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Failure of β-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects


Magnesium Research. Volume 22, Numéro 3, 151-6, september 2009, Original article

DOI : 10.1684/mrh.2009.0180

Summary  

Auteur(s) : Luis E Simental-Mendía, Martha Rodríguez-Morán, Fernando Guerrero-Romero , Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico, and The Research Group on Diabetes, Durango, Mexico.

Illustrations

ARTICLE

Auteur(s) : Luis E Simental-Mendía, Martha Rodríguez-Morán, Fernando Guerrero-Romero

Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico, and The Research Group on Diabetes, Durango, Mexico

Magnesium, the second most abundant intracellular cation [1], is an essential cofactor of enzymatic pathways involved in energetic metabolism and the modulation of glucose transport across cell membranes [2].

A large body of evidence shows that hypomagnesemia reduces tyrosine-kinase activity at the insulin receptor level resulting in the impairment of insulin action [2-8] and that oral magnesium supplementation improves insulin sensitivity [9-13]. These data support the important role that magnesium plays in the regulation of insulin action; however, data regarding the link between magnesium and insulin secretion are controversial.

The physiological relationship between beta cell function and insulin sensitivity is distributed as a hyperbolic line [14] that shows that the increase in insulin secretion compensates the decrease in insulin sensitivity [15, 16]. The product of insulin secretion and insulin sensitivity, the disposition index, is a useful tool for identifying at-risk individuals [17, 18]; however, because determination of the disposition index is based on data derived from the hyperinsulinemic-euglycemic and hyperglycemic clamp [14], it is not available in a clinical setting. In this regard, based on a 5-y follow-up study, we recently reported that the relationship between insulin secretion and insulin action estimated by the HOMA-β and Belfiore indexes is distributed as a hyperbolic line that represents the progressive adaptation of β-cells to compensate the decrease in insulin sensitivity [19].

In this study, we tested the hypothesis that the decreased insulin sensitivity is not appropriately compensated by β-cell function in individuals with hypomagnesemia.

Material and methods

With the approval of the protocol by the Mexican Social Security Institute Research Committee and after obtaining written informed consent, a cross-sectional study was performed.

One-hundred and sixty-five individuals 20 to 65 years of age, inhabitants of Durango, a city in northern Mexico, were randomly enrolled in a cross-sectional study. Subjects were allocated into groups with and without hypomagnesemia, matched by age, gender, waist circumference (WC), and Body Mass Index (BMI).

Pregnancy, smoking, alcohol consumption, high blood pressure, type 2 diabetes, chronic diarrhea, renal disease, malignancy, and heavy physical activity were exclusion criteria. The clinical condition was corroborated by medical history, physical examination, and laboratory tests.

Definitions

Hypomagnesemia was defined by serum magnesium concentration < 1.8 mg/dL and normomagnesemia by serum magnesium ≥ 1.8 mg/dL.

As a surrogate of the hyperbolic model of β-cell function [20], we used the relationship between Belfiore’s and HOMA-β indices, as measurements of insulin sensitivity and β-cell function [19]. The fasting Belfiore’s index [21] was estimated by the formula 2/[1 + (Fasting insulin pmol/L x Fasting glucose mmol/L)] and the β-cell function index [22] as the 20 x Fasting insulin μU/mL/(Fasting glucose mmol/L – 3.5). The cut off point of normal Belfiore and HOMA-β indexes are ≤ 0.034 and ≥ 107.

Measurements

In the standing position, weight and height were measured using a fixed scale with stadimeter with the subjects in light clothing and without shoes. Body Mass Index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. The WC was measured to the nearest centimeter with a flexible steel tape measure with the subjects in standing position. The anatomical landmarks were: laterally, midway between the lowest portion of the rib cage and iliac crest, and the umbilicus anteriorly.

The technique for measurement of blood pressure was that recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [23].

Assays

Whole blood samples were collected from antecubital venous after 8-10 h overnight fasting. The blood samples were centrifuged at 3 000 x G for 30 min. The serum was separated and kept frozen at – 80oC until further analysis. Serum magnesium concentrations were measured by colorimetric methods that comprise putting the serum sample in contact with the reagent, a metallochromic dye substance together with a selective complexing agent for removing interfering cations; the intra- and interassay variations were 1.0 and 2.5%, respectively. Serum glucose was measured using the glucose-oxidase method, the intra- and inter-assay coefficients of variation were 1.1% and 1.5%. Insulin levels were measured by microparticle enzyme immunoassay (Abbot Axsym System, Chicago IL, USA), with intra- and inter-assay coefficients of variation 4.5% and 6.9%. Measurements were performed in a Data Pro Plus Clinical Analyzer (Arlington, TX, USA).

Statistical analysis

Differences were assessed using the unpaired Student t test (Mann-Whitney U test for skewed data) for numeric variables, and the Chi-squared test for testing differences between proportions.

The mean Area Under Curve (AUC), which evaluates the adaptation of beta-cell function to variation in insulin sensitivity, was calculated for each group using the trapezoidal rule [24], which facilitates the calculation of the AUC in standard units of area (cm2).

The correlation between serum magnesium levels and the HOMA-β index was estimated using Pearson’s correlation analysis.

Data were analyzed using the statistical package SPSS 15.0 (SPSS Inc., Chicago Il).

Results

A total of 50 subjects with hypomagnesemia were compared with 115 normomagnesemic subjects. Subjects with hypomagnesemia had significantly higher FPG and 2-h post load glucose than subjects in the control group; nonetheless, the groups in study were comparable in terms of the distribution of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) (table 1).

The proportion of subjects with insulin resistance (Belfiore index ≤ 0.034) was similar in the groups with hypomagnesemia (46%) and normomagnesemia (31.3%), p = 0.10. Although the mean Belfiore index was significantly lower in the subjects with hypomagnesemia, the mean HOMA-β index and insulin levels were similar between the groups in study. Other variables showed not significant differences between the groups (table 1).

Serum magnesium levels and the HOMA-β index showed a significant inverse correlationship (r = - 0.187, p = 0.02).

The relationship that evaluates the adaptation of β-cell function to variation in insulin sensitivity in the hypomagnesemic and normomagnesemic individuals is given in figure 1. Subjects with hypomagnesemia showed a curve displaced to the left and below, that suggests the failure of insulin secretion to compensate the decrease in insulin sensitivity. The AUC in the hypomagnesemic and normomagnesemic groups was 7.955 cm2 and 19.906 cm2 (proportion 1:2.5), respectively. Subsequent analysis adjusted by BMI, showed that the AUC which evaluates the adaptation of beta-cell function to variation in insulin sensitivity was 6.891.and 19.121 (proportion 1:2.8).
Table 1 Characteristics of the targeted population according to serum magnesium levels.

Hypomagnesemia

Normomagnesemia

p value

n = 50

n = 115

Age, years

43.6 ± 13.6

43.4 ± 11.4

0.77

Male/Female, n (%)

24.3/75.7

34.0/66.0

0.27

Obesity (BMI ≥ 30 kg/m2)

21 (42.0)

45 (39.1)

0.86

Impaired Fasting Glucose, n (%)

20 (40.0)

29 (25.2)

0.08

Impaired Glucose Tolerance, n (%)

15 (30.0)

50 (43.3)

0.14

Waist circumference, cm

101.6 ± 12.9

101.9 ± 13.4

0.92

Body Mass Index, kg/m2

28.4 ± 5.7

29.5 ± 6.3

0.34

Systolic blood pressure, mmHg

114.2 ± 24.2

119.1 ± 21.9

0.27

Diastolic blood pressure, mmHg

71.4 ± 11.1

75.2 ± 11.8

0.08

Fasting glucose, mg/dL

113.6 ± 23.0

106.8 ± 18.4

0.04

Postload glucose, mg/dL

134.6 ± 32.9

121.4 ± 29.7

0.01

Fasting insulin, μU/mL

8.6 ± 5.4

9.6 ± 4.8

0.17

Magnesium, mg/dL

1.4 ± 0.2

2.3 ± 0.4

<0.0001

Triglycerides, mg/dL

141.3 ± 65.5

145.0 ± 66.1

0.72

HDL-cholesterol, mg/dL

42.4 ± 14.4

44.5 ± 22.0

0.42

Fasting Belfiore index

0.041 ± 0.021

0.053 ± 0.030

0.005

HOMA-β index

82.5 ± 48.5

91.2 ± 79.9

0.32

Discussion

Results of this study indicate that variations of insulin sensitivity are not appropriately compensated by β-cell function in the individuals with hypomagnesemia.

The body of evidence shows that magnesium has an important role in insulin-mediated glucose uptake [25-29]; however, reports regards the role of magnesium on insulin secretion in subjects with hypomagnesemia are controversial, with some studies showing a high insulin response [26, 30] but others an impairment of insulin secretion [12, 13]. Among non-diabetic subjects, a low magnesium concentration has been associated with relative insulin resistance and hyperinsulinemia [30] and among diabetic subjects, the direct relation of plasma magnesium concentration with glucose disposal is related to insulin sensitivity but is unexplained in its influence on insulin secretion [26]. These findings suggest that hypomagnesemia may be an important determinant of insulin sensitivity but they are not conclusive regarding the link between hypomagnesemia and insulin secretion.

In this study, individuals with hypomagnesemia exhibited significantly higher glucose levels and insulin resistance but similar β-cell function and insulin levels than those found in normomagnesemic subjects, suggesting that the β-cell function to compensate the decrease in insulin sensitivity was inappropriate. Normal glucose tolerance is maintained by a precise balance between insulin secretion and insulin action on sensitive tissues, in a way that a reduction of insulin sensitivity is compensated by an increase in insulin secretion, and the improvement of insulin action by a decrease of β-cell insulin secretion, a relationship consistent with a classic feedback loop [31, 32]. On the basis of this hyperbolic relationship, the product of these two variables, referred to as the disposition index, can be calculated and it has highlighted the inability of the β-cell to compensate for insulin resistance in subjects at risk for diabetes [33]. Thus, our results support the statement that subjects with hypomagnesemia are at high risk of developing type 2 diabetes [8], and that, in addition to a decrease in insulin sensitivity, an inappropriate compensatory β-cell function contributes to the increased risk. Furthermore, our results suggest that hypomagnesemia could be linked to inadequate β-cell compensation.

To the best of our knowledge, this study is the first that evaluates the response of β-cells to compensate for insulin resistance using a hyperbolic model that represents the physiological relationship between insulin secretion and insulin sensitivity.

Some limitations of this study deserve to be mentioned. First, assessment of the β-cell response is a complex issue that requires use of mathematical models applying data derived from the hyperglycemic clamp [34] so, approximations from a fasting state for evaluating β-cell function do not accurately reflect the β-cell function. However, the fasting model for estimating the relationship between insulin secretion and action that we used proved to be a good predictor for progression from IFG to IGT, and diabetes, which supports its reliability for use in epidemiological studies. Second, subjects were classified according to their serum magnesium concentrations; because magnesium is predominantly an intracellular ion, its serum measurements could be not representative of the magnesium status or intracellular pool. In this regard, is necessary to keep in mind that, although significant intracellular magnesium depletion can be seen with normal serum concentrations, once serum magnesium declines, normal intracellular levels of magnesium are unlikely to be found [35]; therefore, because we included only patients with decreased serum magnesium levels, the possibility of normal intracellular magnesium in the study population, which might be a source of bias, is minimal.

On the other hand, the main strength of our study is that the population included subjects with different glucose tolerance and insulin sensitivity status and that the evaluation of insulin secretion was performed in the context of insulin action.

As a conclusion, our results show that the decrease in insulin sensitivity is not appropriately compensated by β-cell function in individuals with hypomagnesemia, suggesting that hypomagnesemia could be linked to inadequate β-cell compensation.

Acknowledgments

This work was supported by grants from the Fundación IMSS, A.C.

References

1 Lopez Martínez J, Sanchez Castilla M, García de Lorenzo y Mateos A, Culebras Fernandez JM. Magnesium: metabolism and requeriments. Nutr Hosp 1997: 4-14.

2 Paolisso G, Barbagallo M. Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Am J Hypertens 1997; 10: 346-55.

3 Kao WH, Folsom AR, Nieto FJ, Mo JP, Watson RL, Brancati FL. Serum and Dietary Magnesium and the Risk for Type 2 Diabetes Mellitus: The Atherosclerosis Risk in Communities Study. Arch Intern Med 1999; 159: 2151-9.

4 Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993; 21: 1024-9.

5 Paolisso G, Scheen A, D’Onofrio F, Lefebvre P. Magnesium and glucose homeostasis. Diabetologia 1990; 33: 511-4.

6 Tosiello L. Hypomagnesemia and diabetes mellitus. A review of clinical implications. Arch Intern Med 1996; 156: 1143-8.

7 Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA, Hutchinson RG, Metcalf PA. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: The ARIC study. Atherosclerosis Risk in Communities Study. J Clin Epidemiol 1995; 48: 927-40.

