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Increasing Plasma Glucose Before the Development of Type 1 Diabetes – The TRIGR Study

Sep 25, 2021
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Erica Hicks, PharmD Candidate 2022, South College School of Pharmacy

Investigation into plasma glucose and HbA1c before a diagnosis of type 1 diabetes in children.

This study aims to investigate the B-cell stress hypotheses, which suggest that increased insulin demand contributes to the development of type 1 diabetes. This study assesses plasma glucose and HbA1c before the diagnosis of diabetes compared to those children who do not have diabetes. Studies previously done include “Psychological stress and the risk of diabetes-related autoimmunity: a review article” and “Environmental risk factors for type one diabetes.” These two studies investigate the factors that can lead to stressing out of the beta-cell, therefore, leading to a diagnosis of diabetes. 

 

When a patient develops type 1 diabetes, it’s usually preceded by a long clinical autoimmune process. Several environmental and developmental components contribute to the autoimmune process that leads to the development of diabetes. Some functions that lead to this autoimmune process are viral infections and rapid growth. Psychological stress is said to increase the beta cell decline, therefore precipitating the diabetic disease process. This trial followed children from the age of 1 until the development of single or multiple autoantibodies and subsequently until the diagnosis of type 1 diabetes; this investigated whether plasma glucose increases more in children who later develop diabetes-related autoantibodies and or clinical diabetes type 1 than those children who do not develop diabetes type 1. TRIGR study is an international, double-blind, multicenter trial, designed to determine if weaning infants from cows’ milk to hydrolyzed infant formula reduces the incidence of diabetes-related autoantibodies and type 1 diabetes in children with an affected first-degree relative HLA conferred disease susceptibility. There were 2159 participants enrolled in the trial. The primary outcomes were:

  • The development of an autoantibody.
  • The development of multiple autoantibodies.
  • The development of type 1 diabetes.

HbA1c and random plasma glucose were measured at ages 12, 18, and 24 months, then annually after that. The participants were followed until at least age 10. Participants who developed at least a single autoantibody differed from those who did not by HLA risk status. Likewise, participants who developed multiple autoantibodies differed from those who did not establish any autoantibodies by HLA status. Likewise, those who progressed to type 1 diabetes differed from those who did not develop any autoantibodies by HLA status and relative proband status (P <0.001).

A familial history of type 2 diabetes led to an increase in plasma glucose. An increase in glucose from the previous sample predicted clinical diabetes but no autoantibodies. An increase in the HbA1c of 20% or 30% of the prior sample indicated the development of any autoantibody along with the development of type 1 diabetes. Participants without autoantibodies had lower HbA1c levels than those who developed type 1 diabetes, but higher than those who developed autoantibodies or multiple autoantibodies. 

It can be concluded that increased plasma glucose and HbA1c precede the clinical development of diabetes type 1. The association between plasma glucose and HbA1c and the development of autoantibodies is complex and cannot be concluded. The study shows that a more rapid and pronounced increase of plasma glucose and or HbA1c is related to any but not multiple autoantibodies. The onset of clinical disease is regularly preceded by a significant rise in plasma glucose and HbA1c caused by failing beta-cells and insufficient insulin secretion, leading to overt type 1 diabetes as per our existing definitions. In conclusion, plasma glucose and HbA1c are shown to increase years before diagnosing type 1 diabetes in a population with a familial history of type 1 diabetes and a high risk of HLA genotype. The rapid and pronounced increase in plasma glucose levels may support the hypothesis that increased insulin demand is one factor contributing to the progression to type 1 diabetes.  

Practice Pearls:

  • When a patient develops type 1 diabetes, it’s usually preceded by a long clinical autoimmune process.
  • The rapid and pronounced increase in plasma glucose levels may support the hypothesis that increased insulin demand is one factor contributing to the progression to type 1 diabetes.
  • More studies would need to be done to associate HbA1c and plasma glucose levels with the development of multiple autoantibodies.

 

  1. Ludvigsson J, Cuthbertson D, Becker DJ, Kordonouri O, Aschemeier B, Pacaud D, Clarson C, Krischer JP, Knip M; TRIGR Investigators. Increasing plasma glucose before the development of type 1 diabetes – the TRIGR study. Pediatr Diabetes. 2021 August 9. doi: 10.1111/pedi.13251. Epub ahead of print. PMID: 34369627. Increasing plasma glucose before the development of type 1 diabetes – the TRIGR study
  2. Sepa A, Ludvigsson J. Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation. 2006;13(5-6):301-8. doi: 10.1159/000104858. Epub 2007 August 6. PMID: 17709952.

 

Erica Hicks, PharmD Candidate 2022, South College School of Pharmacy