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

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1 Magnesium Research 2009; 22 (3): ORIGINAL ARTICLE Failure of β-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects 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 Correspondence: F. Guerrero-Romero, MD, PhD, FACP, Siqueiros 225 esq/castañeda, 34000, Durango, Dgo., Mexico Abstract. To evaluate if decreased insulin sensitivity is appropriately compensated by β-cell function in subjects with hypomagnesemia, 165 individuals, 20 to 65 years of age, were randomly enrolled in a cross-sectional study. Subjects were allocated into groups with and without hypomagnesemia, matched by age, gender, waist circumference, and body mass index. Pregnancy, smoking, alcohol consumption, high blood pressure, type 2 diabetes, chronic diarrhea, renal disease, malignancy, and heavy physical activity were exclusion criteria. Hypomagnesemia was defined by a serum magnesium concentration of < 1.8 mg/dl. As a surrogate of the hyperbolic model of β-cell function, the relation between Belfiore s index {2/[1 + (Fasting insulin pmol/l x Fasting glucose mmol/l)]} and the HOMA-β index {20 X Fasting insulin μu/ml /(Fasting glucose mmol/l 3.5)} was used. The mean Area Under Curve (AUC) was calculated for each group. Although the Belfiore index was significantly lower (0.041 ± and ± 0.030, p = 0.005) and fasting plasma glucose higher (113.6 ± 23.0 and ± 18.4 mg/dl, p = 0.04) in the subjects with hypomagnesemia, the HOMA-β index (82.5 ± 48.5 and 91.2 ± 79.9, p = 0.32) and insulin levels (8.6 ± 5.4 and 9.6 ± 4.8 μu/ml, p = 0.17) were similar between the groups studied. The AUC which evaluates the adaptation of beta-cell function to variation in insulin sensitivity was significantly higher in the normomagnesemic than the hypomagnesemic group (proportion 1:2.5). Results of this study show that the decrease in insulin sensitivity is not appropriately compensated by β-cell function in individuals with hypomagnesemia; our finding suggests that hypomagnesemia could be linked to inadequate β-cell compensation. Key words: beta-cell function, insulin sensitivity, magnesium doi: /mrh 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 151

2 L.E. SIMENTAL-MENDÍA, ET AL. 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 crosssectional 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 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 x G for 30 min. The serum was separated and kept frozen at 80 o C 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 glucoseoxidase 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 (cm 2 ). 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). 152

3 HYPOMAGNESEMIA AND INSULIN SECRETION 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 = 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 = , 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 cm 2 and cm 2 (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 and (proportion 1:2.8). 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 unex- Table 1. Characteristics of the targeted population according to serum magnesium levels. Hypomagnesemia Normomagnesemia p value n = 50 n = 115 Age, years 43.6 ± ± Male/Female, n (%) 24.3/ / Obesity (BMI 30 kg/m 2 ) 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 ± ± Body Mass Index, kg/m ± ± Systolic blood pressure, mmhg ± ± Diastolic blood pressure, mmhg 71.4 ± ± Fasting glucose, mg/dl ± ± Postload glucose, mg/dl ± ± Fasting insulin, μu/ml 8.6 ± ± Magnesium, mg/dl 1.4 ± ± 0.4 < Triglycerides, mg/dl ± ± HDL-cholesterol, mg/dl 42.4 ± ± Fasting Belfiore index ± ± HOMA-β index 82.5 ± ± Hypomagnesemia, serum magnesium concentration < 1.8 mg/dl. Normomagnesemia, serum magnesium concentration 1.8 mg/dl. 153

4 L.E. SIMENTAL-MENDÍA, ET AL. A B HOMA-b index HOMA-b index Belfiore index Belfiore index 0.15 Figure 1. Relationship between insulin sensitivity, using the Belfiore index [2/(Fasting Glucose mmol/l x Fasting Insulin pmol/l)+1] and insulin secretion, estimated by the HOMA-β cell index [(20 x Fasting Insulin μui/ml)/(fasting Glucose mmol/l 3.5)] which evaluates the adaptation of β-cell function to variations in insulin sensitivity. n = 165. The curve of individuals with hypomagnesemia is displaced to the left and below, A) showing the failure of insulin secretion to compensate the increase of insulin resistance. The curve of normomagnesemic control subjects shows a hyperbolic distribution (B). plained 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. 154

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