may be prevented by keeping a healthy weight

Combined lifestyle factors and the risk of LADA and type 2 diabetes - Results from a Swedish population-based case-control study

Aims: We investigated the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes in relation to a healthy lifestyle, the proportion of patients attributable to an unhealthy lifestyle, and the influence of family history of diabetes (FHD) and genetic susceptibility. Methods: The population-based study included incident LADA (n = 571), type 2 diabetes (n = 1962), and matched controls (n = 2217). A healthy lifestyle was defined by BMI < 25 kg/m2, moderate-to-high physical activity, a healthy diet, no smoking, and moderate alcohol consumption. We estimated odds ratios (OR) with 95% confidence intervals (CIs) adjusted for age, sex, education, and FHD. Results: Compared to a poor/moderate lifestyle, a healthy lifestyle was associated with a reduced risk of LADA (OR 0.51, CI 0.34-0.77) and type 2 diabetes (OR 0.09, CI 0.05-0.15). A healthy lifestyle conferred a reduced risk irrespective of FHD and high-risk HLA genotypes. Having a BMI < 25 kg/m2 conferred the largest risk reduction for both LADA (OR 0.54, CI 0.43-0.66) and type 2 diabetes (OR 0.12, CI 0.10-0.15) out of the individual items. Conclusion: People with a healthy lifestyle, especially a healthy body weight, have a reduced risk of LADA including those with genetic susceptibility to diabetes. (C) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Overweight, obesity and the risk of LADA : results from a Swedish case-control study and the Norwegian HUNT Study

Aims/hypothesis Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies. Methods Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case-control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984-2008). We present adjusted ORs and HRs with 95% CI. Results In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA; Conclusions/interpretation Overweight/obesity is associated with increased risk of LADA, particularly when in combination with FHD. These findings support the hypothesis that, even in the presence of autoimmunity, factors linked to insulin resistance, such as excessive weight, could promote onset of diabetes.Peer reviewe

Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes

Objective: We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods: We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI >= 25 kg/m(2)) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP). Results: The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO. Conclusions: Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.Peer reviewe

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes

Purpose: Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 ( TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609. Methods: We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (>= 30 minutes of moderate activity 3 times/ week) self-reported leisure time PA, compared to sedentariness. Results: High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype. Main Conclusions: Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.Peer reviewe

Cockpit and the battle against fatigue : a qualitative interview study

Sammanfattning Syfte och frågeställningar Det primära syftet med denna studie är att belysa hur piloter upplever att kommunikationen i cockpit påverkas av trötthet. Vårt sekundära syfte är att ge exempel på vad piloterna gör för att motverka trötthet under arbetet.  Hur påverkas piloternas kommunikationsförmåga under trötthet? Hur påverkas kommunikationen mellan piloterna under trötthet? Vilka strategier använder piloterna för att minska tröttheten under flygningar; både förebyggande, livsstilsrelaterade strategier samt direkta åtgärder?   Metod För att få en nyanserad bild av hur piloterna upplever att tröttheten påverkar kommunika-tionen dem emellan samt vilka strategier de använder sig av för att minska tröttheten under flygningen ansågs en kvalitativ ansats med semistrukturerade intervjuer vara den lämpligaste datainsamlingsmetoden. Sex intervjuer med manliga piloter mellan 31 och 37 år genom-fördes. Resultat Studiens resultat följer det nuvarande forskningsläget. Samtliga piloter upplevde att tröttheten hade en negativ inverkan på kommunikationsförmågan samt kommunikationen dem emellan. Detta leder i sin tur till missförstånd och ökar risken för olyckor. Under flygningarna finns väl utarbetade strategier som piloterna använder sig av för att bli piggare. Den främsta förebyggande strategin är planering av vila. Däremot fanns ingen tydlig fokus på kost och fysisk aktivitet. Slutsats För att öka medvetenheten, möjligheten samt motivationen till en hälsosammare livsstil med syfte att minska tröttheten under arbetet, bör ett preventivt tankesätt först och främst grund-läggas inom flygbranschen. Ett första steg dit kan vara att ta de föreslagna schema-regleringarna från SubpartQ-utvärderingen på allvar.Abstract Aim The primary aim with this study is to illustrate how communication in cockpit interacts with fatigue according to the pilots’ experience. The secondary aim with the study is to exemplify what the pilots do to prevent fatigue during work.  What effect does fatigue have on pilots’ ability to communicate? How does fatigue affect the communication between the pilots? Which strategies do the pilots use in order to decrease fatigue during flights; both preventive, lifestyle-related strategies and direct actions?   Method To get a nuanced picture of how fatigue affects communication and which strategies the pilots use in minimizing the effects of fatigue on communication, a qualitative method with semi-structured interviews was chosen as the most suitable method for the collection of data. Six interviews with male pilots between 31 and 37 years were carried out. Results The result of this study follows the current research situation. All pilots experienced that fatigue had a negative effect on the ability to communicate and having communication between them. This leads to miscommunication and increases the risk for accidents. Established strategies during flights exist for the pilots to use in order to stay alert. The main preventive strategy is planning the rest, but no clear focus on nutrition and physical activity could be found. Conclusions In order to increase awareness, possibility, and motivation for a healthier lifestyle with purpose to decrease fatigue during work, should a preventive attitude first of all be implemented in aviation. A first step could be taking the suggested regulations in scheduling from the SubpartQ-evaluation seriously

Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case-control study

Aims/hypothesis Our aim was to investigate the association between birthweight and latent autoimmune diabetes in adults (LADA), a common diabetes form with features of both type 1 and type 2 diabetes. Methods We used data from the Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes (ESTRID), a Swedish population-based study. Eligible for the analysis were 134 incident LADA cases (glutamic acid decarboxylase antibody [GADA] positive), 350 incident type 2 diabetes cases (GADA negative) and 603 randomly selected controls. We present ORs and 95% CIs for LADA and type 2 diabetes in relation to birthweight, adjusted for sex, age, BMI and family history of diabetes. Results Low birthweight increased the risk of LADA as well as the risk of type 2 diabetes; OR per kg reduction was estimated as 1.52 (95% CI 1.12, 2.08) and 1.58 (1.23, 2.04), respectively. The OR for participants weighing = 4 kg at birth was estimated as 2.38 (1.23, 4.60) for LADA and 2.37 (1.37, 4.10) for type 2 diabetes. A combination of low birthweight (= 25) further augmented the risk: LADA, OR 3.26 (1.69, 6.29); and type 2 diabetes, OR 39.93 (19.27, 82.71). Family history of diabetes had little impact on these estimates. Conclusions/interpretation Our results suggest that low birthweight may be a risk factor for LADA of the same strength as for type 2 diabetes. These findings support LADA, despite its autoimmune component, having an aetiology that includes factors related to type 2 diabetes

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes

Purpose Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609. Methods We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness. Results High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype. Main Conclusions Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility