The Influence of Type 2 Diabetes-Associated Factors on Type 1 Diabetes

Abstract

Current efforts to prevent progression from islet autoimmunity to type 1 diabetes largely focus on immunomodulatory approaches. However, emerging data suggest that the development of diabetes in islet autoantibody-positive individuals may also involve factors such as obesity and genetic variants associated with type 2 diabetes, and the influence of these factors increases with age at diagnosis. Although these factors have been linked with metabolic outcomes, particularly through their impact on β-cell function and insulin sensitivity, growing evidence suggests that they might also interact with the immune system to amplify the autoimmune response. The presence of factors shared by both forms of diabetes contributes to disease heterogeneity and thus has important implications. Characteristics that are typically considered to be nonimmune should be incorporated into predictive algorithms that seek to identify at-risk individuals and into the designs of trials for disease prevention. The heterogeneity of diabetes also poses a challenge in diagnostic classification. Finally, after clinically diagnosing type 1 diabetes, addressing nonimmune elements may help to prevent further deterioration of β-cell function and thus improve clinical outcomes. This Perspectives in Care article highlights the role of type 2 diabetes-associated genetic factors (e.g., gene variants at transcription factor 7-like 2 [TCF7L2]) and obesity (via insulin resistance, inflammation, β-cell stress, or all three) in the pathogenesis of type 1 diabetes and their impacts on age at diagnosis. Recognizing that type 1 diabetes might result from the sum of effects from islet autoimmunity and type 2 diabetes-associated factors, their interactions, or both affects disease prediction, prevention, diagnosis, and treatment.

Figure 1

Postulated model for the relative contributions of autoimmune and nonimmune pathogenic mechanisms to the glucose levels observed in various settings. Individuals with classic type 1 diabetes (T1D) usually present with extreme hyperglycemia and autoimmune destruction of β-cells as the main pathogenic mechanisms. Individuals with only mild autoimmunity (e.g., positive for a single autoantibody) may exceed the glycemic threshold for diabetes in the presence of additional diabetogenic factors, such as type 2 diabetes (T2D)–associated TCF7L2 gene variants, other T2D-associated mechanisms (e.g., insulin resistance), or both. Individuals with classic T2D may exceed the glycemic threshold for diabetes because of the combination of genetic (e.g., TCF7L2 gene) and other (e.g., insulin resistance) mechanisms. Individuals with islet autoantibody positivity (Ab+) in the early stages do not exceed the diabetes threshold, but their glucose may be higher than that in control individuals. Similarly, individuals who carry the T2D-associated TCF7L2 genetic variant have higher glucose than controls but may not exceed the glycemic threshold for diabetes if they lack other risk factors. N.O., new onset.

Figure 2

Hypothesis of the role of type 2 diabetes (T2D) factors in the pathogenesis of type 1 diabetes (T1D). Compared with individuals with high-risk factors for T1D (e.g., multiple positive islet autoantibodies) (A), those with low-risk factors (e.g., single islet autoantibody positivity) (B) have low rate of progression to T1D and most of them never develop diabetes. However, the presence of T2D factors can accelerate progression to diabetes in at least three ways (C and D). Firstly, the balance between insulin needs and insulin secretion that maintains euglycemia (horizontal red line) could be altered by insulin resistance induced by obesity and/or T2D-associated TCF7L2 genetic variants. Secondly, T2D-associated TCF7L2 SNPs and obesity can accelerate the rate of progression to T1D (yellow slope) by increasing the risk of conversion from single to multiple autoantibody positivity. Finally, β-cell function before the start of the autoimmune destruction of β-cells could be decreased because of T2D-associated genetic variants (start of the horizontal segment in yellow line on the y-axis). Although T2D factors could be present in individuals with high T1D risk factors (C) and accelerate their onset of clinical disease, the relative effect of T2D factors in these individuals is small because of the overwhelming aggressivity of their β-cell destruction. In comparison, in individuals with low risk T1D factors (D), T2D factors are decisive in their progression to diabetes.

Figure 3

Postulated model for the relative proportions of autoimmune and nonimmune factors, by age at presentation, in individuals with autoimmune diabetes. Aggressive autoimmune destruction of β-cells is the main cause of type 1 diabetes in young children. Older youth may have milder islet autoimmunity, but the addition of (or interaction with) nonimmune factors (e.g., puberty-induced insulin resistance) can cause progression to diabetes. As age advances, the relative proportion of autoimmune factors is smaller (because islet autoimmunity tends to be milder), and thus nonimmune factors (e.g., type 2 diabetes–associated TCF7L2 gene variants, obesity-induced mechanisms) contribute to diabetes in individuals who develop clinical disease. The autoimmune component is minimal in older individuals, and most of their diabetes has a nonimmune origin.