Association of Plasma Ghrelin Levels with Insulin Resistance in Type 2 Diabetes Mellitus among Saudi Subjects

BACKGROUND: Although the exact mechanism of insulin resistance (IR) has not yet been established, IR is the hallmark characteristic of type 2 diabetes mellitus (T2DM). The aim of this study was to examine the relationship between plasma ghrelin levels and IR in Saudi subjects with T2DM. METHODS: Patients with T2DM (n=107, cases) and non-diabetic apparently healthy subjects (n=101, controls) from Saudi Arabia were included in this study. The biochemical profiles and plasma insulin levels of all subjects were analyzed, and IR was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR) index. Active ghrelin levels in plasma were measured using the radioimmunoassay technique. RESULTS: Only 46.7% (50 of 107) of the T2DM subjects had IR, including 26% (28 of 107) with severe IR (HOMA-IR ≥5), while 5.9% (six of 101) of the controls had moderate IR (3 ≤HOMA-IR <5). HOMA-IR values were not associated with age, disease duration, or gender. Importantly, T2DM itself and the co-occurrence of IR with T2DM were significantly associated with low plasma ghrelin levels. However, ghrelin levels were inversely correlated with the HOMA-IR index, body weight, and fasting plasma insulin levels, mainly in the control subjects, which was indicative of the breakdown of metabolic homeostasis in T2DM. CONCLUSION: The prevalence of IR was relatively low, and IR may be inversely associated with plasma ghrelin levels among Saudi patients with T2DM.

Leu72Met and Other Intronic Polymorphisms in the GHRL and GHSR Genes Are Not Associated with Type 2 Diabetes Mellitus, Insulin Resistance, or Serum Ghrelin Levels in a Saudi Population

BACKGROUND: Ghrelin (GHRL), a gastric peptide encoded by the GHRL gene, is known to be involved in energy homeostasis via its G protein receptor, encoded by the growth hormone secretagogue receptor (GHSR) gene. Some studies have shown associations between plasma GHRL levels and GHRL single-nucleotide polymorphisms (SNPs), namely the Leu72Met polymorphism (rs696217 TG), with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), while others have not. The controversies in these associations raise the issue of ‘which SNPs in which populations.’ The aim of this study was to investigate whether SNPs in GHRL and/or GHSR genes were associated with T2DM, IR, or plasma GHRL levels among Arab Saudis. METHODS: Blood was collected from 208 Saudi subjects with (n=107) and without (n=101) T2DM. DNA samples from these subjects were analyzed by real-time polymerase chain reaction to genotype five intronic SNPs in the GHRL (rs696217 TG, rs27647 CT, rs2075356 CT, and rs4684677 AT) and GHSR (rs509030 GC) genes. In addition, plasma GHRL levels were measured by a radioimmunoassay. RESULTS: None of the SNPs were associated with T2DM, IR, or plasma GHRL levels. The frequencies of the alleles, genotypes, and haplotypes of the five SNPs were comparable between the T2DM patients and the non-diabetic subjects. A large number of the GHRL haplotypes indicates the molecular heterogeneity of the preproghrelin gene in this region. CONCLUSION: Neither the Leu72Met polymorphism nor the other intronic GHRL and GHSR SNPs were associated with T2DM, IR, or GHRL levels. Further investigations should be carried out to explain the molecular basis of the association of the GHRL peptide with T2DM and IR.

Thyroid function status and echocardiographic abnormalities in patients with Beta thalassemia major in bahrain.

