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 intakean important source of calcium in the dietprotects 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.
- Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and its Burden in the United States, 2014. Atlanta, Georgia: Department of Health and Human Services; 2014.
- Kim M, Kim G, Jang E, et al. Altered calcium homeostasis is correlated with the presence of metabolic syndrome and diabetes in middle-aged and elderly Korean subjects: the Chungju Metabolic Disease Cohort study (CMC study). Atherosclerosis 2010;212:674-81.
- Yamaguchi T, Kanazawa I, Takaoka S, Sugimoto T. Serum calcium is positively correlated with fasting plasma glucose and insulin resistance, independent of parathyroid hormone, in male patients with type 2 diabetes mellitus. Metabolism 2011;60:1334-9.
- Sun G, Vasdev S, Martin GR, Gadag V, Zhang H. Altered calcium homeostasis is correlated with abnormalities of fasting serum glucose, insulin resistance, and β-cell function in the Newfoundland population. Diabetes 2005;54:3336-9.
- Wareham NJ, Byrne CD, Carr C, Day NE, Boucher BJ, Hales CN. Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism 1997;46:1171-7.
- Levy J, Stern Z, Gutman A, Naparstek Y, Gavin JR, Avioli LV. Plasma calcium and phosphate levels in an adult noninsulin-dependent diabetic population. Calcif Tissue Int 1986;39:316-8.
- Sorva A, Tilvis RS. Low serum ionized to total calcium ratio: association with geriatric diabetes mellitus and with other cardiovascular risk factors. Gerontology 1990;36:212-6.
- Jorde R, Schirmer H, Njølstad I, et al. Serum calcium and the calcium-sensing receptor polymorphism rs17251221 in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromsø Study. Eur J Epidemiol 2013;28:569-78.
- Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetologia 2014;57:1366-74.
- Becerra-Tomás N, Estruch R, Bulló M, et al. Increased serum calcium levels and risk of type 2 diabetes in individuals at high cardiovascular risk. Diabetes Care 2014;37:3084-91.
- Rooney MR, Pankow JS, Sibley SD, et al. Serum calcium and incident type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Am J Clin Nutr 2016;104:1023-9.
- Xuan Y, Zhao H-y, Liu J-M. Vitamin D and type 2 diabetes mellitus. J Diabetes 2013;:261-7.
- Mitri J, Pittas AG. Vitamin D and diabetes. Vol 432014:205-232.
- Reis JP, Michos ED, Selvin E, Pankow JS, Lutsey PL. Race, vitamin D-binding protein gene polymorphisms, 25-hydroxyvitamin D, and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2015;101:1232-40.
- Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol 2010:S23-30.
- Bell NH, Yergey AL, Vieira NE, Oexmann MJ, Shary JR. Demonstration of a difference in urinary calcium, not calcium absorption, in black and white adolescents. J Bone Miner Res 1993;8:1111-5.
- Bryant RJ, Wastney ME, Martin BR, et al. Racial differences in bone turnover and calcium metabolism in adolescent females. J Clin Endocrinol Metab 2003;88(3):1043-1047.
- Cosman F, Morgan DC, Nieves JW, et al. Resistance to bone resorbing effects of PTH in black women. J Bone Miner Res 1997;12:958-66.
- Heaney RP. The importance of calcium intake for lifelong skeletal health. Calcif Tissue Int 2002;70:70-3.
- Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000;49:1751-60.
- Draznin B, Lewis D, Houlder N, et al. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology 1989;125:2341-49.
- Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest 1988;82:1848-52.
- Begum N, Leitner W, Reusch JE, Sussman KE, Draznin B. GLUT-4 phosphorylation and its intrinsic activity. Mechanism of Ca(2+)-induced inhibition of insulin-stimulated glucose transport. J Biol Chem 1993;268:3352-6.
- Aune D, Norat T, Romundstad P, Vatten LJ. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. Am J Clin Nutr 2013;98:1066-83.
- Gijsbers L, Ding EL, Malik VS, de Goede J, Geleijnse JM, Soedamah-Muthu SS.Consumption of dairy foods and diabetes incidence: a dose-response meta-analysis of observational studies. Am J Clin Nutr 2016;103:1111-24.
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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