The streetlight effect in type 1 diabetes

Abstract

In the nearly 100 years since the discovery of therapeutic insulin, significant research efforts have been directed at finding the underlying cause of type 1 diabetes (T1D) and developing a "cure" for the disease. While progress has clearly been made toward each of these goals, neither vision has been fulfilled. With increasing pressure from both public and private funders of diabetes research, growing impatience of those with T1D at the lack of practical discoveries, increased competition for research funds, uncertainties on the reproducibility of published scientific data, and questions regarding the value of animal models, the current research environment has become extraordinarily difficult to traverse from the perspective of investigators. As a result, there is an increasing pressure toward performance of what might be considered "safe" research, where the aim is to affirm existing dogmas rather than to pioneer efforts involving unconventional thought. Psychologists refer to this practice as "observational bias" while cartoonists label the process the "streetlight effect." In this Perspective, we consider notions in T1D research that should be subject to bold question and provide additional concepts, many somewhat orphan to research efforts, whose investigation could lead to a means for truly identifying the cause of and a cure for T1D.

Figure 1

The streetlight effect. In June 1942, a version of the streetlight effect appeared in a popular syndicated comic strip, Mutt & Jeff. Three of the five panels in the strip are shown. The gentleman in the top hat is Jeff, and in the final omitted panel the officer joins Jeff in the search beneath the streetlight (1).

Figure 2

The pathogenic basis of β-cell destruction in T1D. Shown are models ascribing the key immunological facets relevant to the destruction of β-cells that result in T1D, considered contemporaneous “state of the art,” based on established literature in (A) 1992 and (B) 2007. Reproduced from Mackay (3) and Roncarolo and Battaglia (4), with permission.

Figure 3

Underinvestigated areas of T1D research due to the streetlight effect. At least eight features, be they pathogenic, immunologic, physiologic, or metabolic, appear to be misunderstood or underappreciated in T1D. The features described within these domains form key areas for research moving forward, when attempting to understand the pathogenesis of this disorder.

Figure 4

Key physiological features, with varying degrees of distinctiveness, that have potential relevance to the pathogenesis of T1D. Indicated (insert) are facets that have been ascribed to the pancreas in T1D, with key anatomical features noted within the illustration. Figure adapted, with permission, from the Yale University Office of Digital Dissemination.

Figure 5

The “classic” model ascribing the natural history of what we now refer to as T1D. Reproduced from Atkinson et al. (26), with permission.

Figure 6

Three key facets of β-cells relevant to the pathogenesis of T1D. Based on a growing body of literature, the quantity of β-cell mass present in early life (i.e., first 1–2 years) is a potential early indicator of both the risk for T1D as well as the time to disease onset. A second feature, the aggressiveness of β-cell loss, is a notion influenced by a combination of genetically or environmentally driven susceptibility of β-cells to their demise, their functional activity, and their resistance to destructive efforts imparted by the immune system. The third facet is that of the mass of β-cells required to avert the symptomatic onset of T1D. Rather than the classic “fixed percentage” so often thought of (i.e., 85–95%), a relatively wide range is a far more likely scenario, influenced by the degree of β-cell loss, quantity of functional β-cell mass, anthropometric factors (e.g., age, sex), and the aggressiveness of the self-directed immune response. Also key to this model is an embedded “stress test” hypothesis for T1D. Building on the three key quantitative facets of β-cell form and function, the quantity of β-cells present in early life represents a key agent of influence for the development of T1D. Specifically, in situations of limited (i.e., reduced) β-cell mass, this physiological setting creates de novo, a degree of stress that promotes a more rapid progression to overt T1D, independent of or beyond the need for additional environmental triggers. The figure was developed, in part, with intellectual contributions from Richard Insel, JDRF, and Alvin Powers, Vanderbilt University.