BACKGROUND: Thyroid gland dysfunction and echocardiographic cardiac abnormalities are well-documented in patients with transfusion dependent beta-thalassemia major (ß-TM). AIM: This cross-sectional analytic study was conducted to investigate left ventricle (LV) diastolic and systolic function using pulsed Doppler (PD) and tissue Doppler (TD) echocardiography and correlate that with serum level thyroid stimulating hormone in patients with ß-TM. METHODS: The study was conducted on patients with ß-TM (n = 110, age 15.9 ± 8.9 years) and compared with a control group (n = 109, age 15.8 ± 8.9 years). In all participants, echocardiographic indices of PD and TD were performed and blood samples were withdrawn for measuring the serum level of TSH, free T4, and ferritin. A linear regression analysis was performed on TSH level as the dependent variable and serum ferritin as independent. Stepwise multiple regression analysis was used to determine the odds ratio of different biochemical and echo variables on the risk of developing hypothyroidism. RESULTS: Patients with ß-TM compared with controls had thicker LV septal wall index (0.65 ± 0.26 vs. 0.44 ± 0.21 cm/M(2), P < 0.001), posterior wall index (0.65 ± 0.23 vs. 0.43 ± 0.21 cm/m(2), P < 0.01) and larger LVEDD index (4.35 ± 0.69 vs.3.88 ± 0.153 mm/m(2), P < 0.001). In addition, ß-TM patients had higher transmitral E wave velocity (E) (70.81 ± 10.13 vs. 57.53 ± 10.13 cm/s, P = 0.02) and E/A ratio (1.54 ± 0.18 vs. 1.23 ± 0.17, P < 0.01) and shorter deceleration time (DT) (170.53 ± 13.3 vs. 210.50 ± 19.20 m sec, P < 0.01). Furthermore, the ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em) was significantly higher in the ß-TM group (19.68 ± 2.81 vs. 13.86 ± 1.41, P < 0.05). The tissue Doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in the ß-TM group compared with controls with Sm, 4.82 ± 1.2 vs. 6.22 ± 2.1 mm/sec, P < 0.05 and (Em), 3.51 ± 2.7 vs. 4.12 ± 2.5 mm/sec. P < 0.05, respectively). The tricuspid valve velocity was significantly higher in ß-TM patients compared with controls 2.85 ± 0.56 vs. 1.743 ± 0.47 m sec, respectively, P < 0.01). The prevalence of subclinical hypothyroidism in patients with ß-TM was 15.4%, with significantly higher mean serum TSH compared with controls (6.78 ± 1.5 vs. 3.10 ± 1.02 µIU/mL, P < 0.01) and positively correlated with the serum ferritin level (r = 0.34, P = 0.014). On multiple regression analysis, the LV mass, LVEF%, and E/A ratio were not positive predictors of hypothyroidism in patients with ß-TM. CONCLUSION: We conclude that patients with ß-TM had a high prevalence of subclinical hypothyroidism of 15.4%. Thyroid stimulating hormone was significantly high and positively correlated with the serum ferritin level. Echo cardiographic pulsed Doppler showed a restrictive LV diastolic pattern suggestive of severe diastolic dysfunction with preserved left ventricle systolic function.

Hypercholesterolemia among apparently healthy university students.

BACKGROUND: Hypercholesterolemia (HC) is a major risk factor in the development of coronary heart disease (CHD). Serum cholesterol is directly related to complications and mortalities associated with heart diseases. There are a few studies that describe HC among youths in the Arab Gulf countries. We sought to evaluate HC among young healthy university students to assess their risk of developing CHD. METHODS: Lipid profile of 166 students between the ages of 16-30 years (Mean: 20.49±2.96) were examined and blood glucose, total protein, albumin, thyroid stimulating hormone (TSH) and the inflammation marker high sensitivity CRP (hsCRP) were determined. Each volunteer filled a questionnaire about her/his lifestyle and personal and family medical histories and height and weight were measured to determine body mass index (BMI). The data were analyzed using SPSS version 17. Chi-Square was used to determine the relation between categorical variables. A p-value <0.05 was considered statistically significant. RESULTS: According to the American Heart Association criteria, 44 (26.5%) students were identified with primary hypercholesterolemia (PHC) in the first testing round. After proper health counseling, the same tests were repeated after 2-3 weeks in all 44 hypercholesterolemic students. We found only 26 (15.6%) of them to be hypercholesterolemic. There was a significant relation between high total cholesterol (TC) and high TC/HDLC, as well as high or very high hsCRP and high TC/HDLC (both, p<0.001). Males tend to have higher TC/HDLC and hsCRP than females (both p0.002 and 0.005, respectively). Family history of CHD was found in 8 students and obesity was recorded in 5 volunteers. CONCLUSION: The results necessitate further studies in determining the cause of PHC. We predict a genetic element contributing to the high percentage of PHC in the current study.

Hyperhomocysteinemia in pregnant rats: effects on arterial pressure, kidneys and fetal growth.

OBJECTIVE: This study aimed to test the hypothesis that hyperhomocysteinemia plays a role in the development of pathological changes similar to human preeclampsia in pregnant rats. STUDY DESIGN: Arterial pressure and 24-h urinary excretion of proteins and electrolytes were measured during pre-pregnancy, pregnancy and postpartum periods in control (n = 12) and methionine-treated (2.0 g/kg/day, n = 11) Sprague-Dawley rats. Rats were then sacrificed at the end of this protocol and renal histological examination was performed. In another protocol, control (n = 6) and methionine-treated (n = 6) rats were anaesthetized at day 20 of gestation and pregnancy outcome was assessed. Hemodynamic and renal excretory differences between groups were analyzed using ANOVA and differences in renal histology and gestation outcome using t-test. RESULTS: Serum homocysteine in the methionine group (24.0+/-2.0 micromol/L) was significantly higher compared with controls (8.5+/-0.5 micromol/L). Systolic pressure, urinary protein excretion and renal histological changes were not significantly different between the two groups. However, fetal weights were significantly smaller and percent of dead fetuses were 15% higher in methionine-treated compared with control rats. CONCLUSION: Hyperhomocysteinemia is unlikely to cause maternal hypertension, proteinuria or renal damage in pregnant rats. However, hyperhomocysteinemia may restrict fetal growth and increase fetal mortality.

