الشواك الأسود وفرط إنسولين الدم وعوامل اختطار الأمراض القلبية الوعائية
عبد الباري بنر وجيلز ج. لسترنجانت وبولانجو ل. نيومبا وفيليب فروسارد وحسين فضل السعدي

خلاصـة: في هذه الدراسة بحثنا الترابط بين الشواك الأسود وفرط إنسولين الدم وعوامل الاختطار الأخرى للأمراض القلبية الوعائية في مرضى من الإمارات العربية المتحدة. فقد تم تسجيل الطول والوزن وضغط الدم في وضع الجلوس وذلك في 122 مريضاً بالشواك الأسود. كما أخذت منهم عينات دم لقياس مستويات الكولستيرول والبروتين الشحمي الرفيع الكثافة وثلاثي الغليسريد وحمض اليوريك، وذلك في حالة الصيام. وفضلاً عن ذلك أجري اختبار تحمُّل الغلوكوز الفموي، وأخذت عينات دم لقياس مستويات الإنسولين والغلوكوز. وتُبيـِّن نتائجنا أن المصابين بالشواك الأسود كان لديهم معدل انتشار مرتفع لعدم تحمُّل الغلوكوز الفموي وفرط إنسولين الدم. وفضلاً عن ذلك فإن المرضى ذوي سكر الدم السوي مع فرط إنسولين الدم كانت لديهم مجموعة من عوامل اختطار الأمراض القلبية الوعائية.

ABSTRACT We examined the association between acanthosis nigricans, hyperinsulinaemia and other risk factors for cardiovascular disease in patients from the United Arab Emirates. Height, weight and sitting blood pressure were recorded in 122 patients with acanthosis nigricans, and blood samples were obtained for measuring fasting cholesterol, high-density lipoprotein cholesterol, triglyceride and uric acid levels. In addition, a glucose tolerance test was performed and blood was sampled for insulin and glucose. Our results indicate that the patients with acanthosis nigricans had a high prevalence of abnormal glucose tolerance and hyperinsulinaemia. In addition, euglycaemic patients with hyperinsulinaemia had a cluster of risk factors for cardiovascular disease.

Acanthosis nigricans, l'hyperinsulinémie et les facteurs de risque de maladies cardiovasculaires

RESUME Dans notre étude, nous avons examiné l'association entre l'acanthosis nigricans, l'hyperinsulinémie et d'autres facteurs de risque de maladies cardiovasculaires chez des patients aux Emirats arabes unis. La taille, le poids et la tension artérielle en position assise ont été enregistrés chez 122 patients atteints d'acanthosis nigricans, et des prélèvements sanguins ont été obtenus pour mesurer les niveaux de cholestérol à jeun, de cholestérol des lipoprotéines lourdes, de triglycérides et d'acide urique. De plus, une épreuve d'hyperglycémie provoquée par voie orale a été réalisée et un prélèvement sanguin a été effectué pour l'insuline et le glucose. Nos résultats indiquent que les patients atteints d'acanthosis nigricans avaient une forte prévalence de tolérance anormale au glucose et d'hyperinsulinémie. De plus, les patients dont la glycémie était normale et qui avaient une hyperinsulinémie avaient un ensemble de facteurs de risque de maladies cardiovasculaires.

Introduction

Prior studies have supported the association between acanthosis nigricans (AN), hyperinsulinaemia and type 2 diabetes mellitus (DM) [1-3]. In addition, a significant correlation has been established between hyperinsulinaemia, hyperuricaemia and a variety of risk factors for cardiovascular disease (CVD), such as hypertension, dyslipidaemia, DM and obesity [4-8]. In this study, we examined the association between AN, hyperinsulinaemia and other risk factors for CVD in patients from the United Arab Emirates (UAE).

Patients and methods

This cross-sectional study was conducted between 1994 and 1997. The study population was UAE nationals who were diagnosed with AN by one of the authors at the time they were attending the dermatology clinic at Tawam Hospital, a tertiary health care centre in Al-Ain, UAE. A total of 122 patients (30 males and 92 females, ages 16-65 years) participated in the study. All the patients were self-referred for various skin problems, and none was known to have DM. AN was identified on the nape of the neck and other body sites. The degree of AN severity was not recorded.

