Sources of Inter-individual Variability in the Therapeutic Response of Blood Glucose Control to Exercise in Type 2 Diabetes: Going Beyond Exercise Dose

Abstract

In the context of type 2 diabetes, inter-individual variability in the therapeutic response of blood glucose control to exercise exists to the extent that some individuals, occasionally referred to as "non-responders," may not experience therapeutic benefit to their blood glucose control. This narrative review examines the evidence and, more importantly, identifies the sources of such inter-individual variability. In doing so, this review highlights that no randomized controlled trial of exercise has yet prospectively measured inter-individual variability in blood glucose control in individuals with prediabetes or type 2 diabetes. Of the identified sources of inter-individual variability, neither has a prospective randomized controlled trial yet quantified the impact of exercise dose, exercise frequency, exercise type, behavioral/environmental barriers, exercise-meal timing, or anti-hyperglycemic drugs on changes in blood glucose control, in individuals with prediabetes or type 2 diabetes. In addition, there is also an urgent need for prospective trials to identify molecular or physiological predictors of inter-individual variability in the changes in blood glucose control following exercise. Therefore, the narrative identifies critical science gaps that must be filled if exercise scientists are to succeed in optimizing health care policy recommendations for type 2 diabetes, so that the therapeutic benefit of exercise may be maximized for all individuals with, or at risk of, diabetes.

Keywords: HbA1c; blood glucose control; exercise; heterogeneity; non-responder; training; type 2 diabetes; variability.

FIGURE 1

A cartoon depicting the inter-individual variability of changes in HbA1c levels following exercise training in individuals with prediabetes or type 2 diabetes. The y-axis represents the training-induced change in HbA1c (post- minus pre-intervention value). The x-axis represents the individual participants taking part in a study. Adverse outcomes are illustrated as participants’ responses showing a training-induced increase in HbA1c that is more than 1.96 times the technical error (TE). Therapeutic outcomes are shown as training-induced decreases in HbA1c that are greater than 1.96 times the technical error.

FIGURE 2

(A) A schematic for a repeated-measures double-crossover study design which, if the patient-by-treatment interaction term were statistically significant, would accurately indicate the presence of inter-individual variability. All patients undergo all interventions twice. The type of trial each participant first undergoes should be randomized and the primary outcome is measured at the beginning and the end of each intervention period. The time between interventions would have to be sufficient such that training effect was washed out. (B) Perhaps a more practical and logistically feasible method for determining the technical error of measurement, and thereby identifying non-responders, is a randomized controlled intervention where the primary outcome variable is measured repeatedly within an intervention. Participants are randomized to either the control arm (no training) or the treatment arm (exercise training). Ideally, the variable would be repeatedly measured within a time frame where intervention-induced changes are unlikely (e.g., measuring HbA1c three times within a 2-week period towards the end of a long-term training intervention). Gray stars indicate repeated measurement of the variable, HbA1c, for example.

FIGURE 3

Evidence-based sources of inter-individual variability in the blood glucose lowering effects of exercise in individuals with prediabetes or T2DM. Other sources that have not been adequately studied to conclusively state that they contribute to this variability in individuals with prediabetes or T2DM include age, sex, race, body weight, family history of diabetes, and duration of diabetes.