Prevention and Delay of Type 1 Diabetes

If sustained elevated BMI can accelerate the progression of islet autoimmunity in people not yet diagnosed with diabetes, is there a way to delay the progression to type 1? 

Both genetic and environmental risk factors play a vital role in the development of type 1 diabetes. This study aims to examine the impact of modifiable risk factors, such as obesity and multiple autoantibodies, before the progression of clinical T1D. The accelerator hypothesis states that autoimmune B-cell destruction is triggered by obesity-induced insulin resistance. The threshold hypothesis proposes that a combination of environmental and genetic diabetogenic factors exceeding a threshold leads to diabetes. This study investigates the effect of cumulative BMI (ceBMI)  in exacerbating the autoimmune process by observing the function of a single autoantibody form into multiple autoantibodies.   

The study includes 706 pediatric participants (1.6-18.6 years of age) taken from the TrialNet PTP cohort. The cohort consisted of first, second-and third-degree relatives of people with T1D who do not have diabetes themselves. All those included were autoantibody-positive and had two BMI measurements before a diagnosis of T1D. The BMI measurements were obtained by following the Centers for Disease Control and Prevention (CDC) criteria for overweight and obesity. 

The American Diabetes Association (ADA) criteria were used to determine if a participant had developed diabetes. Participants must have met the ADA criteria upon two visits to confirm a diagnosis. HbA1C and OGTT were obtained at every visit, along with the 85th percentile for BMI adjusted for age and sex by using the CDC 2000 growth charts. The ceBMI score was calculated using weighted sums of the difference between the BMI obtained in the CDC 2000 charts and the actual BMI. A participant was classified as underweight if they were in the <5th percentile, average weight if they were between the 5th-85th percentile, overweight if they were ≥ 85th percentile, and obese if in the ≥ 95th percentile.  A ceBMI ≥ 0 kg/m2 designated a participant’s BMI with an ≥85th percentile average based on their age and sex during observation.  This study’s primary measurement was time to conversion of an autoantibody positivity obtained at first BMI assessment to the presence of multiple autoantibody positivity.   

To determine categorical and continuous variable significance, Cox proportional hazards models were used. Age cut points for when progression was made to multiple positive autoantibodies were obtained through a Recursive portioning analysis. Statistical program R (v.2.5.1 for windows) was used for all the analyses.  A P-value of < 0.05 determined statistical significance. A  P-value < 0.1 was encouraged for further examination. 

Age and HLA haplotypes, such as HLA DR3-DQ2 and DR4-DQ8, can affect multiple positive autoantibodies’ progression. The rate of progression is decreased by 7% (HR 0.93, 95% CI: 0.89-0.94; P=0.0007) for each  increase in year. The age cut-point was determined to be nine years old. The HLA haplotypes are associated with an increased progression rate in those ≥nine years old (HR:2.27; P=0.019). Individuals ≥ 9 years of age without the HLA- haplotypes but with a ceBMI ≥0 kg/m2 showed a significant factor in determining progression (HR 7.32, 95% CI 1.88-28.5; P=0.004); however, those with the high-risk haplotypes and a ceBMI ≥ kg/m2in the same age group did not show a significant factor (HR 1.38, 95% CI 0.32-2.59, P=0.31).  

Within ten years of seroconversion, 70% of individuals with multiple islet autoantibodies developed clinical diabetes. This study shows that modifiable risk factors like ceBMI can help affect the conversion from a single autoantibody to multiple autoantibodies. The strengths of this study include the large population size with subgroups that were susceptible to ceBMI effects. However, the size of some subgroups was small, which was a limitation. Not following participants from birth led to being unaware of how long a single positive autoantibody was present. The cut point was derived from a recursive portioning analysis and may not apply to the general population. Determining signaling molecules that result in obesity-induced autoimmunity should be an area of interest for future studies.  

Practice Pearls 

• Age, HLA subtypes, and BMI all play a role in the progression of T1D. 
• Elevated BMI  can be a significant indicator in the T1D preclinical phase in older children without the high-risk HLA haplotypes. 
• Progression of clinical T1D may be halted or delayed by maintaining lifestyles encouraging a BMI < 85th percentile. 

Ferrara-Cook, Christine et al. “Excess BMI Accelerates Islet Autoimmunity In Older Children And Adolescents.” Diabetes Care, vol 43, no. 3, 2020,  

Zahra Hashemy, PharmD. Candidate, USF Taneja College of Pharmacy 

See more about possible strategies to delay type 1 diabetes.