The following data were collected at the time of the diagnosis of AN. Height and weight were recorded and obesity was defined as a body mass index (BMI) of ³ 30 kg/m². Blood pressure was measured with a mercury sphygmomanometer while the patients were sitting. Systolic and diastolic pressures were determined at the time of the appearance and disappearance of Korotkoff sounds respectively. Venous blood samples for uric acid, triglycerides, total cholesterol and high-density lipoprotein (HDL) cholesterol were collected after an overnight fast. A standard (75 g) oral glucose tolerance test (OGTT) was performed according to World Health Organization (WHO) recommendations, and blood was sampled at 0, 30, 60 and 120 minutes for the determination of serum insulin and glucose levels [9].

Samples of insulin were centrifuged and the serum was stored at -20 °C until assay. Serum insulin levels were determined by a solid-phase ¹²⁵I radioimmunoassay kit [Diagnostic Products, United States of America (USA)]. This assay indicated a fasting 2-SD insulin range of 0-180 pmol/L for healthy patients. The intra- and inter-assay coefficients of variation were 5% and 10% respectively. Serum glucose was determined by the glucose dehydrogenase method (Dimension Clinical Chemistry System, Dade International Incorporated, USA). Total cholesterol and triglycerides were measured using enzymatic techniques on a Technicon Analyzer (Technicon In-struments). Measurement of HDL cholesterol was performed using the same technique following heparin manganese precipitation of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol. The level of LDL cholesterol was calculated using the Friedewald formula [10]. Uric acid levels were determined using a commercial kit (Dimension Clinical Chemistry System, Dade International Incorporated, USA).

Data were coded and analysed using SPSS. Data are expressed as mean and standard deviation unless otherwise stated. The Student t-test was used to ascertain the significance of differences between mean values of two continuous variables. A chi-squared analysis was performed to test for differences in proportions of categorical variables between two or more groups. An ANOVA test was used for comparison of several group means and to determine the presence of significant differences between group means of continuous variables. A multiple regression model was fitted to adjust for potential confounding variables. P < 0.05 was considered significant.

Results

A total of 122 patients (30 males and 92 females) with AN were enrolled in the study. The physical and metabolic characteristics of the patients by sex are shown in Table 1. Overall, the patients were normotensive, but the men had significantly higher systolic blood pressure than the women. As expected, the women had higher HDL cholesterol levels. Most of the patients were overweight but fewer than half had a BMI of ³ 30 kg/m².

The patients were divided into three groups based on the results of the OGTT. Although this test was not repeated to confirm the results, we labelled 18 patients as having DM based on a 2-hour OGTT serum glucose of ³ 11.1 mmol/L (11 patients), or a fasting serum glucose value of ³ 7 mmol/L (7 patients). Twenty-six (26) were labelled as having impaired glucose tolerance (IGT) based on a 2-hour OGTT serum glucose value of 7.8-11.0 mmol/L, or a fasting serum glucose value of 6.1-6.99 mmol/L. Patients with normal fasting and 2-hour OGTT glucose were labelled as euglycaemic. The physical and metabolic characteristics of the patients grouped by glucose tolerance are shown in Table 2. Diabetic patients were significantly older in age (P < 0.01), had significantly higher systolic blood pressure (P < 0.05), and a significantly lower fasting insulin level (P < 0.01) than euglycaemic and IGT patients.

Of the 78 euglycaemic patients, 16 had missing insulin results. The remaining 62 patients were included in subsequent analyses (Tables 3-5). Thirty-two (32) (51.6%) patients had hyperinsulinaemia (defined as fasting serum insulin level > 180 pmol/L).

Table 3 shows the baseline characteristics of euglycaemic patients (with and without hyperinsulinaemia) as well as their mean serum insulin and glucose levels before and after OGTT. Hyperinsulinaemic patients had mean fasting and post-OGTT insulin levels that were twice those of patients with normal insulin levels. In addition, BMI and fasting glucose level were significantly higher in hyperinsulinaemic patients (P < 0.05).

