Our results show that lactate’s association with prevalent type 2 diabetes is strong, graded and independent. The graded association occurred across the normal clinical range of lactate values. The strength of the association was robust and independent of measures of adiposity. Among non-diabetics, plasma lactate was associated with higher fasting glucose, triglycerides and triglyceride–HDL ratio, a marker of insulin resistance.36,37
Our results are consistent with previous studies reporting an association between lactate, adiposity and type 2 diabetes. Small clinical studies have shown that lactate is higher among obese subjects23,24
and decreases with weight loss.25
Work by Chen and colleagues demonstrated that lactate is low in lean subjects, higher in non-diabetic obese subjects and still higher in obese diabetics.38
In two small, cross-sectional studies, lactate was correlated with insulin resistance independent of obesity.39,40
In a longitudinal analysis of Swedish men, elevated serum lactate was associated with a 2.4-fold higher incidence of type 2 diabetes.26
The association was attenuated after adjusting for BMI and other factors, however, and lactate was not included in the final model based on a step-wise regression analysis.26
Taken together, these studies suggest that lactate is associated with both obesity and its downstream complications including insulin resistance and type 2 diabetes. Although compelling, these findings were from small clinical studies or of limited generalizability. Our study is the largest population-based study to date investigating the association of lactate and type 2 diabetes. Strengths of our study include the large community-based sample of white and African American men and women, and extensive data on potential confounders.
Adipose tissue is responsible for a large portion of the lactate produced in obesity.25,41
Among obese subjects, decreased blood flow to adipose tissue leads to local hypoxia and increased lactate production.42
Furthermore, adipocyte production of lactate increases as adipocyte size increases,24,41,43
approaching the diffusion limit of oxygen.42
Therefore, decreased oxygen availability in adipocytes may drive a major portion of the excess lactate production associated with obesity. There is also evidence that hypoxia drives adipocytokine dysregulation42
and decreased insulin signalling44
in adipocytes from obese individuals. In this study, lactate’s association with type 2 diabetes was independent of BMI, however, suggesting that lactate is not solely a marker of adiposity. Alternatively, blood lactate may indicate the activity of adipose tissue, or its degree of hypoxia and decreased oxidative capacity, which is not captured by BMI and other measures of adiposity.
Oxidative capacity may also be decreased in insulin-resistant skeletal muscle. The evidence supporting this notion includes the association of insulin resistance and type 2 diabetes with increased glycolysis in muscle,3–5
decreased mitochondrial size and density,6–10
decreased oxidative gene expression,10–14
decreased oxidative phosphorylation14–18
and decreased aerobic capacity.13,19,20
The decrease in oxidative capacity may account for the markedly altered lactate metabolism in insulin-resistant muscle, where lactate concentration is increased and the lactate–pyruvate interconversion rates are enhanced as much as 3- to 4-fold.45,46
The expression of the lactate transporter monocarboxylate transport protein 1 (MCT1) is altered as well.46
In skeletal muscle, lactate functions to shuttle oxidative precursors from glycolytic fibres to oxidative fibers.47
MCT4 facilitates lactate’s transfer out of glycolytic fibres and MCT1 facilitates lactate’s transfer into oxidative fibres where it is oxidized.48
The expression of MCT1 is markedly decreased in insulin-resistant muscle.46
Although the reason for the decreased expression is unknown, these findings are consistent with a decreased capacity to oxidize exogenous lactate in oxidative fibres, leading to decreased expression of MCT1. Taken together, the association of blood lactate with type 2 diabetes may result from a global decrease in oxidative capacity which leads to altered lactate metabolism in insulin-resistant muscle and increased lactate release from adipose tissue.
Lactate’s association with type 2 diabetes may also be causal. DiGirolamo and colleagues have argued that the elevated lactate associated with obesity may be at least partially responsible for insulin resistance.24
Elevated lactate may promote hepatic gluconeogenesis and interfere with glucose uptake in muscle by substituting for glucose utilization.49
The evidence in support of this notion is mixed; lactate infusion decreases glucose oxidation, for example, but does not increase the rate of glucose production.50
Lactate’s potential causal role in insulin resistance needs further study.
Several limitations of our study deserve mention. First, because our study was cross-sectional, it was not possible to determine whether elevated lactate is a cause or consequence of type 2 diabetes. Therefore, we cannot rule out the possibility that type 2 diabetes leads to higher lactate levels. However, lactate was associated with markers of fasting glucose among non-diabetics, suggesting that lactate elevation is not just a consequence of type 2 diabetes. A specific mechanism potentially linking diabetes with elevated lactate is poor tissue oxygenation due to cardiovascular disease in diabetic participants. Adjustment for prevalent coronary heart disease, however, attenuated the association between lactate and prevalent diabetes only slightly. Second, lactate can be artificially elevated because of ongoing glycolysis following the blood draw. This effect was minimized through the rapid processing and cooling of blood samples and would have biased our results toward the null; it is highly unlikely that glycolysis in the samples would produce the large and graded associations here described. Third, the day-to-day repeatability of resting blood lactate is moderate, reflecting known diurnal variation in lactate levels and sensitivity of lactate to changes in the metabolic state. Despite this variation, lactate was strongly associated with type 2 diabetes. Finally, we recognize that lactate is only an indirect indicator of oxidative capacity.
Our results show that plasma lactate is strongly associated with prevalent type 2 diabetes among non-diabetics. The association of lactate with type 2 diabetes supports the potential role of decreased oxidative capacity in the aetiology of insulin resistance. Plasma lactate deserves greater attention in epidemiologic and physiologic studies of oxidative capacity and diabetes risk. Further work must be carried out to reassess the prospective association of plasma lactate and type 2 diabetes in a modern cohort. If confirmed, blood lactate measurement could be used as a marker of oxidative capacity in clinical and population studies.