Smoking and the Risk of LADA: Results From a Swedish Population-Based Case-Control Study

Abstract

OBJECTIVESmoking is an established risk factor for type 2 diabetes. In contrast, it has been proposed that smoking may reduce the risk of latent autoimmune diabetes in adults (LADA), but studies are scarce. We aimed to study the impact of smoking on LADA and type 2 diabetes risks. RESEARCH DESIGN AND METHODSWe used data from a Swedish case-control study including incident case patients with LADA (GAD antibody [GADA] positive, n = 377) and type 2 diabetes (GADA negative, n = 1,188) and control subjects randomly selected from the population (n = 1,472). We calculated odds ratios (ORs) with 95% CIs by logistic regression, adjusted for age, sex, BMI, family history of diabetes, and alcohol consumption. RESULTSThere was no indication of reduced risk of LADA in smokers; instead, heavy smoking was associated with an increased risk of LADA (OR 1.37, 95% CI 1.02-1.84). Heavy smokers had higher levels of HOMA of insulin resistance (9.89 vs. 4.38, P = 0.0479) and HOMA of b-cell function (55.7 vs. 42.5, P = 0.0204), but lower levels of GADA (75 vs. 250, P = 0.0445), compared with never smokers. Smokers also displayed an increased risk of type 2 diabetes (OR in ever smokers 1.53, 95% CI 1.25-1.88). CONCLUSIONSIn this large population of LADA patients, we did not observe a protective effect of smoking on autoimmunity and the risk of LADA. A protective effect could possibly be masked by a smoking-induced aggravation of insulin resistance, akin to the diabetogenic effect seen in individuals with type 2 diabetes.Smoking increases the risk of type 2 diabetes (1). This effect is exerted mainly through a decrease in insulin sensitivity (2). Knowledge about the impact of smoking on other forms of diabetes is limited. In a study based on the Norwegian HUNT study (3), we showed that smoking is associated with a reduced risk of latent autoimmune diabetes in adults (LADA). These findings fit with previous observations (4,5) in individuals with type 1 diabetes, indicating a reduced risk in the offspring of smoking parents. A suggested mechanism behind a protective effect could be the modulating effect of smoking/exposure to nicotine on immune response and an inflammatory process (6,7). The clinical impact of such a biological mechanism has been debated

Use of Swedish smokeless tobacco (snus) and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA)

“…We previously found a reduced risk of LADA in smokers and based on this we hypothesized that snus may be associated with an even more pronounced risk reduction, due to its high nicotine content. By contrast, data from ESTRID indicate that snus use is unrelated to the risk of LADA and furthermore, that heavy smoking may increase the risk . These findings are compatible with both negative and beneficial effects of nicotine on the pathogenesis of LADA and the lack of association with overall risk may reflect that a potential beneficial effect on autoimmunity is counterbalanced by increased insulin resistance.…”

“…Combining exposure from snus use and cigarettes showed that only smoking was associated with the risk of diabetes (Tables S2 and S3). In ESTRID, those who only smoke cigarettes (‘ever’) had increased risk (OR, 1.59; 95% CI, 1.16 to 2.18) of Type 2 diabetes (the details are reported elsewhere ), a risk that was even more pronounced in heavy smokers (OR, 2.20; 95% CI, 1.40 to 3.45); whereas no increased risk was seen in those who use only snus, or in those who combine snus use and smoking (Table S2). Similar findings were seen in HUNT; in those who only smoke, the OR for Type 2 diabetes was 1.63 (95% CI, 1.36 to 1.96) (Table S3).…”

Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes

“…There are no unified criteria for LADA diagnosis and classification, but the criteria used in ANDiU and ANDIS are in line with previous literature . The exception is fC‐peptide, which is used in ANDiU and ANDIS as an indicator of remaining insulin production to separate LADA from T1D . It replaces the insulin therapy criterion (i.e.…”

Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA)

“…In conclusion, having both T1D and T2D in the family is associated with the risk of LADA, and the strong association with FHD-T1D suggests that genes related to autoimmunity are more influential in the development of LADA than those related to T2D. Given this situation, it is noteworthy that, with regard to lifestyle, studies to date indicate that LADA shares several risk factors with T2D, including smoking [38], alcohol consumption (protective) [39] and low birth weight [40]. Taken together, these findings indicate that LADA development is promoted by genes related to autoimmunity and by lifestyle factors that increase insulin resistance.…”