Mitochondrial Biomarker Predicts Type 2 Diabetes Risk

Miriam E. Tucker, for Medscape

July 25, 2022

The study covered in this summary was published on as a preprint and has not yet been peer reviewed.

Key Takeaway

  • ATPase inhibitory factor 1 (IF1) has been hypothesized as a biomarker of mitochondrial energy metabolism in which higher levels are associated with protection against insulin resistance. Among people with prediabetes who had low plasma levels of IF1, the rate of incident type 2 diabetes was significantly higher, independently of age, sex, and fasting plasma glucose levels.

Why This Matters

  • The authors say that this the first study in which an inverse relationship was found between plasma IF1 level and a person's risk of developing type 2 diabetes.

  • Dysfunction in a mitochondrial energy pathway may contribute to insulin resistance. Low plasma levels of IF1 appear to flag this condition and reflect biological processes not captured by conventional risk factors for diabetes or bioclinical variables and current biomarkers of glycemic control.

  • Higher levels of plasma IF1 may indicate optimal mitochondrial energetics.

Study Design

  • The 5-year, prospective, observational IT-DIAB study included 307 people with prediabetes. The study was designed to identify new biomarkers of type 2 diabetes risk in people prediabetes (fasting plasma glucose of ≥110 and <126 mg/dL; 6.0–7.0 mmol/L).

  • The primary outcome was the association between baseline plasma IF1 levels and subsequent development of type 2 diabetes during a median 4.9-year follow-up.

  • The researchers also ran cross-sectional analyses of data collected in two independent, interventional studies.

Key Results

  • During follow-up, 115 of the IT-DIAB participants (37%) developed type 2 diabetes.

  • Among those who developed type 2 diabetes, baseline IF1 levels were lower compared to those who did not: 537 ng/mL vs 621 ng/mL (P = .010).

  • After adjustment for age, sex, and fasting plasma glucose level, higher baseline plasma levels of IF1 were significantly and negatively linked with development of type 2 diabetes, with a hazard ratio of 0.76 for each standard deviation increase in baseline IF1 (P = .012). Further adjustment for either baseline levels of triglycerides or A1c made the association less robust and nonsignificant, although the directionality of effect was the same.

  • In the two cross-sectional studies as well as in the primary cohort, plasma levels of IF1 were negatively associated with body mass index and plasma triglyceride levels, and there were positive correlations with plasma levels of high-density lipoprotein cholesterol and apolipoprotein A-I.


  • The relatively small size of the prospective cohort limits the study's statistical power. The authors suggest that prospective studies with larger cohorts be conducted.

  • The study design did not allow determination of the optimal level of plasma IF1 that was associated with protection against the development of type 2 diabetes.


  • The study received no commercial funding.

  • The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, "Plasma Level of ATPase Inhibitory Factor 1 (IF1) Is Associated With Type 2 Diabetes Risk in Humans: A Prospective Cohort Study," by researchers primarily at the University of Toulouse, France, published on Research Square, and brought to you by Medscape. The study has not yet been peer reviewed. The full text of the study can be found on

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