Mitochondrial Biomarker Predicts Type 2 Diabetes Risk

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia primarily caused by both impaired insulin secretion by pancreatic β-cells (insulinopenia) and defective insulin signaling in metabolically active tissues (insulin resistance).

The nuclear-encoded protein ATPase inhibitory factor 1 (IF1) is an endogenous inhibitor of the mitochondrial ATP synthase. For a long time, IF1 was thought to act only as an inhibitor of the reverse ATPase activity of the ATP synthase. However, recent data indicate that IF1 also partially inhibits the synthetic activity of the ATP synthase in mitochondria, thus limiting oxidative phosphorylation (OXPHOS).

Molecular Biochemists at the Université de Toulouse (Toulouse, France) and their colleagues conducted a prospective study, where the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of new onset diabetes (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.

Biological analyses including plasma triglycerides (TG), total cholesterol, HDL-cholesterol (HDL-C), glucose, glycated hemoglobin (HbA1c), aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (g-GT), insulin and high-molecular-weight adiponectin (HMW-adiponectin) were performed. Plasma apoA-I and IF1 were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. Analyses were performed on a Xevo TQD mass spectrometer with an electrospray interface and an Acquity H-Class UPLC device (Waters, Milford, MA, USA).

The scientists reported that 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). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the BMI and HOMA-IR. Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C and apoA-I. These correlations were confirmed in cross-sectional analyses. In Therapeutic Innovation in Type 2 DIABetes (IT-DIAB) cohort, 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].

The authors concluded that they had identified plasma IF1 as a determinant of T2D onset in high-risk populations, independently of age, sex, and fasting plasma glucose levels. IF1 measurements are foreseen within the framework of other prospective cohorts of individuals at different risks of T2D to more firmly establish the predictive value of IF1 measurements in the assessment of T2D risk along with established risk factors. The study was published on July 26, 2022 in the journal Research Square.

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