Table 4 shows blood pressure, fasting serum uric acid, and lipid and lipoprotein values in the euglycaemic patients with and without hyperinsulinaemia. Uric acid and triglyceride levels were significantly higher in the hyperinsulinaemic group (P < 0.05). Total cholesterol and HDL cholesterol levels, however, were not significantly different between the two groups. Systolic and diastolic blood pressure was also significantly higher in the hyperinsulinaemic group (P < 0.01).

Multiple regression analysis was used to examine further the relationship between hyperinsulinaemia and the variations in the dependent variables uric acid, triglycerides, lipid and lipoprotein levels and blood pressure. Other independent variables, such as age ³ 30 years, sex, fasting glucose and obesity (BMI ³ 30 kg/m²), were also evaluated. The results of these analyses are shown in Table 5. Hyperinsulinaemia remained significantly associated with systolic blood pressure (t = 2.319, P < 0.05), diastolic blood pressure (t = 2.047, P < 0.05) and uric acid (t = 2.983, P < 0.01), independent of age, sex, obesity and fasting glucose. However, the association between hyperinsulinaemia and triglyceride levels became statistically insignificant (t = 1.642, P = 0.107). The relationship between insulin, cholesterol and HDL cholesterol did not change when the other variables were considered. The analysis also showed that males had higher systolic blood pressure, lower HDL cholesterol and higher uric acid levels. In addition, patients who were ³ 30 years had higher triglyceride and lower uric acid levels.

Discussion

We studied patients from the UAE, a population in which insulin resistance and DM are particularly prevalent [11-13]. In addition, all the patients had AN, a hyperplastic skin lesion that is known to be associated with DM and a variety of insulin-resistance states [1-3]. Indeed, more than one-third of these patients had abnormal OGTT and nearly half of the remaining patients had hyperinsulinaemia. Unfortunately, we did not study a control group and did not repeat the OGTT. Thus, the relative risk of hyperinsulinaemia, undiagnosed DM or IGT in patients with AN cannot be accurately determined from this study. The reported prevalence of abnormal OGTT and hyperinsulinaemia in the UAE, however, is substantially lower than our findings, which suggests that AN plays an important role [12,14].

There is considerable evidence linking hyperinsulinaemia to hyperuricaemia, and multiple risk factors for CVD such as hypertension, dyslipidaemia, DM and obesity [4-8]. In addition, hyperinsulinaemia, without fasting hyperglycaemia, has been shown to be a significant risk factor for the development of CVD [15-17]. Insulin also has a direct regulatory effect on triglyceride and HDL cholesterol levels, and has a possible role in blood pressure regulation [18].

Similar to other cross-sectional studies, we found that patients with hyperinsulinaemia and normal glucose tolerance had higher blood pressure, uric acid and triglyceride levels than those with normal insulin levels [19-23]. Although in some of these studies the strength of the correlation was substantially diminished once obesity was accounted for, the correlation was independent of BMI in our study [22,23]. When age and sex were entered as independent variables, however, the correlation between hyperinsulinaemia and triglyceride level became statistically insignificant. Total cholesterol, LDL cholesterol and HDL cholesterol levels were not significantly different between the patients with hyperinsulinaemia and those with normal insulin levels. Although total and LDL cholesterol levels are not closely related to hyperinsulinaemia, several studies have shown that inverse relationships exist between insulin and HDL cholesterol levels in patients with this condition and normal glucose tolerance, and in patients with IGT and DM [24]. In some studies, however, HDL cholesterol levels in women did not correlate with insulin sensitivity [25]. Thus, the lack of correlation between hyperinsulinaemia and HDL cholesterol levels in our study may be related to the relatively high proportion of female patients included.

Conclusions

Our results indicate that patients with AN have a high prevalence of abnormal OGTT and insulin resistance. In addition, these results are in agreement with previous conclusions that patients with hyperinsulinaemia and normal glucose tolerance, who are presumably insulin resistant, have a cluster of risk factors for CVD. The implications of these findings are important as CVD and DM are emerging as major causes of morbidity and mortality in the UAE [11,26].

Acknowledgement

We are indebted to Dr Anthony Townsend for critical review of our manuscript.

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