A population-based screening for gestational diabetes mellitus in non-diabetic women in Bahrain.

BACKGROUND: Maternal hyperglycemia is considered a risk factor for fetal morbidity. Since there is a high prevalence of diabetes mellitus among the population of Bahrain, we conducted a prospective population-based study of gestational diabetes mellitus (GDM) in non-diabetic pregnant women. SUBJECTS AND METHODS: All non-diabetic pregnant women attending antenatal clinics during January 2001 to December 2002 (n=10,495) were screened for GDM during the 24th to 28th weeks of gestation. All positive subjects based on a 50-g glucose challenge test (GCT) were further evaluated by a diagnostic 75-g oral glucose tolerance test (OGTT). The birth weight of the child and post-delivery insulin resistance were monitored. The homeostasis model of insulin resistance (HOMA-IR) was used to assess insulin resistance. RESULTS: Of 10,495 non-diabetic pregnant women screened, 32.8% (n=3443) had plasma glucose > or = 7.8 mmol/L (140 mg/dL) in the GCT. The 75-g OGTT found a prevalence of GDM of 13.5%. There were twice as many Bahrainis as expatriates. Of children born to women with GDM, 6.5% had a birth weight > 4000 g. Post-delivery evaluation of insulin resistance indicated that 33% of women with GDM had a HOMA-IR value > 2. CONCLUSION: The population of Bahrain is a high-risk ethnic group for GDM. The association of insulin resistance in the post-gravid state with GDM among 33% of the study population suggests that insulin resistance, the possible cause of the pathophysiological mechanism underlying the development of gestational diabetes, continues in the post gravid state.

Interactions between leptin, neuropeptide-Y and insulin with chronic diurnal fasting during Ramadan.

BACKGROUND: Fasting during the month of Ramadan for Muslims is a unique metabolic model that includes abstinence from food and fluid intake during the period from dawn to sunset as well as a reduction in meal frequency and alterations in the sleep-wakefulness cycle. Leptin, neuropeptide-Y and insulin are thought to play an important role in long-term regulation of caloric intake and energy expenditure. However, the long-term changes and interactions between these factors during this pattern of fasting are not known. SUBJECTS AND METHODS: The study was conducted on 46 healthy female volunteers (age, 22+/-2 years; BMI, 25.3+/-0.7 kg/m2). Anthropometrical measurements, estimation of body fat and fasting serum levels of neuropeptide Y, leptin, insulin and glucose were estimated at baseline (day 1), days 14 and 28 of the month of Ramadan and 2 weeks after Ramadan. RESULTS: Baseline serum levels of leptin correlated positively with body fat (r=0.87, P=0.0002). Serum leptin levels exhibited a significant increase by approximately 41% and neuropeptide-Y levels were decreased by 30.4% throughout the month of Ramadan. In addition, a significant correlation (r=0.63, P=0.0001) was found between changes in serum leptin and serum insulin. However, changes in serum neuropeptide-Y levels did not correlate with those of leptin or insulin CONCLUSIONS: Long-term fasting with interrupted nocturnal eating is associated with significant elevations in serum leptin and insulin and reduction in serum neuropeptide-Y. The changes in serum leptin are likely mediated through insulin. However, changes in neuropeptide-Y appears to be mediated independently of leptin or insulin during this type of fasting

Serum leptin and insulin levels during chronic diurnal fasting.

Ramadan fasting is a unique model that is associated with restriction of the timing of food and fluid intake food from dawn to sunset and reduction in meal frequency and sleep duration. Leptin levels are thought to play a role in long-term regulation of caloric intake and fat deposition. However, the long-term changes in leptin levels during this pattern of fasting are not known. The study was conducted on lean (N=6, BMI=22.5+/-0.4) and obese (N=18, BMI=33.1+/-1.0) healthy female volunteers. Fasting serum levels of leptin, insulin and glucose were estimated at baseline (day 1), days 14 and 28 of the month of Ramadan and 2 weeks after Ramadan. Baseline serum levels of leptin were significantly higher in obese (13.5+/-1.96 microg/L,P<0.05) compared with lean subjects (9.60+/-0.80 microg/L) and correlated positively with body fat (r=0.82, P=0.0004). Serum leptin levels exhibited a significant and comparable increase by 39% and 37% throughout the month in lean and obese subjects, respectively. In addition, a significant correlation (r=0.52, P=0.003) was found between changes in serum leptin and serum insulin levels. We conclude that chronic diurnal fasting is associated with significant elevations in serum leptin. These elevations appear to be mediated by changes in serum levels of insulin. These data support the role of insulin in the long-term regulation of leptin secretion during chronic diurnal fasting followed by nocturnal eating during the month of Ramadan.