, Volume 57, Issue 7, pp 1366–1374 | Cite as

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

  • Carlos LorenzoEmail author
  • Anthony J. Hanley
  • Marian J. Rewers
  • Steven M. Haffner



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.


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.


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.


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.


Clinical science Epidemiology Human Insulin sensitivity and resistance Pathogenic mechanisms Prediction and prevention of type 2 diabetes 



Acute insulin response


Cardiovascular disease


Estimated GFR


Insulin Resistance Atherosclerosis Study


Insulin sensitivity index



This study was supported by National Heart, Lung, and Blood Institute grants HL-47887, HL-47889, HL-47890, HL-47892 and HL-47902, and the General Clinical Research Centers Program (NCRR GCRC, M01 RR431 and M01 RR01346).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CL contributed to the conception and design of the study, analysis and interpretation of data and drafting the article. AJH and MJR contributed to the analysis and interpretation of data and revised the manuscript critically for important intellectual content. SMH contributed to the acquisition of data, conception and design of the study, analysis and interpretation of data and drafting the article. All authors gave final approval of the version to be published. CL is responsible for the integrity of the work as a whole.

Supplementary material

125_2014_3241_MOESM1_ESM.pdf (266 kb)
ESM Fig. 1 (PDF 266 kb)


  1. 1.
    Leiffsson BG, Ahren B (1996) Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab 81:2149–2153Google Scholar
  2. 2.
    Håglin L, Törnkvist B, Bäckman L (2007) Prediction of all-cause mortality in a patient population with hypertension and type 2 DM by using traditional risk factors and serum-phosphate, -calcium and -magnesium. Acta Diabetol 44:138–143PubMedCrossRefGoogle Scholar
  3. 3.
    Walsh JP, Divitini ML, Knuiman MW (2013) Plasma calcium as a predictor of cardiovascular disease in a community-based cohort. Clin Endocrinol (Oxf) 78:852–857CrossRefGoogle Scholar
  4. 4.
    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 28:569–578PubMedCrossRefGoogle Scholar
  5. 5.
    Andersson P, Rydberg E, Willenheimer R (2004) Primary hyperparathyroidism and heart disease: a review. Eur Heart J 25:1776–1787PubMedCrossRefGoogle Scholar
  6. 6.
    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 19:958–961PubMedCrossRefGoogle Scholar
  7. 7.
    Taylor WH, Khaleeli AA (2001) Coincident diabetes mellitus and primary hyperparathyroidism. Diabetes Metab Res Rev 17:175–180PubMedCrossRefGoogle Scholar
  8. 8.
    Stefenelli T, Mayr H, Bergler-Klein J, Globits S, Woloszczuk W, Niederle B (1993) Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 95:197–202PubMedCrossRefGoogle Scholar
  9. 9.
    Richards ML, Thompson NW (1999) Diabetes mellitus with hyperparathyroidism: another indication for parathyroidectomy? Surgery 126:1160–1166PubMedCrossRefGoogle Scholar
  10. 10.
    Wareham NJ, Byrne CD, Carr C, Day NE, Boucher BJ, Hales CN (1997) Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism 46:1171–1177PubMedCrossRefGoogle Scholar
  11. 11.
    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 54:3336–3339PubMedCrossRefGoogle Scholar
  12. 12.
    Hagström E, Hellman P, Lundgren E, Lind L, Arnlöv J (2007) Serum calcium is independently associated with insulin sensitivity measured with euglycaemic-hyperinsulinaemic clamp in a community-based cohort. Diabetologia 50:317–324PubMedCrossRefGoogle Scholar
  13. 13.
    DeLuca HF (1975) The kidney as an endocrine organ involved in the function of vitamin D. Am J Med 58:39–47PubMedCrossRefGoogle Scholar
  14. 14.
    National Kidney Foundation (2003) K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42:S77–S84Google Scholar
  15. 15.
    Block GA, Port FK (2000) Re‐evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendation for a change in management. Am J Kidney Dis 35:1226–1237PubMedCrossRefGoogle Scholar
  16. 16.
    Mills WR, Einstadter D, Finkelhor RS (2004) Relation of calcium-phosphorus product to the severity of aortic stenosis in patients with normal renal function. Am J Cardiol 94:1196–1198PubMedCrossRefGoogle Scholar
  17. 17.
    Dhingra R, Sullivan LM, Fox CS et al (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885PubMedCrossRefGoogle Scholar
  18. 18.
    Tonelli M, Sacks F, Pfeffer M et al (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633PubMedCrossRefGoogle Scholar
  19. 19.
    Haap M, Heller E, Thamer C, Tschritter O, Stefan N, Fritsche A (2006) Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects. Eur J Clin Nutr 60:734–739PubMedCrossRefGoogle Scholar
  20. 20.
    DeFronzo RA, Lang R (1980) Hypophosphatemia and glucose intolerance: evidence for tissue insensitivity to insulin. N Engl J Med 303:1259–1263PubMedCrossRefGoogle Scholar
  21. 21.
    Wittmann I, Nagy J (1997) Effectiveness of phosphate supplementation in glucose intolerant, hypophosphatemic patients. Miner Electrolyte Metab 23:62–63PubMedGoogle Scholar
  22. 22.
    Wagenknecht LE, Mayer EJ, Rewers M et al (1995) The Insulin Resistance Atherosclerosis Study: design, objectives and recruitment results. Ann Epidemiol 5:464–472PubMedCrossRefGoogle Scholar
  23. 23.
    Herbert V, Lau K, Gottlieb C, Bleicher S (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 25:1375–1384PubMedCrossRefGoogle Scholar
