The Possible Role of Elevated Serum Calcium in the Development of Type 2 Diabetes

Type 2 diabetes imposes a major public health burden and disproportionally affects the black population in the United States.1 Identification of novel factors of diabetes risk may aid etiologic understanding of this highly prevalent disease.

Calcium is traditionally thought of in relation to bone health; however, emerging epidemiologic evidence has suggested an association between elevated serum calcium concentration and metabolic abnormalities,2-10 including the development of type 2 diabetes. Consistent with this literature, we recently reported a positive association between serum calcium and incident diabetes.11 Importantly, this association remained even after accounting for biomarkers related to calcium metabolism (25-hydroxyvitamin D [25(OH)D], parathyroid hormone [PTH], and phosphorus), which have themselves been associated with diabetes.12-14 This suggests that these metabolically-related nutritional biomarkers do not fully capture the association with diabetes.

Serum calcium is tightly regulated within the body. Briefly, calcium homeostasis involves numerous negative feedback loops, involving 1,25-dihydroxyvitamin D [1,25(OH)2D], PTH, and ionized calcium. Upon sensing an increase or decrease in circulating calcium concentration, the body adjusts calcium transport in the bone, kidneys and/or intestine to restore concentrations.15 The calcium-sensing receptor (CaSR), located within the parathyroid gland and kidneys, also plays a noteworthy role in calcium homeostasis. The CaSR detects important changes in circulating calcium concentration, which triggers an increase in PTH secretion and calcium absorption to restore calcium concentration.

We analyzed the calcium-diabetes association among middle-aged black and white Atherosclerosis Risk in Communities (ARIC) study participants free of diabetes at baseline in 1987-89 (N=12,800). After the baseline clinic visit, participants have since attended up to four visits (1990-92, 1993-95, 1996-98, 2011-13). For this analysis, participants were stratified by quintiles of baseline serum calcium concentration. As is commonly done in clinical settings, calcium was corrected for albumin concentration. Incident diabetes was defined by: 1) fasting blood glucose ≥126 mg/dL; 2) non-fasting glucose ≥200 mg/dL; 3) self-report physician diagnosis; or 4) current medication use for diabetes. Multi-variable Cox proportional hazards regression was used.

Over a mean follow-up period of 9 years, we found that those in the highest quintile had 1.34 times higher risk of diabetes than those in the lowest quintile (95% CI: 1.14, 1.57; p for linear trend <0.001) after adjusting for demographic and lifestyle characteristics. Once adjusting for measures of adiposity, the association was attenuated [HR Q5 v Q1 = 1.26; 1.07, 1.48; p-trend=0.004]. The association remained even after adjusting for phosphorus, 25(OH)D, and PTH [1.28; (1.08, 1.52); p-trend=0.005].

As prior studies have noted potential race differences in calcium metabolism, such that blacks may be more efficient at its metabolism,16-19 we decided a priori to examine race-stratified results. Mean baseline serum calcium concentration levels were slightly higher among black participants as compared to white participants. While there was not a statistically significant race interaction, we noted a somewhat stronger association between high serum calcium among black participants [1.48; (1.11, 1.98); p-trend=0.002] than for white participants [1.17; (0.96, 1.43); p-trend=0.17].

While there are plausible mechanisms for the association, any role of calcium in the pathogenesis of diabetes is nevertheless complex. Abnormal calcium regulation may contribute to reduced β-cells function,4 thereby promoting altered glucose homeostasis.20 In vitro studies have also found that high cytosolic calcium may contribute to insulin resistance within adipocytes and skeletal muscle.21-23 It is also possible that the relationship between abnormal glucose and calcium homeostasis is cyclical.

Overall, these recent findings are consistent with three prior cohort studies examining the serum calcium association. Extending the results of prior cohort studies, we examined this association in African Americans as well as whites. We also incorporated 25(OH)D and PTH in analyses, which are related to calcium homeostasis and the metabolism of these markers may also vary by race.12,13

As our study was observational in design, a causal interpretation of these findings should be avoided since residual confounding may have influenced our effect estimates. Furthermore, approximately half of the participants in the highest calcium quintile had clinical hypercalcemia, which may reflect an underlying health problem. Though, in sensitivity analyses, the association appeared robust after excluding those with possible hyperparathyroidism. Lastly, it is important to note that our study focused on serum calcium, which is tightly regulated and correlates poorly with dietary intake. Prior studies have suggested that dairy intake—an important source of calcium in the diet—protects against the development type 2 diabetes risk.24,25 As such, we would not recommend dietary changes as a result of our findings. More work is needed to understand factors that influence serum calcium levels.

So, what does this mean for those with high serum concentrations? Due to the complexity and of calcium homeostasis, it is presently unclear how or when to intervene on elevated serum calcium to specifically minimize diabetes risk. Yet, it is possible that treatment of the underlying cause of hypercalcemia may also reduce a patient's risk of type 2 diabetes. Randomized clinical trials would be needed to test this hypothesis.

References

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Keywords: Adipocytes, Adiposity, Albumins, Atherosclerosis, Biological Markers, Blood Glucose, Demography, Diabetes Mellitus, Type 2, Glucose, Homeostasis, Hypercalcemia, Hyperparathyroidism, Insulin Resistance, Life Style, Obesity, Parathyroid Glands, Parathyroid Hormone, Phosphorus, Receptors, Calcium-Sensing, Vitamin D


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