Analysis of the relationship between PPAR-gamma 2 gene variants and severe insulin resistance in obese patients with impaired glucose tolerance.

Mutations in the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene may cause obesity and insulin resistance. Therefore we investigated whether known variants in the PPAR-gamma 2 gene are associated with obesity and extreme insulin resistance in obese patients with impaired glucose tolerance (IGT). The Pro115 Gln, Pro12Ala, Pro467Leu, Val290Met and a silent polymorphism C478 T were examined in 48 subjects with IGT and insulin resistance (IR), characterized by euglycemic hyperinsulinemic clamps, and in 52 healthy insulin sensitive (IS) controls. We found one proband in the IR group with the Pro115 Gln variant. This subject showed a lower whole body glucose uptake (18 micromol/kg per min) compared to the entire IR group (29 micromol/kg per min). The body weight of the proband (BMI 28.5 kg/m2) was within the average of the IR group (30.3 +/- 0.8 kg/m2). The Pro12Ala variant was not associated with differences in BMI, in the degree of insulin resistance between the IR and IS group. The Pro467Leu, Val290Met mutations and the silent polymorphism CAC478CAT were not detected in any group. In conclusion, the Pro115 Gln variant, but not the Pro12Ala mutation in the PPAR-gamma 2 gene, could be a rare cause of severe insulin resistance.     

Association between the Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma2 gene and increased 24-h diastolic blood pressure in obese patients with type II diabetes

The aim of the study was to examine an association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-gamma2 gene and blood pressure values assessed by 24-h ambulatory blood pressure monitoring (ABPM) in obese patients with long-lasting type II diabetes. Two hundred and fourteen obese patients (95 men and 119 women) with above 10-year history of type II diabetes were recruited for the study. In all the patients, ABPM was performed and other parameters, including age, body mass index (BMI), waist/hip ratio (WHR), haemoglobin A1c (HbA(1c)), serum lipids and creatinine were also evaluated. The Pro12Ala polymorphism was analysed by polymerase chain reaction-restriction fragment length polymorphism. Two subgroups of patients were compared: (a) Pro/Pro: homozygotic Pro/Pro (n=154) and (b) Ala: Ala allele carriers (Ala/Ala+Ala/Pro) (n=60). The studied groups were not different when age, BMI, WHR, HbA(1c), lipids, creatinine and frequency of hypertension were compared. A similar ratio of patients from both groups were treated with angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, beta-blockers and alpha-blockers. A difference was observed in a mean 24-h (Ala: 71.9+/-8.1 vs Pro/Pro: 69.4+/-7.8 mm Hg, P=0.034) and a mean night time (Ala: 67.1+/-7.8 vs Pro/Pro: 64.5+/-8.4 mm Hg, P=0.025) diastolic blood pressure, which was significantly higher in patients with Ala variant. There was also a trend towards a higher mean daytime diastolic blood pressure in this group. It seems that the Pro12Ala variant is associated with an increased mean 24-h diastolic blood pressure in obese diabetic patients. Different reaction for antihypertensive medication depending on a variant of the PPAR-gamma2 gene should also be considered as a possible cause of the presented results.     

Association between Pro12Ala polymorphism of the PPAR-gamma2 gene and insulin sensitivity in Brazilian patients with type-2 diabetes mellitus

AIM: Peroxisome-proliferator-activated receptor-gamma2 (PPAR-gamma2) is a nuclear receptor that plays an important role in lipid metabolism and insulin sensitivity. The purpose of this study is to investigate the association of Pro12Ala polymorphism at the PPAR-gamma2 gene in Brazilian patients with type-2 diabetes mellitus (T2Dm) and controls (CG). METHODS: Genomic DNA was obtained from 207 unrelated white people presenting with T2Dm and from 170 controls. Anthropometric data included body mass index and waist to hip ratio. Biochemical parameters included fasting plasma glucose, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, glycated haemoglobin and insulin. Systolic and diastolic blood pressures were also measured. Screening for mutations in the entire coding region of the PPAR-gamma gene was performed by means of polymerase chain reaction (PCR), single-strand conformational polymorphism and sequencing. Pro12Ala polymorphism was analysed by using PCR-RFLP (restriction fragment-length polymorphism). RESULTS: One base substitution was identified - a C to G substitution in exon B of the PPAR-gamma2 gene. The frequency of the Ala12 allele in T2Dm (0.09) was similar to that found in CG (0.06, p = 0.185). In the T2Dm group, Ala12 allele was associated with lower fasting plasma insulin levels (p = 0.036) and higher insulin sensitivity (p = 0.049) by means of homeostasis model assessment. Among obese people, there was no association between any of the T2Dm or obesity-related traits and the Pro12Ala polymorphism. CONCLUSIONS: The results of our study suggest that people with the Ala12 allele of the PPAR-gamma2 gene could be more sensitive to insulin than those carriers of the Pro12 allele among Brazilian Caucasians.     