  24. 24.
    Macy EM, Hayes TE, Tracy RP (1997) Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem 43:52–58PubMedGoogle Scholar
  25. 25.
    Lott JA, Manning NR, Kyler MK (1989) Proficiency testing in a medical-needs context. Clin Chem 35:347–354PubMedGoogle Scholar
  26. 26.
    Guynn RW, Veloso D, Veech RL (1972) Enzymic determination of inorganic phosphate in the presence of creatine phosphate. Anal Biochem 45:277–285PubMedCrossRefGoogle Scholar
  27. 27.
    Payne RB, Little AJ, Williams RB, Milner JR (1973) Interpretation of serum calcium in patients with abnormal serum proteins. BMJ 4:643–646PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Levey AS, Coresh J, Balk E et al (2003) National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 139:137–147PubMedCrossRefGoogle Scholar
  29. 29.
    Ma B, Lawson AB, Liese AD, Bell RA, Mayer-Davis EJ (2006) Dairy, magnesium, and calcium intake in relation to insulin sensitivity: approaches to modeling a dose-dependent association. Am J Epidemiol 164:449–458PubMedCrossRefGoogle Scholar
  30. 30.
    Harrell FE (2001) Regression modeling strategies. Springer, New YorkCrossRefGoogle Scholar
  31. 31.
    Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760PubMedCrossRefGoogle Scholar
  32. 32.
    Pittas AG, Lau J, Hu FB, Dawson-Hughes B (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    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 55:137–142PubMedCrossRefGoogle Scholar
  34. 34.
    Resnick LM (1991) Calcium metabolism in hypertension and allied metabolic disorders. Diabetes Care 14:505–520PubMedCrossRefGoogle Scholar
  35. 35.
    Lind L, Jakobsson S, Lithell H, Wengle B, Ljunghall S (1988) Relation of serum calcium concentration to metabolic risk factors for cardiovascular disease. BMJ 297:960–963PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Saltevo J, Niskanen L, Kautiainen H et al (2011) Serum calcium level is associated with metabolic syndrome in the general population: FIN-D2D study. Eur J Endocrinol 165:429–434PubMedCrossRefGoogle Scholar
  37. 37.
    Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S (1997) Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 50:967–973PubMedCrossRefGoogle Scholar
  38. 38.
    Levy J, Stern Z, Gutman A et al (1986) Plasma calcium and phosphate levels in an adult non-insulin-dependent diabetic population. Calcif Tissue Int 39:316–318PubMedCrossRefGoogle Scholar
  39. 39.
    Heath H, Lambert PW, Service FJ et al (1979) Calcium homeostasis in diabetes mellitus. J Clin Endocrinol Metab 49:462–466PubMedCrossRefGoogle Scholar
  40. 40.
    Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S (2001) Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 50(Suppl 1):S44–S447PubMedCrossRefGoogle Scholar
  41. 41.
    Wang L, Bhattacharjee A, Zuo Z et al (1999) A low voltage-activated Ca2+ current mediates cytokine-induced pancreatic beta-cell death. Endocrinology 140:1200–1204PubMedGoogle Scholar
  42. 42.
    Ramadan JW, Steiner SR, O'Neill CM, Nunemaker CS (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 50:481–490PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Zhou YB, Zhang J, Cai Y et al (2012) Insulin resistance induces medial artery calcification in fructose-fed rats. Exp Biol Med (Maywood) 237:50–57CrossRefGoogle Scholar
  44. 44.
    Ljunghall S, Hedstrand H, Hellsing K, Wibell L (1977) Calcium, phosphate and albumin in serum. A population study with special reference to renal stone formers and the prevalence of hyperparathyroidism in middle-aged men. Acta Med Scand 201:23–30PubMedCrossRefGoogle Scholar
  45. 45.
    Lorenzo C, Nath SD, Hanley AJ, Abboud HE, Haffner SM (2008) The relation of low glomerular filtration rate to metabolic disorders in individuals without diabetes and with normoalbuminuria. Clin J Am Soc Nephrol 3:783–789PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Scragg R (2008) Vitamin D and type 2 diabetes. Are we ready for a prevention trial? Diabetes 57:2565–2566PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G (2005) Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA 294:2336–2341PubMedCrossRefGoogle Scholar
  48. 48.
    Craver L, Marco MP, Martínez I et al (2007) Mineral metabolism parameters throughout chronic kidney disease stages 1–5: achievement of K/DOQI target ranges. Nephrol Dial Transplant 22:1171–1176PubMedCrossRefGoogle Scholar
  49. 49.
    Hsu CY, Chertow GM (2002) Elevations of serum phosphorus and potassium in mild to moderate chronic renal insufficiency. Nephrol Dial Transplant 17:1419–1425PubMedCrossRefGoogle Scholar
  50. 50.
    Levin A, Bakris GL, Molitch M et al (2006) Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 71:31–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Carlos Lorenzo
    • 1
    Email author
  • Anthony J. Hanley
    • 2
    • 3
    • 4
    • 5
  • Marian J. Rewers
    • 6
  • Steven M. Haffner
    • 1
  1. 1.Department of MedicineUniversity of Texas Health Science CenterSan AntonioUSA
  2. 2.Department of Nutritional SciencesUniversity of TorontoTorontoCanada
  3. 3.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  4. 4.Leadership Sinai Centre for DiabetesMt Sinai HospitalTorontoCanada
  5. 5.Department of MedicineUniversity of TorontoTorontoCanada
  6. 6.Barbara Davis Center for Childhood DiabetesUniversity of Colorado School of MedicineAuroraUSA

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