8 Guerrero-Romero F, Rascón-Pacheco RA, Rodríguez-Morán M, de la Peña JE, Wacher N. Hypomagnesaemia and risk for metabolic glucose disorders: a 10-year follow-up study. Eur J Clin Invest 2008; 38: 389-96.

9 Rodríguez-Morán M, Guerrero-Romero F. Oral Magnesium Supplementation Improves Insulin Sensitivity and Metabolic Control in Type 2 Diabetic Subjects: A randomized double-blind controlled trial. Diabetes Care 2003; 26: 1147-52.

10 Ma B, Lawson AB, Liese AD, Bell RA, Mayer-Davis EJ. Dairy, Magnesium, and Calcium Intake in Relation to Insulin Sensitivity: Approaches to Modeling a Dose-dependent Association. Am J Epidemiol 2006; 164: 449-58.

11 Paolisso G, Scheen A, Cozzolino D, Di Mario G, Varricchio M, D’Onofrio F, Lefebvre P. Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients. J Clin Endocrinol Metab 1994; 78: 1510-4.

12 Lefebvre PJ, Paolisso G, Scheen AJ. Magnesium and glucose metabolism. Therapie 1994; 49: 1-7.

13 Sheehan JP. Magnesium deficiency and diabetes mellitus. Magnes Trace Elem 1991; 10: 215-9.

14 Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. Quantification of the relationship between insulin sensitivity and β-cell function in human subjects: evidence for a hyperbolic function. Diabetes 1993; 42: 1663-72.

15 Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787-94.

16 Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003; 46: 3-19.

17 Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennett PH, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus. Prospectives studies of Pima Indians. N Engl J Med 1993; 329: 1988-92.

18 Cavaghan MK, Ehrmann DA, Polonsky K. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest 2000; 106: 329-33.

19 Guerrero F, Rodríguez M. Assessing progression to impaired glucose tolerance and type 2 diabetes mellitus. Eur J Clin Invest 2006; 36: 796-802.

20 Bergman RN, Ader M, Huecking K, Van Citters G. Accurate assessment of β-cell function. The hyperbolic correction. Diabetes 2002; 51: S212-S220.

21 Belfiore F, Lannello S, Volpicelli G. Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 1998; 63: 134-41.

22 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-9.

23 The Seventh Report of the Joint National Committee on Prevention. Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206-52.

24 Shargel L, Wu-Pong S, Yu ABC. Review of mathematical fundamentals. In: Applied Biopharmaceutics and Pharmacokinetics. New York: McGraw-Hill, 2004: 21-51.

25 Bergman RN, Philips LS, Cobelli C. Physiologic evaluation of factors controlling glucose disposition in man: measurement of insulin sensitivity and B-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68: 1456-67.

26 Yajnik CS, Smith RF, Hockaday TDR, Ward NI. Fasting plasma magnesium concentrations and glucose disposal in diabetes. Br Med J (Clin Res Ed) 1984; 288: 1032-4.

27 Paolisso G, Sgambato S, Giuglinao D, Torella R, Varicchio M, Scheen AJ, D’Onofrio F, Lefebvre PJ. Impaired insulin mediated erythrocyte magnesium accumulation is correlated to impaired insulin-mediated glucose disposal in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1988; 31: 910-5.

28 Dzurik R, Stefikova K, Spustova V, Fetkovska N. The role of magnesium deficiency in insulin resistance: an in vitro study. J Hypertens 1991; 9: S312-S313.

29 Guerrero-Romero F, Rodríguez-Morán M. Relationship between serum magnesium levels and C-reactive protein concentration, in non-diabetic, non-hypertensive obese subjects. Int Obes Relat Metab Disord 2002; 26: 469-74.

30 Rosolova H, Mayer Jr O, Reaven G. Effect of variations in plasma magnesium concentration on resistance to insulin-mediated glucose disposal in nondiabetic subjects. J Endocrinol Metab 1997; 82: 3783-5.

31 Bergman RN, Ader M, Huecking K, Van Citters G. Accurate assessment of β-cell function. The hyperbolic correction. Diabetes 2002; 51 (Suppl. 1): S212-S220.

32 Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 1981; 68: 1456-67.

33 Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP, et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002; 51: 2796-803.

34 Ferrannini E, Mari A. Beta cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia 2004; 47: 943-56.

35 Reinhart R, Marx J, Haas R, Desbiens N. Intracellular magnesium of mononuclear cells from venous blood of clinical healthy subjects. Clin Chem Acta 1987; 48: 2415-20.


 

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