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Circulating calcium levels and the risk of type 2 diabetes: a systematic review and meta-analysis

  • J. Zhu (a1) (a2) (a3), P. Xun (a4), J. C. Bae (a5), J. H. Kim (a6), D. J. Kim (a7), K. Yang (a1) (a2) and K. He (a4)...

Abstract

Abnormal Ca homeostasis has been associated with impaired glucose metabolism. However, the epidemiological evidence is controversial. We aimed to assess the association between circulating Ca levels and the risk of type 2 diabetes mellitus (T2DM) or abnormal glucose homeostasis through conducting a systematic review and meta-analysis. Eligible studies were identified by searching electronic database (PubMed, Embase and Google Scholar) and related references with de novo results from primary studies up to December 2018. A random-effects meta-analysis was performed to estimate the weighted relative risks (RR) and 95 % CI for the associations. The search yielded twenty eligible publications with eight cohort studies identified for the meta-analysis, which included a total of 89 165 participants. Comparing the highest with the lowest category of albumin-adjusted serum Ca, the pooled RR was 1·14 (95 % CI 1·05, 1·24) for T2DM (n 51 489). Similarly, serum total Ca was associated with incident T2DM (RR 1·25; 95 % CI 1·10, 1·42) (n 64 502). Additionally, the adjusted RR for 1 mg/dl increments in albumin-adjusted serum Ca or serum total Ca levels was 1·16 (95 % CI 1·07, 1·27) and 1·19 (95 % CI 1·11, 1·28), respectively. The observed associations remained with the inclusion of a cohort study with ionised Ca as the exposure. However, data pooled from neither case–control (n 4) nor cross-sectional (n 8) studies manifested a significant correlation between circulating Ca and glucose homeostasis. In conclusion, accumulated data from the cohort studies suggest that higher circulating Ca levels are associated with an augmented risk of T2DM.

