Figure 1. Fasting serum acetate concentration in a group of lean subjects (95% CI: 33.1 - 101.7), obese subjects (95% CI: 66.3 - 236.5), untreated obese diabetic subjects (95% CI: 279.6 - 450.1), and obese diabetic subjects treated with metformin as the primary component of the therapeutic regimen (95% CI: 35.4 - 308.5). A scatter of the individual data points comprising each group is shown. *Significantly different from the lean group (untreated obese diabetic vs. lean, P value < 0.001). #Significantly different from the obese group (untreated obese diabetic vs. obese, P value < 0.01). †Significantly different from the metformin treated diabetic group (untreated obese diabetic vs. obese diabetic treated with metformin, P value < 0.01). Details of the statistical results are described in the “Results” section. Sample size n = 6 - 9 per group. CI: confidence interval.
Figure 2. Linear regression fit (solid black line), 95% confidence interval (blue lines) and prediction line (red lines) for fasting serum acetate concentrations (µM) with fasting glucose concentrations (mM) (a), HbA1c levels (mmol/mol) (b), and BMI with (c) and without (d) the metformin treated obese diabetic group. The individual data points comprising the four groups are shown in different colors. There was a statistically significant positive relationship for serum acetate with fasting glucose concentrations and HbA1c levels (P = 0.02 and 0.014, respectively) that can be described by the linear equations (Acetate (µM)) = 72.457 + (16.621 × (glcuose (mM))), with an r = 0.422 and an R2 = 0.178, and log(Acetate (µM)) = 72.457 + (16.621 × log(HbA1c (mmol/mol))), with an r = 0.444 and an R2 = 0.168. The unit for HbA1c is in mmoles of glycated hemoglobin for every mole of hemoglobin.
Figure 3. A schematic representation of the factors affecting systemic acetate during metabolic transition to the obese and diabetic states and following metformin treatment. The number of arrows reflects substrate flux in metabolically active tissues and abundance of a product, and their thickness the intensity of a biochemical pathway. (a) In the lean state, glucose is metabolized via glycolysis and the critic acid cycle. The extra carbons are shuttled to the cytoplasm and converted into triglycerides. (b) In the obese state, systemic resistance to insulin and higher adipocyte lipolysis rates allow tissues to take relatively greater amounts of FFAs for mitochondrial β-oxidation and in the process; greater amounts of acetate are formed. Some acetate is contributed through increased microbial fermentation in the intestines. (c) Deterioration of the state in (b) and hyperglycemia occur. The increased availability of FFAs and mitochondrial β-oxidation increases production of acetate. (d) A possible decrease in systemic acetate due to oxidative stress, mitochondrial damage and excessive intracellular fat accumulation. (e) Metformin improves insulin sensitivity and glucose metabolism and decreases adipocyte lipolysis, systemic FFAs and mitochondrial β-oxidation. It also modulates the intestinal microflora. These effects reduce systemic acetate levels. FFAs: free fatty acids.