Brakes on the accelerator: the journey of accelerator hypothesis from “the missing link” to “an evolving concept”

CONTEXT

The accelerator hypothesis (AH) proposed by the late Prof Terence Wilkin attempts to unite the type 1 (T1D) and type 2 diabetes (T2D) by obesity driven insulin resistance (IR) and tends, in part, to explain the rising incidence of T1D by a parallel increase in the incidence of obesity.¹ Since its inception in 2001, several studies have been conducted across the world to test the validity of AH. The results of these studies have shown considerable variability with some studies confirming and others refuting or showing neutrality to the key proposals of AH. This brief communication discusses the journey of AH over the last 16 years in the light of data accumulated from studies that aimed to test relevance and applicability of AH in diverse patient populations.

KEY PREDICTIONS AND CONTROVERSIES

The AH proposes that all the three processes or accelerators i.e. IR, autoimmunity and genetic predisposition that result in presentation of diabetes (either type 1 or 2) are driven by excess weight gain, which is thought to be “the missing link” between the two types of diabetes.¹ In particular, IR associated with recent weight gain is considered the main accelerator of pancreatic β-cell apoptosis that leads to earlier onset of T1D in individuals at genetic risk. The acceleration of diabetes and its presentation at a younger age will, therefore, occur in populations with increasing prevalence of obesity. In relation to childhood diabetes, the two key predictions of AH are that children who develop T1D should be heavier before onset than their peers who do not, and the heavier children should develop diabetes at a younger age.¹ The first prediction has a firm basis in several reports that linked heavier weight in infancy and early childhood to development of T1D.^2,3 However, the second prediction has always remained a matter of debate since the hypothesis was originally proposed in 2001. In the first few years following the hypothesis proposal, 4 studies (Table 1, nos. 1-4) where age at onset of T1D was shown to be inversely related to BMI, supported this prediction. However the support has been dwindling with only three studies over the past decade supporting the AH (Table 1, nos. 10, 11, 17). Simultaneously, the emergence of new data from several independent cohorts during the past decade (Table 1, nos. 5-9, 12-16) has shown no support for AH. The UK study that included Asian children who are generally considered to have greater IR than white children and hence expected to present earlier with T1D, as the hypothesis would predict, was the first one that refuted the hypothesis.⁴ Our own study conducted in an ethnically different patient population and aimed at testing the AH in a developing country setup, demonstrated no association between BMI and age at diagnosis.⁵ This was despite the fact that the prevalence of overweight and obesity in children has shown a significant average increase of 3% in our country during the time frame of our study.^6,7 Furthermore, the incidence of T1D at our hospital has also shown a significant increase over a similar time span.⁸ Similar observations have been made in other studies that refute one of the key predictions of AH (Table 1, nos. 5-9, 12-16).

The AH considers that the two types of diabetes lie at different points of the same spectrum and differ only with respect to the tempo of development of IR which is largely determined by obesity.¹ The development of islet autoimmunity is regarded as secondary to the obesity driven IR postulating that increasing BMI may have an association with risk of development of islet autoimmunity in susceptible individuals.¹ However, the recent data in this regard also has shown variable conclusions. The TEDDY Study Group that explored the relationship between childhood growth and development of islet autoimmunity during the first 4 years of life in 7,468 children at genetic risk for T1D suggested that greater weight was associated with an increased risk of islet autoimmunity and progression to T1D.⁹ A similar study on 1,117 children in the TrialNet pathway to prevention (PTP) cohort (autoantibody-positive relatives of patients with T1D) also showed a positive association of elevated BMI with risk of diabetes progression in autoantibody-positive relatives, but the effect varied by sex and age.¹⁰ However, another study on the TrialNet PTP cohort could not find any significant relationships between BMI, weight status or HOMA1-IR and progression from one to multiple autoantibodies and progression to diabetes in 1,310 single and 1,897 multiple Aab-positive PTP participants, thus negating a broad influence of metabolic variables on diabetes risk.¹¹ Studies on the BABYDIAB cohort also did not find any influence of BMI on islet autoantibody seroconversion indicating that obesity driven IR is not a risk factor for islet autoimmunity.¹² Thus the influence of increasing BMI on progression of islet autoimmunity or progression to diabetes in susceptible populations, too, remains controversial. In other words, the prediction of AH that weight gain accelerates the presentation of T1D may not be relevant in diverse patient populations. Overall, the number of “accelerators” (studies supporting AH) have been fewer as compared to “brakes” (studies that do not support AH) in the 16 year long journey of AH.

