H. Slimane

Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor γ-2 gene on obesity risk and leptin levels in a Tunisian population

OBJECTIVES This study was undertaken to investigate the impact of the Pro12Ala (rs1801282) polymorphism of the peroxisome proliferator-activated receptor gamma-2 (PPARgamma-2) gene on obesity or body mass index (BMI) and plasma leptin, insulin, adiponectin and lipid levels in a sample of the Tunisian population. DESIGN AND METHODS The study included 387 obese patients and 288 control subjects. The Pro12Ala genotype was determined by polymerase chain reaction followed by a digestion with the restriction of endonuclease BstUI. RESULTS In the whole population, there is no significant difference in genotype frequencies of the Pro12Ala polymorphism between obese patients and controls. However, separate analysis by gender revealed that obese men (but not women) had significantly higher frequency of Pro/Ala genotypes compared to controls (12.2% vs. 4.1%; chi(2)=6.76, p=0.009). In comparison to Pro/Pro homozygotes, Ala-allele bearers had a significantly higher risk of obesity [OR (95% CI)=3.26 (1.28-8.33)]. When obese subjects were stratified according to type 2 diabetes status, the association with obesity was only significant in obese non-diabetic patients [OR (95% CI)=3.74 (1.43-9.74), p=0.007]. Additionally, obese male patients carrying the Ala-allele had significantly higher body mass index (p=0.007) and plasma leptin levels (p=0.023) compared to those homozygous for Pro-allele. The significant effect of Pro12Ala polymorphism on plasma leptin levels disappeared after adjustment for age and BMI. CONCLUSION The present study provides evidence that the Pro12Ala polymorphism of the PPARgamma-2 gene is associated with obesity in non-diabetic men from Tunisian origin.

Clinical and metabolic characteristics of newly diagnosed diabetes patients: experience of a university hospital in Tunis.

PURPOSE The aim of our retrospective study was to explore the clinical and metabolic characteristics of newly diagnosed diabetes patients over the age of 30 years. METHODS Study participants were consecutive, newly diagnosed patients with diabetes, over the age of 30 years, presenting to our university hospital department between January 1999 and June 2003. Clinical and metabolic data were collected retrospectively by medical record review. RESULTS Three hundred seventy patients were included; mean age was 54.1+/-14.0 years; 49% were women and a family history of diabetes was reported in 52% of patients. Patients presented with acute complications in 40% of cases. Symptoms of polyuria-polydipsia and weight loss were present at diagnosis in 87% and 76% of cases respectively. 58% of our patients were obese or overweight (BMI> or =25 kg/m(2)), hypertension was present in 22%, hypertriglyceridemia in 27% and high LDL cholesterol in 27%. Neuropathy was diagnosed in 24%, nephropathy in 13%, coronary heart disease in 9%, retinopathy in 8% of cases, stroke in 3% and peripheral arterial disease in 2%. Insulin was prescribed initially in 47% of cases. CONCLUSIONS Our results demonstrate that clinical symptoms and acute ketosis are the most common presenting features of diabetes mellitus in adults at the hospital level. Associated chronic complications are frequent.

Thyroid disorders in pregnancy: Frequency and association with selected diseases and obstetrical complications in Tunisian women

OBJECTIVE To determine the prevalence of thyroid disorders (TDs) and identify groups at risk for TDs in Tunisian pregnant women. METHODS Thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (TPO-Ab) were determined in 1519 pregnant women. Thyroid disorder was defined as hyperthyroidism (TSH< or =0.10 mIU/L) or hypothyroidism (TSH>4.5 mIU/L), and/or positive TPO-Ab (>12 IU/L). RESULTS TDs were observed in 147 women (9.7%). The prevalence was 6.5%, 3.2% and 1.3% for positive anti-TPO, hypothyroidism and hyperthyroidism, respectively. According to a trimester of gestation (first, second, and third, respectively), the prevalence decreases for positive TPO-Ab (7.7%, 7.5% and 4.7%) and for hyperthyroidism (2.7%, 0.7% and 0.5%), but increases for hypothyroidism (2.2%, 3.3% and 3.7%). TDs were more frequent in women with non-thyroid autoimmune disease [25% vs 9.6%; odds ratio (OR), 95% confidence interval (95% CI), 3.16 (1.01-11.8); p=0.05]. Women with positive TPO-Ab showed higher prevalence of non-thyroid autoimmune disease [25% vs 6.4%; OR (95% CI), 4.90 (1.31-18.4); p=0.04] and a trend toward increase of past gestational hypertension (p=0.09), late abortion (p=0.09), and fetal death (p=0.09). Hypothyroidism was more frequent in women with non-thyroid autoimmune disease and those with past pregnancy loss. CONCLUSIONS TDs are common in Tunisian pregnant women and are associated with autoimmune diseases and poor gestational outcomes. These data support the benefit of thyroid testing in pregnant women, especially those with these conditions.

The ‐2548G/A LEP polymorphism is associated with blood pressure in Tunisian obese patients

Objective. To examine the association of a common ‐2548G/A (rs7799039) promoter variant of the human leptin gene (LEP) with obesity or body mass index (BMI) and its associated phenotypes such as blood pressure variability and the prevalence of hypertension in a sample of the Tunisian population. Design and methods. Two hundred and twenty‐nine obese patients were screened and compared with 251 normal weight subjects. The ‐2548G/A LEP polymorphism was analysed by PCR‐RFLP procedure. Results. No significant association was found between the ‐2548G/A polymorphism and obesity or BMI. However, in obese patients subjects with AA genotype had significantly higher systolic (p = 0.003) and diastolic (p = 0.002) blood pressure compared with those with GA or GG genotypes. Stratified analysis by gender revealed that male patients but not female homozygous for ‐2548A allele exhibited significantly increased systolic (p = 0.01) and diastolic (p<0.001) blood pressure than did carriers of ‐2548G allele. Multiple linear regression analysis revealed that AA genotype significantly affect systolic and diastolic blood pressure in obese men. Additionally, significant association between AA genotype and higher prevalence of hypertension was found in male patients (p = 0.03). Conclusion. The present study showed that the ‐2548G/A LEP polymorphism is associated with blood pressure in obese male patients.

Increased expression of plasma membrane Ca2+ATPase 4b in platelets from hypertensives: A new sign of abnormal thrombopoiesis?

Platelet Ca2+ homeostasis is controlled by a multi-Ca2+ATPase system including two PMCA (plasma membrane Ca2+ATPase) and seven SERCA (sarco/endoplasmic reticulum Ca2+ATPase) isoforms. Previous studies have shown similar platelet Ca2+ abnormalities in diabetic and hypertensive patients, including an increase in intracellular [Ca2+]I, a possible modulation of PMCA activity and increased PMCA tyrosine phosphorylation. Very recently, we found that platelets from diabetic patients also exhibited increased PMCA4b expression. In the present study we looked for further similarities between diabetic and hypertensive patients. We first confirmed a decrease in Ca2+ATPase activity (mean 55 + 7%) in mixed platelet membranes isolated from 10 patients with hypertension compared with those from 10 healthy controls. In addition, the decreased Ca2+ATPase activity correlated with the DBP of the different patients, as expected for PMCA activity. Second, we performed a pilot study of six hypertensives to examine their expressions of PMCA and SERCA mRNA and proteins. Like the diabetic patients, 100% of hypertensives were found to present a major increase in PMCA4b expression (mean value of 218 ± 21%). We thus determined that platelets from diabetic and hypertensive patients showed similar increased PMCA4b isoform. Since increased PMCA4b expression was recently found to be associated with a perturbation of megakaryocytopoiesis, these findings may also point to an abnormality in platelet maturation in hypertension.

The Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is associated with type 2 diabetes in Tunisian population.

BACKGROUND AND AIMS Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a transcriptional co-activator involved in adaptive thermogenesis, skeletal muscle metabolism, fatty acid oxidation, and gluconeogenesis. Several studies have suggested that the common PGC-1α polymorphism Gly482Ser (rs8192678) may be associated with risk of type 2 diabetes (T2D), with conflicting results. The aim of this study was to analyze whether the Gly482Ser variant is a risk factor for development of T2D in Tunisian population. METHODS In a case-control study 487 unrelated patients with type 2 diabetes and 402 apparently healthy controls were recruited from January 2008 to August 2010. The Gly482Ser polymorphism was determined by PCR-RFLP analysis. RESULTS A significant difference in genotypes distribution was observed between patients (Gly/Gly: 34.1%; Gly/Ser: 47.1%; Ser/Ser: 18.5%) and controls (Gly/Gly: 43.8%; Gly/Ser: 42.3%; Ser/Ser: 13.9%) (χ(2)=9.44, p=0.009). The T2D patient group showed a significant higher frequency of the Ser allele compared to the controls (43% vs. 34%; OR: 1.35, 95% [CI]: 1.11-1.65, p=0.002). The association between the Gly482Ser polymorphism and T2D remained significant after adjustment for other well-established cardiovascular risk factors. CONCLUSIONS In the current study, a significant and independent association between the Gly482Ser polymorphism (rs8192678) of the PGC-1α gene and T2D in the Tunisian population was found.

