Introduction

Latent autoimmune diabetes in the adult (LADA) is a common form of diabetes [1], yet the risk factors are poorly characterised. Age, overweight and physical inactivity are important risk factors for type 2 diabetes by way of increasing insulin resistance. Whether these factors also increase the risk of LADA is unclear. Previous studies based on cross-sectional data report patients with LADA being younger and less obese than type 2 diabetes subjects [2] or find these variables to be similar to type 2 diabetes [3]. To the best of our knowledge, it has not been investigated whether and to what extent age and obesity influence the risk of LADA. The reason is probably that there are few prospective studies where incident cases of LADA can be separated from cases of type 1 and type 2 diabetes.

The Nord-Trøndelag health survey is a large, population-based, prospective study where incident cases of diabetes were classified according to clinical history and presence or absence of anti-GAD antibody. In this cohort, we investigated the association between age, overweight and physical inactivity on the one hand and the cumulative incidence (risk) of LADA, type 1 diabetes and type 2 diabetes on the other, during an 11-year follow-up.

Subjects and methods

Nord-Trøndelag health study

From 1984 to 1986, all inhabitants of the Norwegian county of Nord-Trøndelag who were aged 20 years or older were invited to take part in the Nord-Trøndelag Health Study (HUNT1) (n = 85,100) [4, 5]. The survey featured a clinical examination, including measurements of height, weight and blood pressure, and questionnaires with questions on current health, diabetes and lifestyle factors such as smoking, alcohol consumption, physical activity and psychosocial conditions. Of those invited, 90.3% participated (n = 76,885).

Between 1995 and 1997 a second, similar health survey (n = 92,703) was conducted in Nord-Trøndelag (HUNT2), again including all subjects aged 20 years or older. The overall response rate in this follow-up investigation was 71.3% (n = 65,258).

From both of these investigations data are available for a cohort of 38,800 men and women, who were free of diabetes at baseline (i.e. at the time of the first health survey between 1984 and 1986) and for whom baseline information on age, BMI and smoking was available.

The regional Ethical Committee and the Norwegian Data Inspectorate approved these studies. All participants gave informed consent.

BMI and physical activity

Based on measures of height and weight from the baseline investigation we calculated BMI as kg/m2. Physical activity was measured by the question ‘How often do you exercise?’ with five response options ranging from ‘never’ to ‘every day’. Information on current and previous smoking was used to classify subjects as never, former and current smokers.

Identification of diabetes cases

The follow-up questionnaire identified 1,130 incident cases of diabetes. These subjects were given an appointment to have their fasting blood glucose measured together with levels of C-peptide and anti-GAD antibody. On this occasion information on treatment was also collected. Altogether 858 (76%) patients completed this investigation.

Patients starting insulin treatment within 6 months of diagnosis were classified as having type 1 diabetes, if, in addition, they were anti-GAD positive or had fasting C-peptide levels <150 pmol/l (n = 18). Patients were classified as having LADA if they were anti-GAD positive and had not been treated with insulin within 12 months of diagnosis (n = 81). Type 2 diabetes cases were anti-GAD negative and without insulin treatment within 1 year of diagnosis (n = 738). In addition we classified three cases as gestational diabetes, three cases as maturity-onset diabetes of the young and one case as having NGT. Fourteen cases were determined unclassifiable because they did not fit into any of the above mentioned categories.

Biochemical analysis

Anti-GAD and fasting C-peptide were analysed at the Hormone Laboratory of Aker University Hospital, Oslo. Anti-GAD was analysed by an immunoprecipitation radioligand assay based on a previously validated method [6]. The level of GAD antibodies was expressed as an index value relative to a standard serum. From the start of the assay in 1995, an index value >0.08 was considered positive. At this cut-off level, sensitivity was 0.64 and specificity 1.00.