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Corresponding author

*Corresponding author: K. He, email kahe@indiana.edu

References

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1. World Health Organization (2014) Global status report on noncommunicable diseases. https://www.who.int/nmh/publications/ncd-status-report-2014/en/ (accessed January 2019).
2. Seshasai, SR, Kaptoge, S, Thompson, A, et al. (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 364, 829841.
3. Jorde, R, Schirmer, H, Njølstad, I, et al. (2013) 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 28, 569578.
4. Becerra-Tomás, N, Estruch, R, Bulló, M, et al. (2014) Increased serum calcium levels and risk of type 2 diabetes in individuals at high cardiovascular risk. Diabetes Care 37, 30843091.
5. American Diabetes Association (2013) Standards of medical care in diabetes. Diabetes Care 36, S11S66.
6. Rooney, MR, Pankow, JS, Sibley, SD, et al. (2016) Serum calcium and incident type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Am J Clin Nutr 104, 10231029.
7. Sorva, A & Tilvis, RS (1990) Low serum ionized to total calcium ratio: association with geriatric diabetes mellitus and with other cardiovascular risk factors. Gerontology 36, 212216.
8. Peacock, M (2010) Calcium metabolism in health and disease. Clin J Am Soc Nephrol 5, S23S30.
9. Sing, CW, Cheng, VK, Ho, DK, et al. (2016) Serum calcium and incident diabetes: an observational study and meta-analysis. Osteoporos Int 27, 17471754.
10. Zaccardi, F, Webb, DR, Carter, P, et al. (2015) Association between direct measurement of active serum calcium and risk of type 2 diabetes mellitus: a prospective study. Nutr Metab Cardiovasc Dis 25, 562568.
11. Mears, D (2004) Regulation of insulin secretion in islets of Langerhans by Ca(2+) channels. J Membr Biol 200, 5766.
12. Wollheim, CB & Sharp, GW (1981) Regulation of insulin release by calcium. Physiol Rev 61, 914973.
13. Ojuka, EO, Jones, TE, Nolte, LA, et al. (2002) Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+). Am J Physiol Endocrinol Metab 282, E1008E1013.
14. Begum, N, Leitner, W, Reusch, JE, et al. (1993) GLUT-4 phosphorylation and its intrinsic activity. Mechanism of Ca(2+)-induced inhibition of insulin-stimulated glucose transport. J Biol Chem 268, 33523356.
15. American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33, S62S69.
16. Procopio, M, Magro, G, Cesario, F, et al. (2002) The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed type 2 diabetes mellitus in primary hyperparathyroidism. Diabet Med 19, 958961.
17. Lorenzo, C, Hanley, AJ, Rewers, MJ, et al. (2014) Calcium and phosphate concentrations and future development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetologia 57, 13661374.
18. Levy, J, Stern, Z, Gutman, A, et al. (1986) Plasma calcium and phosphate levels in an adult noninsulin-dependent diabetic population. Calcif Tissue Int 39, 316318.
19. Kim, MK, Kim, G, Jang, EH, et al. (2010) 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 212, 674681.
20. Yamaguchi, T, Kanazawa, I, Takaoka, S, et al. (2011) 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 60, 13341339.
21. Sun, G, Vasdev, S, Martin, GR, et al. (2005) Altered calcium homeostasis is correlated with abnormalities of fasting serum glucose, insulin resistance, and beta-cell function in the Newfoundland population. Diabetes 54, 33363339.
22. Kim, KN, Oh, SY & Hong, YC (2018) Associations of serum calcium levels and dietary calcium intake with incident type 2 diabetes over 10 years: the Korean Genome and Epidemiology Study (KoGES). Diabetol Metab Syndr 10, 50.
23. Wareham, NJ, Byrne, CD, Carr, C, et al. (1997) Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism 46, 11711177.
24. Hagström, E, Hellman, P, Lundgren, E, et al. (2007) Serum calcium is independently associated with insulin sensitivity measured with euglycaemic–hyperinsulinaemic clamp in a community-based cohort. Diabetologia 50, 317324.
25. Shalileh, M, Shidfar, F, Haghani, H, et al. (2010) The influence of calcium supplement on body composition, weight loss and insulin resistance in obese adults receiving low calorie diet. J Res Med Sci 15, 191201.
26. Mitri, J, Dawson-Hughes, B, Hu, FB, et al. (2011) Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 94, 486494.
27. Suh, S, Bae, JC, Jin, SM, et al. (2017) Serum calcium changes and risk of type 2 diabetes mellitus in Asian population. Diabetes Res Clin Pract 133, 109114.
28. Williamson, GD, Rennie, D, Moher, D, et al. (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 283, 20082012.
29. Wells, GA, Shea, B, O’Connell, D, et al. (2019) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed January 2019).
30. Zhao, D, Khawaja, AT, Jin, L, et al. (2018) The directional and non-directional associations of periodontitis with chronic kidney disease: a systematic review and meta-analysis of observational studies. J Periodontal Res 53, 682704.