Comment: studies of the Pro12Ala polymorphism of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the Ala allele confers a decreased risk of the insulin resistance syndrome

The Pro12Ala polymorphism of PPAR-gamma 2 has been shown to influence insulin sensitivity and the risk of type 2 diabetes in various ethnic populations. We examined whether the polymorphism was related to the insulin resistance syndrome (IRS) among nondiabetic Danish subjects. The Pro12Ala variant was examined using PCR-restriction fragment length polymorphism in a phenotypically well characterized population-based sample of 2245 nondiabetic subjects. The study participants were characterized by a number of anthropometric and biochemical measurements and the European Group for the Study of Insulin Resistance criteria enabling a classification of the study population in an IRS group and a non-IRS group. The allelic frequency of the Pro12Ala polymorphism in the total study sample was 14% (95% confidence interval, 13-15%). Two hundred ninety-four subjects fulfilled the European Group for the Study of Insulin Resistance criteria defining the IRS. The frequency of the Ala allele was 12.6% in the IRS group and 14.2% among subjects classified as not having the IRS (P = 0.15). However, the frequency of the variant in the homozygous form was significantly lower in the IRS group [0.7% (0-1.6%)] compared with the frequency in the non-IRS group [2.8% (2.1-3.5%); P = 0.02; odds ratio, 0.24 (0.06-0.99)]. Moreover, in the total study population, homozygous carriers of the variant had lower levels of fasting serum triglyceride [1.1 +/- 0.4 mmol/liter (means +/- SD) vs. 1.4 +/- 0.9 mmol/liter; P = 0.04] and a lower diastolic blood pressure (79 +/- 8 mm Hg vs. 82 +/- 11 mm Hg; P = 0.01) compared with wild-type carriers. The same tendency was observed with regard to the homeostasis model assessment estimate of insulin resistance (P = 0.16). There were no differences between genotype groups with respect to measures of body composition (BMI and waist circumference). In conclusion, homozygosity of the codon 12 variant of PPAR-gamma 2 confers a reduced risk of the IRS among Danish Caucasian subjects.     

Combined treatment with an AT1 receptor blocker and angiotensin converting enzyme inhibitor has an additive effect on inhibiting neointima formation via improvement of nitric oxide production and suppression of oxidative stress.

Accumulating evidence shows that inhibition of the vascular renin-angiotensin system results in suppression of injury-elicited neointima formation. We attempted to determine whether or not combined treatment with an angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) has an additive inhibitory effect on balloon-injury-elicited neointima formation in the carotid artery. Male Sprague-Dawley rats were treated with an ARB (valsartan: 3 mg/kg/day) and/or an ACEI (benazepril: 0.3 mg/kg/day) from 1 week before until 2 weeks after balloon injury. Experiments were also conducted with one-third of the dose combination used in the original experiments. Both ARB and ACEI inhibited neointima formation without any blood pressure changes. The full-dose combination lowered blood pressure and suppressed neointima formation significantly compared with the levels in the groups treated with either ACEI or ARB alone. The low-dose combination without blood pressure reduction also inhibited neointima formation to a similar extent as the full-dose combination. We measured 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a marker of oxidative stress, and nitrite and nitrate (NOx), an index of nitric monoxide production, in media conditioned by the injured artery. NOx production was lower and 8-iso-PGF2alpha was higher in the media of the injured artery, compared with those in the normal artery. ACEI restored NOx production more dramatically than ARB, and ARB suppressed 8-iso-PGF2alpha markedly compared with ACEI. These results suggest that the combination of an ARB and an ACEI exerts an additive inhibitory effect, presumably through an increase in production and bioavailability of NO from the endothelium.     

No association of Pro12Ala polymorphism of PPAR-gamma gene with coronary artery disease in Korean subjects.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-gamma was investigated in Korean adults. METHODS AND RESULTS: The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD. CONCLUSIONS: There was no significant association between Pro12Ala polymorphism in exon B of PPAR-gamma and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future.     

