Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study

Abstract

Aims/hypothesis Low phosphate and high calcium concentrations have been linked to altered glucose tolerance and reduced insulin sensitivity in non-diabetic individuals. The aim of this study was to examine the relationships of calcium and phosphate levels and the calcium–phosphate product with the development of type 2 diabetes. Methods Participants were 863 African-Americans, Hispanics and non-Hispanic whites in the Insulin Resistance Atherosclerosis Study who were free of diabetes at baseline. The mean follow-up period was 5.2 years. The insulin sensitivity index (SI) and acute insulin response (AIR) were directly measured using the frequently sampled IVGTT. Results Calcium concentration (OR per 1 SD unit increase, 1.26 [95% CI 1.04, 1.53]) and calcium–phosphate product (OR 1.29 [95% CI 1.04, 1.59]) were associated with incident diabetes after adjustment for demographic variables, family history of diabetes, and 2 h glucose. The relationship between phosphate concentration and progression to diabetes was close to statistical significance (OR 1.21 [95% CI 0.98, 1.49]). Calcium concentration (OR 1.37 [95% CI 1.09, 1.72]) and calcium–phosphate product (OR 1.39 [95% CI 1.09, 1.77]) remained associated with incident diabetes after additional adjustment for BMI, plasma glucose, SI, AIR, C-reactive protein, estimated GFR, diuretic drugs and total calcium intake. Conclusions/interpretation Elevated serum calcium and calcium–phosphate product are associated with increased risk of developing type 2 diabetes independently of measured glucose, insulin secretion and insulin resistance. Future studies need to analyse the role of calcium–phosphate homeostasis in the pathophysiology of diabetes.

Association between direct measurement of active serum calcium and risk of type 2 diabetes mellitus: A prospective study

“…However, this study has also shown no relationship between two single nucleotide polymorphisms associated with calcium concentration (rs1801725 and rs17251221) and risk of diabetes. More recently, two other smaller studies have investigated the link between fasting albumin-corrected serum calcium and incident T2DM, reporting positive associations (17,18). Of note, in both studies the Authors acknowledged as a major limitation the unavailability of direct measurement of iCa.…”

“…Similarly, crosssectional and case-control studies investigating the relationship between calcium homeostasis and glucose metabolism have reported conflicting results (7)(8)(9)(10)(11)(12)(13)(14)(15); however, only a few studies have prospectively evaluated the association between serum calcium and risk of incident T2DM, suggesting that higher levels of serum calcium predict an increased risk of T2DM (16)(17)(18). These studies have relied either on total serum calcium or the indirect, albumincorrected estimate of serum calcium: these measurements, however, only approximate the levels biological-active serum calcium (iCa) (19).…”

Increased Serum Calcium Levels and Risk of Type 2 Diabetes in Individuals at High Cardiovascular Risk

“…To the best of our knowledge, only two prospective studies have recently evaluated this association in adults (15,16). They both showed that elevated serum calcium concentrations were associated with increased risk of developing diabetes.…”

Association of serum calcium concentrations with fibrinogen and homocysteine in non-diabetic Korean subjects

“…[8] Moreover, several recent studies show that serum calcium levels predict the incidence of type 2 diabetes. [7,8] Experimental data demonstrate that increased cytosolic calcium levels attenuate the effect of insulin on glucose uptake by decreasing insulin receptor activity and reducing glucose transporter expression in adipocytes and muscle cells. [31,32] Lastly, calcium may mediate hemostatic imbalance through increased oxidative stress, which has been implicated as a common pathway promoting atherosclerosis and thrombosis.…”

“…Regarding calcium imbalances, considerable evidence shows that hypercalcemia is associated with increased risks of developing of cardiovascular disease (CVD) and mortality. [2] Recent population-based studies indicate that a slight imbalance in serum calcium, even within a normal range, is closely associated with metabolic disorders [3][4][5][6] and predicts development of type 2 diabetes, [7,8] suggesting a physiological link between serum calcium and increased cardiovascular (CV) risk. Although some studies report that high normal serum calcium levels can predict the incidence of myocardial infarction [9] and CV mortality, [10,11] it is still unclear whether slight changes in serum calcium induce CVD.…”