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Are Individuals With Type 2 Diabetes Metabolically Inflexible? A Systematic Review and Meta-Analysis
Maria Hansen1, Kristine Kjær Lange1, Martin Bjørn Stausholm2,3
1Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Endocrinology, Diabetes & Metabolism
|May 3, 2025
Summary
Metabolic flexibility, the body's fuel-switching ability, is reduced in overweight/obese and type 2 diabetes (T2D) individuals compared to lean people. This suggests weight status, not T2D itself, is the primary driver of metabolic inflexibility.
Area of Science:
- Metabolic Physiology
- Endocrinology
- Human Metabolism
Background:
- Type 2 diabetes (T2D) is characterized by insulin resistance and potentially impaired metabolic flexibility.
- Metabolic flexibility refers to the body's capacity to efficiently switch between metabolizing carbohydrates and fats for energy.
- Impaired metabolic flexibility may contribute to the pathophysiology of T2D.
Purpose of the Study:
- To systematically review and meta-analyze metabolic flexibility across lean, overweight/obese, and T2D populations.
- To assess how metabolic flexibility, measured by changes in respiratory exchange ratio (ΔRER) during hyperinsulinemic-euglycemic clamps, differs between these groups.
- To investigate the influence of body mass index (BMI) and other factors on metabolic flexibility.
Main Methods:
- A comprehensive literature search of PubMed was conducted to identify relevant studies.
- Sixty-five studies were included, with 35 using a standardized insulin infusion rate for comparative analysis.
- Data from 985 participants (256 lean, 497 overweight/obese, 232 T2D) were meta-analyzed.
Main Results:
- Insulin-stimulated ΔRER was significantly higher in lean individuals (0.10) compared to overweight/obese (0.07) and T2D (0.07) groups, indicating greater metabolic flexibility in lean individuals.
- High statistical heterogeneity was observed within groups, suggesting significant variability in ΔRER measurements.
- Meta-regression analysis revealed that only BMI was significantly associated with ΔRER, with other factors contributing to heterogeneity.
Conclusions:
- Metabolic flexibility is reduced in individuals with overweight/obesity and type 2 diabetes compared to lean individuals.
- Overweight status appears to be a more significant determinant of metabolic flexibility than type 2 diabetes per se.
- The findings challenge the concept of a distinct metabolic inflexibility threshold specific to type 2 diabetes and emphasize the need for standardized data reporting in metabolic research.
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