Acidosis is associated with lower insulin sensitivity and incident type 2 diabetes in indigenous Americans: A prospective cohort study

Aim: Whether markers of acid accumulation [decreased plasma bicarbonate, increased anion gap (AG) and corrected anion gap (CAG)] are associated with insulin sensitivity and alter diabetes risk is unclear. We aimed to examine the association of these markers with the gold-standard measure of insulin sensitivity and incident type 2 diabetes. Materials and methods: Healthy adults without diabetes enrolled in a longitudinal study had baseline measures of acidosis (bicarbonate, AG, CAG), insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, and body composition. In cross-sectional analysis (n = 296, 188 male), the relationship between acid markers and insulin sensitivity (M-low) was evaluated. Progression to type 2 diabetes was evaluated by Cox regression models (per 1-SD change) in those with appropriate follow-up visits (n = 233). Results: Increased AG and CAG were associated with lower M-low, adjusting for age, sex, body fat (%) and estimated glomerular filtration rate (AG: partial r = -0.22, CAG: partial r = -0.24, both p < 0.0001) but not with bicarbonate. During a median follow-up time of 8.0 years, 50 participants developed type 2 diabetes. CAG was associated with increased risk of type 2 diabetes (HR: 1.32, 95% CI 1.01-1.74, p = 0.044) in a model adjusted for age, sex, body fat (%) and baseline plasma glucose, but not after further adjusting for M-low (p = 0.17). Bicarbonate and AG were not associated with risk of diabetes. Conclusion: Acidosis was associated with lower insulin sensitivity and increased risk of type 2 diabetes that was attenuated by measures of lower insulin sensitivity. Acidosis as reflected by CAG may be a target for intervention.