Association of the PRO12ALA polymorphism of the PPAR-gamma2 gene with oxidized low-density lipoprotein and cardiolipin autoantibodies in nondiabetic and type 2 diabetic subjects

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a key component in adipocyte differentiation and fat-specific gene expression and may modulate macrophage functions, like proinflammatory activities, and stimulate oxidized low-density lipoprotein (ox-LDL) uptake. We hypothesized that the Pro12Ala polymorphism of the PPAR-gamma2 gene may affect the immune response to ox-LDL. Therefore, we investigated the association of the Pro12Ala polymorphism of the PPAR-gamma2 gene with ox-LDL autoantibodies, as well anticardiolipin antibodies, in a 10-year prospective study. The Pro12Ala polymorphism was genotyped in 119 nondiabetic subjects (age, 45 to 64 years; body mass index [BMI], 19 to 46 kg/m(2)) and 70 type 2 diabetic patients (age, 45 to 65 years; BMI, 19 to 46 kg/m(2)) by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method. Ox-LDL autoantibodies and anticardiolipin antibodies were determined at baseline and after 10 years of follow-up. At baseline, the Pro12Ala polymorphism was not associated with ox-LDL autoantibodies in nondiabetic subjects, whereas type 2 diabetic patients having the Pro12Ala or the Ala12Ala genotypes tended to have higher levels of ox-LDL autoantibodies than did type 2 diabetic patients with the Pro12Pro genotype. At the 10-year follow-up, diabetic subjects having the Ala12 allele had higher ox-LDL autoantibody levels than did diabetic subjects with the Pro12Pro genotype (P =.043 after adjustment for age, gender, BMI, and hemoglobin A(1c) [HbA(1c)] at 5 years). In nondiabetic subjects and regarding anticardiolipin antibodies, no such relationship was observed. We conclude that the Pro12Ala polymorphism of the PPAR-gamma2 gene was associated with increased ox-LDL autoantibodies in type 2 diabetic subjects. Genotype may therefore modulate the oxidative modification of LDL in hyperglycemic milieu.     

不同降压药物对痛风合并高血压患者代谢指标的影响

目的探讨痛风合并高血压患者同一高血压分级情况下服用不同种类降压药物对其代谢指标的影响。方法选取未行降压治疗或规律服用单一种类降压药物8周以上的痛风合并高血压患者902例,按照血压水平将其分为3组;比较3组高血压患者临床指标的差异及同一高血压等级患者在分别服用利尿剂、β受体阻滞剂、钙通道阻滞剂(CCB)、血管紧张素转化酶抑制剂(ACEI)及血管紧张素Ⅱ受体阻滞剂(ARB)进行降压治疗后的临床指标变化。结果随着血压水平的增高,受试者体质量指数(BMI)、血糖(PG)、甘油三酯(TG)、总胆固醇(TC)、尿素氮(BUN)、肌酐(Cr)、尿酸(SUA)均呈上升趋势;1级高血压患者中,利尿剂组TG、Cr显著高于未用药组,CCB、ACEI及ARB组TG、BUN、Cr、SUA水平显著低于利尿剂组,ARB组尿酸排泄分数(FEUA)较其他各组显著升高(P均<0.05);2级高血压患者中,CCB、ACEI、ARB组与利尿剂组及β受体阻滞剂组相比SUA降低,ACEI及ARB组较其他各组Cr降低,ARB组较其他各组FEUA升高(P均<0.05);3级高血压患者中ACEI及ARB组TG、SUA、Cr低于利尿剂组,ARB组FEUA显著高于其他各组(P均<0.05)。结论痛风合并高血压患者应根据自身情况正确选择降压药物。     

Liver fat and insulin resistance are independently associated with the -514C>T polymorphism of the hepatic lipase gene