Statistical analysis

To analyse the association between baseline age, physical activity and overweight and incident LADA, type 1 and type 2 diabetes, we calculated odds ratios together with 95% CIs using multiple logistic regression analysis (Proc Logistic, SAS/STAT; SAS Institute, Cary, NC, USA). Categorical variables (age, BMI, physical activity and smoking) were included as dummy variables in the regression model. Age and BMI were also analysed continuously and included in their original form in the regression model. Confounding was adjusted for by inclusion of age, sex, BMI and smoking in the regression model (see footnotes to Table 1). The odds ratios are referred to as relative risks (RRs), since the incidence of diabetes during the follow-up was low enough to allow such an approximation.

Table 1 Baseline age, BMI and physical activity and the RR of type 2 diabetes, LADA and type 1 diabetes
Full size table

We calculated attributable proportions (APs) to estimate the proportion of disease that could be attributed to overweight. This was calculated as ([RR - 1]/RR)×f where f is the proportion of exposed cases. CIs for the crude AP were calculated with the formula suggested by Fleiss [7].

Results

The risk of LADA and type 2 diabetes increased progressively with age (Table 1). After adjustment for sex, BMI and smoking, subjects ≥60 years at baseline had an approximately six times increased risk of developing LADA and type 2 diabetes during the 11-year follow up compared with subjects aged 18–39 years. Such an association with age was not found for type 1 diabetes.

Baseline overweight was associated with an increased risk of LADA and type 2 diabetes but not of type 1 diabetes (Table 1). BMI ≥30 kg/m2 was associated with a 15 times increased risk of LADA and type 2 diabetes after adjustment for age, sex and smoking. The AP of LADA and type 2 diabetes associated with overweight (BMI ≥25.0 kg/m2) was 75.8% (95% CI 58.1–86.0) and 77.2% (95% CI 73.9–80.2), respectively. If we used the adjusted RR, the AP was slightly lower (70.6% [LADA] and 73.5% [type 2 diabetes]).

Subjects who at baseline reported that they never exercised were twice as likely to develop type 2 diabetes and three times more likely to develop LADA during the 11-year follow-up compared with subjects who exercised every day. When the analyses were adjusted for BMI, the association was attenuated but those who reported that they never exercised still displayed an increased risk of type 2 diabetes (RR = 1.35, 95% CI 1.00–1.82) and a non-significantly increased risk of LADA (RR = 2.01, 95% CI 0.74–5.45).

Discussion

This study suggests that increased age, overweight and physical inactivity are as strong risk factors for LADA as for type 2 diabetes. These findings have important public health implications since they imply that LADA to a large part is influenced by environmental factors and hence preventable. In our population, 70% of the cases of LADA could be attributed to overweight. If these results are confirmed in other populations they imply that we can expect increasing rates of LADA to result from the current obesity epidemic and demographic transition.

Age, BMI and physical inactivity have been shown to increase the risk of type 2 diabetes primarily by way of insulin resistance. The association that we see between these factors and LADA suggests a role for insulin resistance in the development of LADA. This would fit with the accelerator hypothesis, which states that insulin resistance participates in the development of autoimmune diabetes [8]. This does not necessarily mean equal insulin resistance in LADA and type 2 diabetes, since insulin secretion is reportedly lower in LADA [3]. In this context it should be mentioned that evaluation of fasting C-peptide levels in our cohort is difficult due to influence of treatment and diabetes duration.

The concept of LADA is ambiguous. The controversy primarily concerns whether it can be viewed as a separate form of diabetes or rather a mild form of type 1 diabetes [9]. With regard to the aetiological differences between type 1 diabetes, type 2 diabetes and LADA we have previously found that smoking is associated with a reduced risk of LADA and type 1 diabetes but an increased risk of type 2 diabetes [10]. In contrast, the results of the present study indicate that with regard to age, BMI and physical inactivity there is a similarity between LADA and type 2 diabetes. Hence, these two studies suggest that LADA shares risk factors with both type 2 diabetes and type 1 diabetes. These findings support a role for insulin resistance in the pathogenesis of LADA.