Background: Mitochondrial dysfunction is associated with the development of type 2 diabetes (T2D). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2D.ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes.Methods: In the IT-DIAB prospective study, the plasma level of IF1 was measured at baseline in 307 participants with prediabetes, defined as a moderately elevated fasting plasma glucose, i.e., 110–125 mg/dL (6.0–7.0 mmol/L). The primary outcome was the incidence of NOD, defined as the first fasting plasma glucose value ≥ 1.26 g/L (7.0 mmol/L) within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman’s correlation coefficients, and the association with the risk of NOD was determined using Cox proportional‐hazards models.Results: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, p=0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the BMI (r = -0.20, p=0.0005) and HOMA-IR (r = -0.37, p<0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, p<0.0001) and apoA-I (r = 0.33, p<0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2D after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.64; 0.94], p=0.012).Conclusion: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2D. As a biomarker, circulating IF1 can be considered to be a surrogate of mitochondrial energetics. IF1 can potentially be used to select patients for clinical trials of therapeutics that target mitochondrial function.

Aim: Mitochondrial dysfunction is associated with the development of type 2 diabetes (T2D). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2D.ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes.Methods: In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman’s correlation coefficients, and the association with the risk of NOD was determined using Cox proportional‐hazards models.Results: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, p=0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the BMI (r = -0.20, p=0.0005) and HOMA-IR. (r = -0.37, p<0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, p<0.0001) and apoA-I (r = 0.33, p<0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2D after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], p=0.012).Conclusion: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2D.