CONTEXT: Liver fat predicts insulin resistance in humans. So far, there is not much information on genetic determinants of liver fat. Hepatic lipase is a liver-specific enzyme that regulates lipid metabolism. OBJECTIVE: First, our object was to investigate whether the functional -514C>T polymorphism of the hepatic lipase gene is associated with liver fat content and with insulin sensitivity. Second, because this polymorphism displays gene-nutrient interactions, we assessed gene-gene interactions with the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma(2) on liver fat content and insulin sensitivity. DESIGN AND METHODS: Cross-sectional data from a total of 1070 nondiabetic subjects were analyzed. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test. A subgroup of 115 subjects underwent measurements of liver fat. RESULTS: The -514C>T polymorphism of the hepatic lipase gene was associated with higher liver fat content (P = 0.005) and lower insulin sensitivity (P = 0.02), both after adjustment for age, gender, and percentage of body fat. This was independent of serum adiponectin concentrations (P = 0.01 and 0.03). However, there was an interaction of the -514C>T polymorphism with the Pro12Ala variant on liver fat (P = 0.09) and insulin sensitivity (P = 0.01). Subjects carrying the -514C>T polymorphism had higher liver fat content and were insulin resistant only before the background of the Pro/Pro genotype of the Pro12Ala polymorphism. CONCLUSIONS: The -514C>T polymorphism of the hepatic lipase gene is associated with higher liver fat content and lower whole-body insulin sensitivity. However, these effects are modulated by the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(2). These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.     

Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis.

AIMS: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevent the progression of diabetic nephropathy (DN). Studies suggest that combination renin-angiotensin-aldosterone system (RAAS)-inhibiting therapy provides additive benefit in DN. However, these studies are small in size. We performed a meta-analysis of studies investigating combination therapy for DN. METHODS: Studies were identified through a search of medline, embase, cinahl and the Cochrane Database. All trials involving combined ACEI and ARB for slowing progression of DN were included. The primary end point was 24-h urinary protein excretion. Blood pressure, serum potassium and glomerular filtration rate (GFR) were secondary end points. RESULTS: In the 10 included trials, 156 patients received ACEI + ARB and 159 received ACEI only. Most studies were 8-12 weeks in duration. Proteinuria was reduced with ACEI + ARB (P = 0.01). This was associated with significant statistical heterogeneity (P = 0.005). ACEI + ARB was associated with a reduction in GFR [3.87 ml/min (7.32-0.42); P = 0.03] and a trend towards an increase in serum creatinine (6.86 micromol/l 95% CI -0.76-13.73; P = 0.09). Potassium was increased by 0.2 (0.08-0.32) mmol/l (P < 0.01) with ACEI + ARB. Systolic and diastolic blood pressure were reduced by 5.2 (2.1-8.4) mmHg (P < 0.01) and 5.3 (2.2-8.4) mmHg (P < 0.01), respectively. CONCLUSIONS: This meta-analysis suggests that ACEI + ARB reduces 24-h proteinuria to a greater extent than ACEI alone. This benefit is associated with small effects on GFR, serum creatinine, potassium and blood pressure. These results should be interpreted cautiously as most of the included studies were of short duration and the few long-term studies (12 months) have not demonstrated benefit.     

The association of the K121Q polymorphism of the plasma cell glycoprotein-1 gene with type 2 diabetes and hypertension depends on size at birth

Birth weight and length serve as indicators of the intrauterine environment, and a small body size at birth is a predictor of type 2 diabetes and hypertension. Insulin is one of the growth factors regulating fetal growth. The plasma cell glycoprotein 1 (PC-1) gene impairs insulin signaling at the insulin receptor level. Therefore, we investigated whether the K121Q polymorphism of the PC-1 gene association with insulin sensitivity, insulin levels, and the prevalence of diabetes and hypertension in adult life depends on size at birth in 489 subjects born in Helsinki during 1924-1933. We found that the effect of the PC-1 gene polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, depended on birth length because fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). Additionally, in those whose birth length was up to 49 cm, the K121Q polymorphism of the PC-1 gene was associated with a 2-fold higher incidence of type 2 diabetes. Moreover, subjects who were short at birth and who had the 121Q allele had the highest incidence (31.6%) of type 2 diabetes together with hypertension. We conclude that the interaction between the K121Q polymorphism of the PC-1 gene and birth length affects insulin sensitivity and increases susceptibility to type 2 diabetes and hypertension in adulthood.     

Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.

