Unraveling the Magnesium Connection: The Cincinnati PPG's Pioneering Work on Mineral Metabolism in Diabetes and Pregnancy

Francis B. Mimouni; Jane C. Khoury; Shelley Ehrlich; Barak Rosen; Galit Sheffer-Mimouni; Menachem Miodovnik

doi:10.1055/a-2382-7475

American Journal of Perinatology, Table of Contents

Am J Perinatol 2025; 42(06): 691-696
DOI: 10.1055/a-2382-7475

Review Article

Unraveling the Magnesium Connection: The Cincinnati PPG's Pioneering Work on Mineral Metabolism in Diabetes and Pregnancy

Authors

Francis B. Mimouni

¹Department of Pediatrics and Research Institute, Leumit Health Services, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Jane C. Khoury

²Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

³Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

⁴Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Shelley Ehrlich

²Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

³Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

⁵Department of Environmental and Public Health Sciences, University of Cincinnati, College of Medicine, Cincinnati, Ohio
Barak Rosen

⁶Department of Maternal–Fetal Medicine, Rutgers New Jersey Medical School, Newark, New Jersey
Galit Sheffer-Mimouni

¹Department of Pediatrics and Research Institute, Leumit Health Services, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Menachem Miodovnik

⁷Department of Obstetrics and Gynecology, Inova Health System, Falls Church, Virginia

Abstract

This study aimed to review the Cincinnati PPG's contribution to the understanding and treatment of neonatal hypocalcemia (NHC) in infants of diabetic mothers. This study is a retrospective review of the NIH-funded Program Project Grant (PPG) works related to mineral metabolism in type 1 diabetic pregnant women. The PPG investigators first described the epidemiology and the additional risk factors for NHC, namely prematurity and neonatal asphyxia, but also recognized the independent effect of maternal diabetes mellitus. They explored the link between NHC and maternal/neonatal hypomagnesemia. They finally conducted a randomized control trial of prevention of NHC by early administration of magnesium sulfate soon after birth to prevent NHC. The PPG in its various phases has allowed to reveal the important role that magnesium plays in the regulation of mineral metabolism in pregnancy and in particular the pregnancy complicated by pregestational diabetes.

Key Points

Poor glycemic control during pregnancy leads to maternal magnesium deficiency.
Maternal magnesium deficiency leads to fetal and neonatal magnesium deficiency.
Neonatal magnesium deficiency leads to functional hypoparathyroidism and parathyroid hormone resistance.

Keywords

magnesium deficiency - neonatal hypocalcemia - neonatal hypomagnesemia - type 1 diabetes mellitus

