The Relationship between Serum Calcium Level and Early-phase Insulin Secretion in Normoglycemic and Pre-diabetic Individuals

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) is linked to altered calcium metabolism. However, little is known about the relationship between serum calcium levels and early-phase insulin secretion in subjects with normoglycemic tolerance (NGT) or prediabetes (preDM).

Methods: In this gender-separated cross-sectional study, 352 subjects with NGT (215 men and 137 women; age: 48.8±9.1 years and 51.6±6.7 years, respectively) and 316 subjects with preDM (231 men and 85 women; age: 52.5±8.6 years and 54.2±8.0 years, respectively) were examined. Following a 75-g oral glucose tolerance test, early-phase insulin secretion was estimated using the insulinogenic index (IGI) [ΔInsulin_{(30–0 min)}/ΔGlucose_{(30–0 min)}].

Results: Simple linear regression analysis showed that IGI was positively correlated with serum calcium and albumin-adjusted calcium levels in men with NGT and preDM. However, IGI was not correlated with calcium levels in women with NGT and preDM. Multivariate linear regression analysis of men with NGT revealed that the albumin-adjusted calcium level was the major predictor of IGI, responsible for 5.1% of its variation (P=0.003). In addition, in men with preDM, the albumin-adjusted calcium level was one of the predictors of IGI, responsible for 3.8% of its variation (P=0.004). These associations were independent of age, BMI, and HbA1c.

Conclusions: In non-diabetic Japanese men, serum calcium levels significantly correlate with early-phase insulin secretion. Serum calcium levels may be an independent predictor of β-cell function in men.

Key words

diabetes - insulinogenic index - insulin secretion - prediabetes - serum calcium

• References

• 1 Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 2000; 1: 11-21
• 2 Curry DL, Bennett LL, Grodsky GM. Requirement for calcium ion in insulin secretion by the perfused rat pancreas. Am J Physiol 1968; 214: 174-178
• 3 Henquin JC, Ravier MA, Nenquin M et al. Hierarchy of the beta-cell signals controlling insulin secretion. Eur J Clin Invest 2003; 33: 742-750
• 4 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: 212-216
• 5 Wareham NJ, Byrne CD, Carr C et al. Glucose intolerance is associated with altered calcium homeostasis: a possible link between increased serum calcium concentration and cardiovascular disease mortality. Metabolism 1997; 46: 1171-1177
• 6 Lind L, Jakobsson S, Lithell H et al. Relation of serum calcium concentration to metabolic risk factors for cardiovascular disease. Bmj 1988; 297: 960-963
• 7 Sun G, Vasdev S, Martin GR et al. Altered calcium homeostasis is correlated with abnormalities of fasting serum glucose, insulin resistance, and beta-cell function in the Newfoundland population. Diabetes 2005; 54: 3336-3339
• 8 Yamaguchi T, Kanazawa I, Takaoka S et al. 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: 1334-1339
• 9 Hagstrom E, Hellman P, Lundgren E et al. Serum calcium is independently associated with insulin sensitivity measured with euglycaemic-hyperinsulinaemic clamp in a community-based cohort. Diabetologia 2007; 50: 317-324
• 10 American Diabetes Association . Standards of medical care in diabetes – 2014. Diabetes Care 2014; 37 (Suppl. 01) S14-S80
• 11 Baird GS. Ionized calcium. Clin Chim Acta 2011; 412: 696-701
• 12 Matsuo S, Imai E, Horio M et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982-992
• 13 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 14 Jensen CC, Cnop M, Hull RL et al. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 2002; 51: 2170-2178
• 15 Faul F, Erdfelder E, Lang AG et al. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175-191
• 16 Aoki K, Miyagawa K. Correlation of increased serum calcium with elevated blood pressure and vascular resistance during calcium infusion in normotensive man. J Hypertens 1990; 8: 579-583
• 17 Jing X, Li DQ, Olofsson CS et al. CaV2.3 calcium channels control second-phase insulin release. J Clin Invest 2005; 115: 146-154
• 18 Taylor WH, Khaleeli AA. Coincident diabetes mellitus and primary hyperparathyroidism. Diabetes Metab Res Rev 2001; 17: 175-180
• 19 Tassone F, Procopio M, Gianotti L et al. Insulin resistance is not coupled with defective insulin secretion in primary hyperparathyroidism. Diabet Med 2009; 26: 968-973
• 20 Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000; 49: 1751-1760
• 21 Saltevo J, Niskanen L, Kautiainen H et al. Serum calcium level is associated with metabolic syndrome in the general population: FIN-D2D study. Eur J Endocrinol 2011; 165: 429-434
• 22 Lind L, Skarfors E, Berglund L et al. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 1997; 50: 967-973
• 23 Lorenzo C, Hanley AJ, Rewers MJ et al. Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetologia 2014; 57: 1366-1374
• 24 Haglin L, Backman L, Tornkvist B. A structural equation model for assessment of links between changes in serum triglycerides, -urate, and -glucose and changes in serum calcium, -magnesium and -phosphate in type 2 diabetes and non-diabetes metabolism. Cardiovasc Diabetol 2011; 10: 116
• 25 Liu S, Mauvais-Jarvis F. Minireview: Estrogenic protection of beta-cell failure in metabolic diseases. Endocrinology 2010; 151: 859-864
• 26 Lee S, Clark SA, Gill RK et al. 1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology 1994; 134: 1602-1610
• 27 Hitman GA, Mannan N, McDermott MF et al. Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians. Diabetes 1998; 47: 688-690
• 28 Sergeev IN, Rhoten WB. 1,25-Dihydroxyvitamin D3 evokes oscillations of intracellular calcium in a pancreatic beta-cell line. Endocrinology 1995; 136: 2852-2861
• 29 Stumvoll M, Mitrakou A, Pimenta W et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 2000; 23: 295-301
• 30 Faerch K, Pacini G, Nolan JJ et al. Impact of glucose tolerance status, sex, and body size on glucose absorption patterns during OGTTs. Diabetes Care 2013; 36: 3691-3697
• 31 Cade C, Norman AW. Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology 1986; 119: 84-90
• 32 Guynn RW, Veloso D, Veech RL. Enzymic determination of inorganic phosphate in the presence of creatine phosphate. Anal Biochem 1972; 45: 277-285