BACKGROUND: Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration. OBJECTIVE: To investigate whether, in hypertensive patients with glomerulonephritis, a combination of an angiotensin converting enzyme inhibitor (ACEI, fosinopril 20 mg/day) with an angiotensin receptor blocker (ARB, irbesartan 150 mg/day) produces a more profound antiproteinuric effect than either drug alone. METHODS : Ten non-diabetic patients with glomerulonephritis, normal or slightly reduced but stable renal function (creatinine clearance 40-106 ml/min) without immunosuppression were studied. Clinical evaluations, 24 h blood pressure measurements and laboratory tests were performed as follows: (1) without medication (baseline) and in random sequence; (2) ACEI alone; (3) ARB alone; and (4) combination of ACEI + ARB. Each period lasted for 6 weeks, separated by three washout periods of 4 weeks each without therapy. RESULTS: ACEI and ARB alone reduced proteinuria from 7.9 +/- 7.1 to 5.3 +/- 5.2 and 5.0 +/- 4.9 g/24 h (mean +/- SD), respectively. The combination of ACEI + ARB induced a more remarkable reduction of proteinuria in every patient (to 3.3 +/- 3.7 g/24 h) than either drug alone (P = 0.039 by ANOVA). The enhanced antiproteinuric effect of the combined therapy could not be attributed to a more pronounced reduction of 24 h mean arterial pressure (basal, 106 +/- 8; ACEI, 97 +/- 5; ARB, 98 +/- 5; ACEI+ARB, 95 +/- 5 mmHg) or creatinine clearance (basal, 77 +/- 27; ACEI, 73 +/- 31; ARB 80 +/- 30; ACEI + ARB, 73 +/- 32 ml/min). CONCLUSIONS: A combination of ACEI and ARB in patients with glomerulonephritis produces a more profound decrease in proteinuria than either drug alone. This additive antiproteinuric effect is not dependent on changes in blood pressure or creatinine clearance. A long-term controlled study is required to confirm the positive effect of this treatment on the progression of renal function loss.     

Patterns of antihypertensive therapy among patients with diabetes

BACKGROUND: Hypertension is extremely prevalent in patients with diabetes. Limited data exist on whether patterns of antihypertensive use in this population are consistent with evidence-based practice guidelines. OBJECTIVE: To evaluate utilization patterns of antihypertensive agents and blood pressure (BP) control among diabetic patients with hypertension. DESIGN: Retrospective cohort study. PATIENTS/PARTICIPANTS: In all, 9,975 patients with diabetes and hypertension as of March 2001 from an outpatient medical center of the Department of Veterans Affairs. MEASURES: Proportions of use of 6 different antihypertensive drug classes were compared for all patients receiving 1, 2, 3, or 4 or more drugs, and separately among patients with and without coronary artery disease (CAD). Blood pressure control (<130/85 mmHg) was compared for untreated patients, those on monotherapy, and patients on multi-drug regimens. RESULTS: Over 60% of patients were receiving angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB), followed by diuretics (38.1%), calcium channel blockers (35.3%) and beta-blockers (28.5%) with 19.1% of patients untreated. Patients on monotherapy were mostly receiving ACEI/ARB (59.5%). The majority (70.7%) of treated patients were on multidrug regimens. In patients with CAD, beta-blocker and ACEI/ARB use was higher, and 70.5% of patients on single-drug regimens received either ACEI/ARB or beta-blockers. The proportions of patients not on medications, on monotherapy, or multidrug regimens achieving BP control were 23.4%, 27.4%, and 24.9%, respectively. CONCLUSIONS: Patterns of anti-hypertensive therapy were generally consistent with evidence-based practice guidelines. Areas of improvement include increasing ACEI/ARB and diuretic use, decreasing the number of untreated patients, and increasing the proportion of patients with controlled BP in this population.     

Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity,insulin sensitivity and lipid profile in the Spanish population

OBJECTIVE: To investigate the role of the Pro12Ala peroxisome proliferator-activated receptor (PPAR) gamma-2 polymorphism in the susceptibility to the insulin resistance syndrome and its metabolic complications in a population-based nationwide multicenter study in Spain. DESIGN: 464 unrelated adults (45.3% men and 54.7% women) aged between 35 and 64 years were randomly chosen from a nationwide population-based survey of obesity and related conditions including insulin resistance and cardiovascular risk factors. METHODS: Anthropometric determinations included: body mass index (BMI), waist-to-hip ratio, sagittal abdominal diameter; biochemical determinations included: fasting plasma glucose concentration and concentration 2 h after an oral glucose tolerance test (OGTT), total cholesterol, high and low density lipoprotein-cholesterol, triglycerides, leptin and insulin. Systolic and diastolic blood pressure were also measured. Genotyping of the PPARgamma-2 Pro12Ala polymorphism was determined by polymerase chain reaction and single strand conformation polymorphism analysis. RESULTS: The Ala12 allele frequency was higher in obese men than in lean men (0.15 vs 0.08, P=0.03). Men carriers of the Ala12 allele had a higher BMI than non-carriers (38.9% vs 21.3%; adjusted odds ratio 2.36, 95% confidence interval 1.10-5.05, P=0.03). However, despite higher BMI obese men carriers of the Ala12 allele had lower sagittal abdominal diameter than Pro12 homozygotes (24.1+/-3.2 vs 26.3+/-2.5 cm, P=0.01). The Ala12 allele was associated with lower total triglycerides levels in the overall population and it was also associated with lower fasting insulin levels and a higher insulin sensitivity by homeostasis model assessment (HOMA) in women. CONCLUSIONS: Our results suggest that the Pro12Ala polymorphism of the PPARgamma-2 gene promotes peripheral deposition of adipose tissue and increased insulin sensitivity for a given BMI. The results in women might be due to their different adipose tissue distribution.     

Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin

OBJECTIVE: To determine whether the response to angiotensin-converting enzyme inhibitor (ACEI) monotherapy in subjects of African origin is determined by genetic variants within the angiotensinogen (AGT) gene. METHODS: A total of 194 hypertensive patients of African ancestry were recruited from district clinics in Johannesburg, South Africa. Eighty patients received open-label ACEI (enalapril or lisinopril) monotherapy, and 114 open-label calcium antagonist (nifedipine) as a drug class comparator. Twenty-four hour ambulatory blood pressure (ABP) monitoring was performed at baseline (off medication) and after 2 months of therapy. DNA was analysed for functional variants (-217G-->A and -20A-->C) of the AGT gene. The impact of genotype on ABP responses to ACEI monotherapy or calcium antagonists; and on plasma aldosterone and renin levels after ACEI monotherapy was assessed. RESULTS: Adjusting for baseline ABP and type of ACEI in the ACEI-treated group, the -217G-->A variant predicted ABP responses to ACEI (n = 77; P < 0.01), but not to nifedipine (n = 108). ACEI in patients with the AA genotype of the -217G-->A variant failed to elicit an antihypertensive response [change in ABP, mmHg: systolic blood pressure (SBP) +0.84 +/- 2.89, P = 0.78; diastolic blood pressure (DBP) -0.47 +/- 1.74, P = 0.79]. In contrast, those patients with at least one copy of the -217G allele developed a 7.23 +/- 1.55 and 5.38 +/- 1.12 mmHg decrease (P < 0.0001) in SBP and DBP, respectively, after ACEI administration. Similarly, the -20A-->C variant predicted ABP responses to ACEI monotherapy (P < 0.01) but not to nifedipine. Moreover, patients who were AA genotype for both variants failed to develop an antihypertensive response to ACEI (change in ABP, mmHg: SBP +1.06 +/- 3.05, P = 0.73; DBP -0.39 +/- 1.83, P = 0.83); whereas patients with at least one copy of both the -217G and the -20C allele developed substantial decreases in ABP (change in ABP, mmHg: SBP -14.08 +/- 3.72, P < 0.0001; DBP -9.62 +/- 2.74, P < 0.0001). Patients with at least one copy of the -217G allele demonstrated a significant reduction in the aldosterone-to-renin ratio (-0.098 +/- 0.035, P < 0.01), whereas in those patients who were -217AA genotype the ratio was unchanged (-0.03 +/- 0.16, P = 0.85). CONCLUSION: Functional variants of the AGT gene contribute to the variability of antihypertensive responses to ACEI monotherapy in individuals of African ancestry, with genotype determining whether or not responses occur.     

Combination therapy with an angiotensin-converting enzyme inhibitor and a calcium channel blocker

More than 1 medication is required in many hypertensive patients to reach blood pressure (BP) goals, and initial treatment with 2 agents has been recommended for patients whose BP level is >20/10 mm Hg above target. Diuretics reduce BP levels and the incidence of target organ complications and together with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers, which are recommended in patients with comorbid cardiovascular disease, nephropathy, or diabetes, are effective antihypertensive combinations. Calcium channel blockers (CCBs) are also effective antihypertensive agents, and evidence suggests that a CCB/ACEI combination is well tolerated and also decreases the risk of cardiovascular and renal disease. Some evidence suggests that this combination may improve endothelial function more than either agent alone, and its use could potentially lead to better cardiovascular outcomes than a diuretic/ACEI or diuretic/ARB combination. The ongoing Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial compares these 2 effective combinations (ie, an ACEI/diuretic and ACEI/CCB) as initial treatment for reducing cardiovascular morbidity and mortality in older high-risk hypertensive patients. The results of this trial, when reported, should help to clarify the relative benefits of these different therapies.