Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes

Abstract

As the heterogeneity of diabetes is becoming increasingly clear, opportunities arise for more accurate assessment of factors influencing disease onset, which may lead to more efficient primary prevention. LADA - latent autoimmune diabetes in adults - is a common, hybrid form of diabetes with features of both type 1 and type 2 diabetes. This review aims to summarize current knowledge on the pathophysiological and etiological overlap and differences between LADA and type 2 diabetes, discuss similarities between LADA and type 1 diabetes and point at future research needs. Studies conducted to date show a clear genetic overlap between LADA and type 1 diabetes with a high risk conferred by variants in the human leukocyte antigen (HLA) region. In contrast, data from the limited number of studies on lifestyle factors available indicate that LADA may share several environmental risk factors with type 2 diabetes including overweight, physical inactivity, alcohol consumption (protective) and smoking. These factors are known to influence insulin sensitivity, suggesting that insulin resistance, in addition to insulin deficiency due to autoimmune destruction of the beta cells, may play a key role in the pathogenesis of LADA. Moreover, this implies that onset of LADA, similar to type 2 diabetes, to some extent could be prevented or postponed by lifestyle modification such as weight reduction and increased physical activity. The preventive potential of LADA is an important topic to elucidate in future studies, preferably intervention studies.

Keywords: LADA; epidemiology; lifestyle; prevention; type 2 diabetes.

FIGURE 1

Relative risk and 95% confidence interval for LADA and type 2 diabetes in relation to lifestyle factors. Results from ESTRID and HUNT studies. Estimates for low birth weight, sweetened beverages, coffee intake and fatty fish are based on data from the ESTRID Study (extracted from Löfvenborg et al., 2014, 2016; Hjort et al., 2015; Rasouli et al., 2018); estimates for BMI, smoking, physical activity and alcohol intake are based on pooled data from ESTRID and HUNT studies (extracted from Rasouli et al., 2013a,b, 2014, 2016; Hjort et al., 2018a,b); estimates for WHR is based on the HUNT Study (Hjort et al., 2018b).

FIGURE 2

Relative risk of LADA and type 2 diabetes (A), and LADA with high and low GADA levels (B) in relation to Body mass index.

FIGURE 3

Association between BMI and HOMA-IR in LADA and type 2 diabetes. The curved line represents results of a regression and the shaded surface represents 95% confidence intervals. Data from the ESTRID-study (data set described in Hjort et al., 2018b).

FIGURE 4

Association between BMI and GADA levels in LADA. The curved line represents results of a regression and the shaded surface represents 95% confidence intervals. Data from the ESTRID-study (data set described in Hjort et al., 2018b).

FIGURE 5

Etiology of LADA, model based on current knowledge.

FIGURE 6

Association between HOMA-IR and GADA levels in LADA. The curved line represents results of a regression and the shaded surface represents 95% confidence intervals. Data from the ESTRID-study (data set described in Hjort et al., 2018b).