Ramadan fasting in patients with adrenal insufficiency

AimThe risks of fasting during Ramadan in patients with adrenal insufficiency are unknown. The aims of this study were to evaluate these risks in such patients, to determine the risk factors and finally to set some recommendations.MethodsIt is a cross-sectional study about 180 patients with known and treated adrenal insufficiency. The patients responded to a 14-item questionnaire concerning their knowledge about the disease and fasting during the last month of Ramadan.ResultsThere were 132 women and 48 men. The mean age was 47.6 ± 15.0 years (14–79). One hundred and thirty eight patients (76.7 %) were advised by their physician not to fast. Ninety-one patients (50.5 %) tried to fast. Complications occurred in 61 cases (67.0 %): asthenia in 88.5 % of cases, intense thirst in 32.8 %, symptoms of dehydration in 49.2 % and symptoms of hypoglycaemia in 18 %. One patient was hospitalized. Fifty-five patients (60.4 %) were able to fast for the whole month. Age, gender, duration of the disease, its primary origin, associated hypothyroidism, diabetes mellitus, hypertension or diabetes insipidus and daily dose of hydrocortisone did not significantly differ between fasters and non-fasters, full-month-fasters and partial-month-fasters, and fasters with complications and fasters without complications. The frequency of adequate knowledge about the disease was significantly higher in full-month-fasters vs. partial-month-fasters, and in fasters without complications vs. those with complications.ConclusionIn patients with adrenal insufficiency, fasting can cause complications especially if the level of knowledge about the disease is low.

Testicular adrenal rest tumours in young adult males with congenital adrenal hyperplasia: prevalence and impact on testicular function.

Testicular adrenal rest tumours (TARTs) have been described in patients with congenital adrenal hyperplasia (CAH). The aim of the study was to determine the prevalence of TARTs in patients with CAH, the associated factors and their impact on gonadal function. It is a prospective study concerning six young adult men with CAH, four cases with 21‐hydroxylase deficiency and two cases with 11‐hydroxylase deficiency. All patients were under glucocorticoid therapy. The mean age was 25 years (range: 20–31). All patients underwent a physical examination with testicular palpation, scrotal ultrasonography, a blood sample for serum testosterone, FSH, LH, inhibin B, ∆4‐androstenedione and 17‐OH‐progesterone measurements and a semen analysis. Ultrasound revealed TARTs in four patients; three were bilateral. The mean tumour size was 6.3 ml (range: 0.02–14.1). The tumours were palpable in two cases. 17‐OH‐progesterone was <10 ng/ml in all cases. Decreased testosterone level was found in one case. The semen analysis revealed azoospermia in one case and poor semen quality in four patients. TARTs were common and associated with impaired spermatogenesis.

Tumor necrosis factor-α (TNF-α) −863C/A promoter polymorphism is associated with type 2 diabetes in Tunisian population

AIMS Tumor necrosis factor α (TNFα) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF α has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The aim of the present study was to investigate the association between the -863C/A polymorphism in the promoter of the TNFα gene and type 2 diabetes in the Tunisian population. METHODS The polymorphism -863C/A in the TNFα gene was determined in 211 type 2 diabetes patients and 345 healthy controls using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis. RESULTS A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with type 2 diabetes had significantly higher frequency of the CA+AA genotypes compared to controls [35.5% vs. 22.3%; OR (95%CI), 1.91 (1.31-2.8); p=0.001]. The type 2 diabetes patient group showed a significant higher frequency of the A allele compared to the controls (0.19 vs. 0.11; p=0.001). After adjustment by a stepwise logistic regression method, hypertension, dyslipidemia, and CA+AA genotype were found to be significantly associated with T2D. CONCLUSION The present study showed a significant and independent association between the -863C/A polymorphism of the TNFα gene and type 2 diabetes in the Tunisian population.

Unusual presentation of multiple endocrine neoplasia type 2A in a patient with the C634R mutation of the RET-protooncogene

The aim of this paper is to report an atypical presentation of MEN2A, in a patient carrying the C634R mutation of the RET-protooncogene. A 41-year-old Tunisian woman was admitted to our department with newly diagnosed hyperglycemia. She had a history of bilateral urinary stone recurrence, managed successfully on two occasions. On physical examination a thyroid node of 1cm on the left side was found. Laboratory evaluation and imaging findings confirmed the diagnosis of primary hyperparathyroidism. During cervicotomy, the parathyroid adenoma was resected and the thyroid node was suspected to be a carcinoma. Total thyroidectomy, with appropriate neck nodal resection, was performed. Histological examination confirmed the diagnosis of parathyroid adenoma and revealed a multifocal and bilateral medullary carcinoma. These findings led to the diagnosis of multiple endocrine neoplasia. DNA-analysis demonstrated a germline Cys634Arg mutation in the RET-protooncogene. During the postoperative follow-up, blood pressure as well as the level of urinary methoxylated metabolites increased progressively. Imaging findings were compatible with the diagnosis of bilateral pheochromocytoma. In conclusion, this case report of MEN 2A linked to a 634 RET mutation was peculiar by its revelation mode (1) hyperparathyroidism moreover linked to an adenoma and (2) associated with diabetes, mechanisms of which are probably multifactorial (familial type 2 diabetes, hypercalcemia, catecholamines excess).