31. Elyasi, M, Abreu, LG, Badri, P, et al. (2015) Impact of sense of coherence on oral health behaviors: a systematic review. PLOS ONE 10, e0133918.
32. Ferreira, MC, Dias-Pereira, AC, Branco-de-Almeida, LS, et al. (2017) Impact of periodontal disease on quality of life: a systematic review. J Periodontal Res 52, 651665.
33. Duval, S & Tweedie, R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56, 455463.
34. Heath, H III, Lambert, PW, Service, FJ, et al. (1979) Calcium homeostasis in diabetes mellitus. J Clin Endocrinol Metab 49, 462466.
35. McNair, P, Fogh-Andersen, N, Madsbad, S, et al. (1983) Decreased serum concentration of ionized calcium in insulin-dependent human diabetes mellitus. Eur J Clin Invest 13, 267270.
36. Cho, GJ, Shin, JH, Yi, KW, et al. (2011) Serum calcium level is associated with metabolic syndrome in elderly women. Maturitas 68, 382386.
37. Shimodaira, M, Niwa, T, Nakajima, K, et al. (2015) The relationship between serum calcium level and early-phase insulin secretion in normoglycemic and pre-diabetic individuals. Exp Clin Endocrinol Diabetes 123, 165169.
38. Guasch, A, Bulló, M, Rabassa, A, et al. (2012) Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: a cross-sectional study. Cardiovasc Diabetol 11, 149.
39. Pittas, AG, Dawson-Hughes, B, Li, T, et al. (2006) Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 29, 650656.
40. Villegas, R, Gao, YT, Dai, Q, et al. (2009) Dietary calcium and magnesium intakes and the risk of type 2 diabetes: the Shanghai women’s health study. Am J Clin Nutr 89, 10591067.
41. van Dam, RM, Hu, FB, Rosenberg, L, et al. (2006) Dietary calcium and magnesium, major food sources, and risk of type 2 diabetes in U.S. black women. Diabetes Care 29, 22382243.
42. Kirii, K, Mizoue, T, Iso, H, et al. (2009) Calcium, vitamin D and dairy intake in relation to type 2 diabetes risk in a Japanese cohort. Diabetologia 52, 25422550.
43. Dong, JY & Qin, LQ (2012) Dietary calcium intake and risk of type 2 diabetes: possible confounding by magnesium. Eur J Clin Nutr 66, 408410.
44. Reis, JP, Selvin, E, Pankow, JS, et al. (2016) Parathyroid hormone is associated with incident diabetes in white, but not black adults: the Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Metab 42, 162169.
45. Song, Y, Wang, L, Pittas, AG, et al. (2013) Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care 36, 14221428.
46. Gray, E, Muller, D, Squires, PE, et al. (2006) Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases. J Endocrinol 190, 703710.
47. Jones, PM, Kitsou-Mylona, I, Gray, E, et al. (2007) Expression and function of the extracellular calcium-sensing receptor in pancreatic beta-cells. Arch Physiol Biochem 113, 98103.
48. Henquin, JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49, 17511760.
49. Jing, X, Li, DQ, Olofsson, CS, et al. (2005) CaV2.3 calcium channels control second-phase insulin release. J Clin Invest 115, 146154.
50. Pittas, AG, Lau, J, Hu, FB, et al. (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92, 20172029.
51. Ko, SH, Lee, GS & Vo, TT (2009) Dietary calcium and 1, 25-dihydroxyvitamin D3 regulate transcription of calcium transporter genes in calbindin-D9k knockout mice. J Reprod Dev 55, 137142.
52. Draznin, B, Lewis, D, Houlder, N, et al. (1989) Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology 125, 23412349.
53. Draznin, B, Sussman, KE, Eckel, RH, et al. (1988) Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest 82, 18481852.
54. Park, S, Scheffler, TL, Gunawan, AM, et al. (2009) Chronic elevated calcium blocks AMPK-induced GLUT-4 expression in skeletal muscle. Am J Physiol Cell Physiol 296, C106C115.
55. Khan, AH & Pessin, JE (2002) Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia 45, 14751483.
56. Chandra, J, Zhivotovsky, B, Zaitsev, S, et al. (2001) Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 50, S44S47.
57. Wang, L, Bhattacharjee, A, Zuo, Z, et al. (1999) A low voltage-activated Ca2+ current mediates cytokine-induced pancreatic beta-cell death. Endocrinology 140, 12001204.
58. Ramadan, JW, Steiner, SR, O’Neill, CM, et al. (2011) The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes. Cell Calcium 50, 481490.
59. Calvi, LM & Bushinsky, DA (2008) When is it appropriate to order an ionized calcium? J Am Soc Nephrol 19, 12571260.
60. Zhao, G, Ford, ES & Li, C (2010) Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among U.S. adults without physician-diagnosed diabetes: NHANES, 2003–2006. Diabetes Care 33, 344347.
61. Guynn, RW, Veloso, D & Veech, RL (1972) Enzymic determination of inorganic phosphate in the presence of creatine phosphate. Anal Biochem 45, 277285.
62. Baird, GS (2011) Ionized calcium. Clin Chim Acta 412, 696701.
63. Bushinsky, DA & Monk, RD (1998) Electrolyte quintet: calcium. Lancet 352, 306311.

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