Full Text

References

References
1 Tsang RC, Oh W. Neonatal hypocalcemia in low birth weight infants. Pediatrics 1970; 45 (05) 773-781
2 Tsang RC, Kleinman LI, Sutherland JM, Light IJ. Hypocalcemia in infants of diabetic mothers. Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness. J Pediatr 1972; 80 (03) 384-395
3 Tsang RC. Neonatal magnesium disturbances. Am J Dis Child 1972; 124 (02) 282-293
4 Levine BS, Coburn JW. Magnesium, the mimic/antagonist of calcium. N Engl J Med 1984; 310 (19) 1253-1255
5 Leicht E, Biro G. Mechanisms of hypocalcaemia in the clinical form of severe magnesium deficit in the human. Magnes Res 1992; 5 (01) 37-44
6 van Dijk PR, Waanders F, Qiu J, de Boer HHR, van Goor H, Bilo HJG. Hypomagnesemia in persons with type 1 diabetes: associations with clinical parameters and oxidative stress. Ther Adv Endocrinol Metab 2020; 11: 2042018820980240
7 Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev 2003; 24 (02) 47-66
8 Garland HO. New experimental data on the relationship between diabetes mellitus and magnesium. Magnes Res 1992; 5 (03) 193-202
9 Song Y, Hsu YH, Niu T, Manson JE, Buring JE, Liu S. Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7), magnesium intake, and risk of type 2 diabetes in women. BMC Med Genet 2009; 10: 4
10 Simental-Mendía LE, Sahebkar A, Rodríguez-Morán M, Guerrero-Romero F. A systematic review and meta-analysis of randomized controlled trials on the effects of magnesium supplementation on insulin sensitivity and glucose control. Pharmacol Res 2016; 111: 272-282
11 Guerrero-Romero F, Tamez-Perez HE, González-González G. et al. Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab 2004; 30 (03) 253-258
12 Grafton G, Bunce CM, Sheppard MC, Brown G, Baxter MA. Effect of Mg²⁺ on Na(+)-dependent inositol transport. Role for Mg²⁺ in etiology of diabetic complications. Diabetes 1992; 41 (01) 35-39
13 Rodrigues AK, Melo AE, Domingueti CP. Association between reduced serum levels of magnesium and the presence of poor glycemic control and complications in type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Syndr 2020; 14 (02) 127-134
14 Tsang RC, Chen I, Friedman MA. et al. Parathyroid function in infants of diabetic mothers. J Pediatr 1975; 86 (03) 399-404
15 Tsang RC, Strub R, Brown DR, Steichen J, Hartman C, Chen IW. Hypomagnesemia in infants of diabetic mothers: perinatal studies. J Pediatr 1976; 89 (01) 115-119
16 Mimouni F, Tsang RC, Hertzberg VS, Miodovnik M. Polycythemia, hypomagnesemia, and hypocalcemia in infants of diabetic mothers. Am J Dis Child 1986; 140 (08) 798-800
17 Malan AF, de V Heese H, Malan AF. The management of polycythaemia in the newborn infant. Early Hum Dev 1980; 4 (04) 393-403
18 Mimouni F, Miodovnik M, Siddiqi TA, Butler JB, Holroyde J, Tsang RC. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet Gynecol 1986; 68 (03) 370-372
19 Mimouni F, Miodovnik M, Tsang RC, Callahan J, Shaul P. Decreased amniotic fluid magnesium concentration in diabetic pregnancy. Obstet Gynecol 1987; 69 (01) 12-14
20 Mimouni F, Miodovnik M, Tsang RC, Holroyde J, Dignan PS, Siddiqi TA. Decreased maternal serum magnesium concentration and adverse fetal outcome in insulin-dependent diabetic women. Obstet Gynecol 1987; 70 (01) 85-88
21 Günther T, Ising H, Mohr-Nawroth F, Chahoud I, Merker HJ. Embryotoxic effects of magnesium deficiency and stress on rats and mice. Teratology 1981; 24 (02) 225-233
22 Mimouni F, Steichen JJ, Tsang RC, Hertzberg V, Miodovnik M. Decreased bone mineral content in infants of diabetic mothers. Am J Perinatol 1988; 5 (04) 339-343
23 Demarini S, Specker BL, Sierra RI, Miodovnik M, Tsang RC. Evidence of increased intrauterine bone resorption in term infants of mothers with insulin-dependent diabetes. J Pediatr 1995; 126 (5 Pt 1): 796-798
24 Belluci MM, de Molon RS, Rossa Jr. C. et al. Severe magnesium deficiency compromises systemic bone mineral density and aggravates inflammatory bone resorption. J Nutr Biochem 2020; 77: 108301
25 Littner Y, Mandel D, Mimouni FB, Dollberg S. Decreased bone ultrasound velocity in large-for-gestational-age infants. J Perinatol 2004; 24 (01) 21-23
26 Mimouni F, Loughead J, Miodovnik M, Khoury J, Tsang RC. Early neonatal predictors of neonatal hypocalcemia in infants of diabetic mothers: an epidemiologic study. Am J Perinatol 1990; 7 (03) 203-206
27 Mimouni F, Loughead JL, Tsang RC, Khoury J. Postnatal surge in serum calcitonin concentrations: no contribution to neonatal hypocalcemia in infants of diabetic mothers. Pediatr Res 1990; 28 (05) 493-495
28 Mimouni F, Mimouni CP, Loughead JL, Tsang RC. A case-control study of hypocalcemia in high-risk neonates: racial, but no seasonal differences. J Am Coll Nutr 1991; 10 (03) 196-199
29 Mimouni F, Tsang RC, Hertzberg VS, Neumann V, Ellis K. Parathyroid hormone and calcitriol changes in normal and insulin-dependent diabetic pregnancies. Obstet Gynecol 1989; 74 (01) 49-54
30 Shaul PW, Mimouni F, Tsang RC, Specker BL. The role of magnesium in neonatal calcium homeostasis: effects of magnesium infusion on calciotropic hormones and calcium. Pediatr Res 1987; 22 (03) 319-323
31 Demarini S, Mimouni F, Tsang RC, Khoury J, Hertzberg V. Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 1994; 83 (06) 918-922
32 Mehta KC, Kalkwarf HJ, Mimouni F, Khoury J, Tsang RC. Randomized trial of magnesium administration to prevent hypocalcemia in infants of diabetic mothers. J Perinatol 1998; 18 (05) 352-356
33 Rosenn B, Miodovnik M, Mimouni F, Khoury JC, Siddiqi TA. Patient experience in a diabetic program project improves subsequent pregnancy outcome. Obstet Gynecol 1991; 77 (01) 87-91