Women whose plasma bicarbonate exceeded the median level of 22.4 mmol/L at baseline were less likely to develop diabetes over a period of 10 years (OR 0.77, 95% CI 0.62 to 0.96, P=0.02), according to Ernest I. Mandel, MD, of Harvard Medical School in Boston, and colleagues.
After adjustment for body mass index (BMI), plasma creatinine and hypertension, there was a 4% decrease in the likelihood for developing type 2 diabetes with each unit increase in bicarbonate (OR 0.96, 95% CI 0.92 to 1.00, P=0.05), the researchers reported online in CMAJ.
Epidemiologic studies have linked biomarkers of metabolic acidosis with insulin resistance and type 2 diabetes, but it has not been clear whether the acidosis plays a causative role in the development of type 2 diabetes.
To examine this prospectively, Mandel and colleagues compared plasma bicarbonate levels among participants in the Nurses' Health Study who had blood drawn in 1989-1990.
Between 1990 and 2000, 630 women developed type 2 diabetes.
When the women who developed type 2 diabetes were compared with controls, those who developed diabetes had higher baseline BMI (30 versus 26), more hypertension (52% versus 31%) and dyslipidemia (49% versus 39%), and more often had a family history of type 2 diabetes (48% versus 23%). All were significant at P<0.01.
Baseline plasma bicarbonate levels were significantly lower in cases than controls (22 versus 22.4 mmol/L, P=0.02).
Women who developed type 2 diabetes also had higher baseline values for C-reactive protein, fasting insulin, and hemoglobin A1c.
In an adjusted model, risk of diabetes was lower in the two highest quartiles of bicarbonate level (P=0.04 for the linear trend):
- Quartile 3 -- 22.4 mmol/L to 23.9 mmol/L, OR 0.70 (95% CI 0.51 to 0.97)
- Quartile 4 -- >23.9 mmol/L, OR 0.75 (95% CI 0.54 to 1.05)
Further adjustments for smoking, physical activity, cholesterol level, and menopausal status had little effect.
In addition, the researchers adjusted for baseline C-reactive protein level and again found no differences in odds ratios.
"The association between lower plasma bicarbonate and development of diabetes may be explained by metabolic acidosis promoting insulin resistance, and this association may be independent of systemic inflammation, given the similar results observed even after we adjusted for C-reactive protein," Mandel and colleagues observed.
The researchers suggested that the association between plasma bicarbonate levels and type 2 diabetes also may be independent of levels of dietary acid, because they adjusted for factors that influence this, such as intake of animal protein and fruits and vegetables.
Further research will be needed "to confirm the association between plasma bicarbonate levels and type 2 diabetes in other populations, to elucidate the mechanism by which this occurs, and to explore increased dietary or supplemental alkali intake as a novel strategy for prevention of type 2 diabetes mellitus," the researchers concluded.
Limitations of the study included the possibility of measurement errors in bicarbonate levels since specimens were shipped and stored and the availability of only a single measure of bicarbonate, so no information was available on how changes in levels might influence risk.
The study received support from the National Institutes of Health (NIH) and the American Kidney Fund Clinical Scientist in Nephrology Program.
One co-author reported financial interests in UpToDate.
Reference: Mandel E, et al "Plasma bicarbonate and risk of type 2 diabetes mellitus" CMAJ 2012; doi:10.1503/cmaj.120438.