At baseline, women in whom type 2 diabetes mellitus later developed had a higher BMI and a greater prevalence of hypertension, hypercholesterolemia and family history of diabetes than those without diabetes (). Further, they were less physically active, had lower alcohol consumption, lower intake of cereal fibre, greater intake of trans fats and had a higher glycemic index. The mean plasma bicarbonate level was significantly lower among those in whom diabetes subsequently developed (p = 0.02). Among those with available levels, the baseline levels of C-reactive protein (619 cases and 471 controls), fasting insulin (393 cases and 354 controls) and hemoglobin A1c (341 cases and 416 controls) were all higher among those with subsequently diagnosed diabetes.
Baseline characteristics of the study population by case status
Baseline characteristics of controls, by quartile of plasma bicarbonate, are shown in . Those in the highest quartile tended to be older, have a lower BMI, higher levels of physical activity, a greater prevalence of hypertension and thiazide use, and slightly higher intakes of potassium and calcium.
Baseline characteristics of controls by quartile of plasma bicarbonate
Each unit increase in plasma bicarbonate was associated with a 4% decrease in the odds of diabetes after adjustment for matching factors (OR 0.96, 95% CI 0.92–1.00; p = 0.03) and after further adjustment for BMI, plasma creatinine and history of hypertension (OR 0.96, 95% CI 0.92–1.00; p = 0.05).
Women with plasma bicarbonate above the median level among controls in our cohort (22.4 mmol/L) had lower odds of incident diabetes (OR 0.77, 95% CI 0.62–0.96; p = 0.02) compared with those below the median after adjustment for matching factors. The ORs were essentially unchanged after further adjustment for BMI, plasma creatinine and history of hypertension (OR 0.76, 95% CI 0.60–0.96; p = 0.02). We further divided plasma bicarbonate into quartiles. Higher plasma bicarbonate was associated with lower odds of incident diabetes across the quartiles in both the crude (p for linear trend = 0.03) and adjusted models (p for linear trend = 0.04) (). Additional adjustment for history of hypercholesterolemia, history of chronic obstructive pulmonary disease, thiazide use, smoking, physical activity, family history of diabetes, menopausal status, use of postmenopausal hormones, alcohol intake and diabetes diet score did not appreciably alter the estimates for the median or quartile analyses, nor did adjustment for intake of animal protein, potassium, calcium and magnesium. Conditional logistic regression in the subgroup with matched cases and controls yielded similar results.
Odds ratios of type 2 diabetes mellitus during the 10-year follow-up period, by baseline level of plasma bicarbonate
Given the association of obesity with type 2 diabetes mellitus, we considered BMI in 3 ways (continuously, continuously with both a linear and squared term, and in categories [< 25.0, 25.0–29.9, ≥ 30.0]) in 3 different models to ensure adequate control for confounding by BMI. The point estimates did not change regardless of the method of controlling for BMI. Finally, to minimize confounding by obesity, we added waist circumference to linear BMI in a secondary analysis, and we observed similar results.
Because incipient type 2 diabetes mellitus can precede overt diagnosis by several years, we performed an additional analysis excluding women (n = 181 cases) who received a diagnosis of diabetes in the first 4 years of follow-up, and we observed similar results.
Recent practice guidelines have been revised to include hemoglobin A1c
greater than 6.5% as a diagnostic criterion for diabetes.22
In our study, 98 cases and 6 matched controls had hemoglobin A1c
levels greater than 6.5% at the baseline blood draw. We performed an additional analysis excluding these individuals, and we observed similar results.
Systemic inflammation, marked by elevated C-reactive protein, is associated with both low serum bicarbonate23
and the development of type 2 diabetes mellitus,24
and it may underlie the association between low plasma bicarbonate and the risk of diabetes. We explored this in the subset of women (618 cases and 471 controls; one case was missing BMI data) who had measurement of C-reactive protein. We used models further adjusted for C-reactive protein. The ORs for diabetes by quartile of plasma bicarbonate were not materially different when we included C-reactive protein in the model.