THE FUTURE OF AH

At the time when the AH was raised, it seemed plausible as it offered an easy explanation for the rising incidence of T1D as secondary to the global increase in rates of childhood obesity. However, in view of the evidence accumulated over the past decade, weight gain reflected in the BMI z-scores at diagnosis of T1D, appears to contribute only a small fraction to the increasing incidence of T1D. In a review article, Prof Terence Wilkin, the proposer of the hypothesis, acknowledged that AH is still “an evolving concept”.¹³ In his own words, “If the AH is to progress beyond speculation, it will be necessary to demonstrate that β-cell loss is slowed (and the incidence of T1D reduced) by protecting the cell against stress, and that β-cell stress is indeed the mechanism that drives the immune response that we call autoimmunity”.¹³ In this regard, the currently recruiting adAPT1 (autoimmune diabetes accelerator prevention trial) study in UK in which children at high risk of T1D (double antibody positive) will receive metformin for five years in order to establish whether β-cell protection can reduce the incidence of diabetes, may truly test the AH.¹⁴ Prof Wilkin believed that a successful outcome of adAPT will lead to a safe, cheap and universal approach to the prevention of T1D probably hinting at the strategies for obesity reduction.^13,14 But what if the results of the adAPT are negative or inconclusive? Will the AH lose its relevance? Probably not. The hypothesis may still remain worth consideration in certain ethnic patient populations of T1D. The recent study from Kuwait does indicate that ethnic differences in patient populations may explain the association between BMI and age at diagnosis.¹⁵ In order to truly test the relevance of AH, there is a need to conduct prospective worldwide studies in ethnically diverse patient populations with a focus similar to adAPT. That will be a true tribute to a legend who sought to challenge some of the major doctrines in endocrinology during his lifetime.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Wilkin TJ. The Accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia. 2001;44:914-22.
2. 2. Johansson C, Samuelsson U, Ludvigsson J. A high weight gain in early life is associated with an increased risk of type 1 (insulin-dependent) diabetes. Diabetologia. 1994;37:91-4.
3. 3. Lammi N, Moltchanova E, Blomstedt PA, Tuomilehto J, Eriksson JG, Karvonen M. Childhood BMI trajectories and the risk of developing young adult-onset diabetes. Diabetologia. 2009;52:408-14.
4. 4. Porter JR, Barrett TG. Braking the accelerator hypothesis? Diabetologia. 2004;47:352-3.
5. 5. Dayal D, Samprathi M, Jayaraman D, Kohat D, Bhalla AK. Secular trends of body mass index in North Indian children with Type 1 diabetes do not support the Accelerator Hypothesis. Clin Endocrinol (Oxf). 2016;84:338-41.
6. 6. Ranjani H, Mehreen TS, Pradeepa R, Anjana RM, Garg R, Anand K, et al. Epidemiology of childhood overweight & obesity in India: A systematic review. Indian J Med Res. 2016;143:160-74.
7. 7. Dayal D, Jain H, Attri SV, Bharti B, Bhalla AK. Relationship of High Sensitivity C-Reactive Protein Levels to Anthropometric and other Metabolic Parameters in Indian Children with Simple Overweight and Obesity. J Clin Diagn Res. 2014;8:PC05-8.
8. 8. Dayal D, Saini AG, Jayashree M, Singhi S, Kumar R, Samprati M, Singh M. Hospital based incidence, patterns of presentation and outcome of Type 1 diabetes: 12 years’ data from a tertiary care center in North India. Int J Diabetes Dev Ctries. 2015;35:103–7.
9. 9. Elding Larsson H, Vehik K, Haller MJ, Liu X, Akolkar B, Hagopian W, et al. Growth and Risk for Islet Autoimmunity and Progression to Type 1 Diabetes in Early Childhood: The Environmental Determinants of Diabetes in the Young Study. Diabetes. 2016;65:1988-95.
10. 10. Ferrara CT, Geyer SM, Liu YF, Evans-Molina C, Libman IM, Besser R, et al. Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development? Diabetes Care. 2017;40:698-701.
11. 11. Meah FA, DiMeglio LA, Greenbaum CJ, Blum JS, Sosenko JM, Pugliese A, et al. The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants. Diabetologia. 2016;59:1186-95.
12. 12. Winkler C, Marienfeld S, Zwilling M, Bonifacio E, Ziegler AG. Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes? Diabetologia. 2009;52:2072-8.
13. 13. Wilkin TJ. The accelerator hypothesis–an evolving concept. Facta Universitatis, Series: Medicine and Biology 2015;17:49-53.
14. 14. Wilkin T, Greene S, McCrimmon R. Testing the accelerator hypothesis: a new approach to type 1 diabetes prevention (adAPT 1). Diabetes Obes Metab. 2016;18:3-5.
15. 15. Channanath AM, Elkum N, Al-Abdulrazzaq D, Tuomilehto J, Shaltout A, Thanaraj TA. Ethnic differences in association of high body mass index with early onset of Type 1 diabetes - Arab ethnicity as case study. PLoS One. 2017;12:e0175728.