Patient-reported outcomes are superior in patients with Type 2 diabetes treated with liraglutide as compared with exenatide, when added to metformin, sulphonylurea or both: results from a randomized, open-label study.

AIMS: The Liraglutide Effect and Action in Diabetes 6 trial was an open-label trial comparing liraglutide with exenatide as an 'add-on' to metformin and/or sulphonylurea. METHODS: Patients with Type 2 diabetes were randomized to liraglutide 1.8 mg once daily or exenatide 10 µg twice daily for 26 weeks. This was followed by a 14-week extension phase, in which all patients received liraglutide 1.8 mg once daily. RESULTS: Patient-reported outcomes were measured in 379 patients using Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and DTSQ change (DTSQc). The change in overall treatment satisfaction (DTSQs score) from baseline at week 26 with liraglutide was 4.71 and with exentaide was 1.66 [difference between groups 3.04 (95% CI 1.73-4.35), P<0.0001]. Five of the six items on the DTSQs improved significantly more with liraglutide than with exenatide (differences: current treatment 0.37, P=0.0093; convenience 0.68, P<0.0001; flexibility 0.57, P=0.0002; recommend 0.49, P=0.0003; continue 0.66, P=0.0001). Patients perceived a greater reduction in hypoglycaemia at week 26 with liraglutide than with exenatide [difference in DTSQc score 0.48 (0.08-0.89), P=0.0193] and a greater reduction in perceived hyperglycaemia [difference 0.74 (0.31-1.17), P=0.0007]. During the extension phase, when all patients received liraglutide, DTSQs scores remained stable in patients who continued on liraglutide and increased significantly (P=0.0026) in those switching from exenatide. CONCLUSIONS: These results demonstrate significant improvements in patients' treatment satisfaction with liraglutide compared with exenatide.

Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, double-blind, active control trial(*).

AIM: To assess and compare the efficacy and safety of liraglutide with those of glimepiride, both in combination with metformin for the treatment of type 2 diabetes in Asian population from China, South Korea and India. METHODS: A 16-week, randomized, double-blind, double-dummy, four-arm, active control trial was carried out. In total, 929 subjects with type 2 diabetes with a mean (±s.d.) age of 53.3 ± 9.5 years, HbA1(c) of 8.6 ± 1.0% and body weight of 68.1 ± 11.7 kg were randomized (liraglutide 0.6, 1.2 or 1.8 mg once daily or glimepiride 4 mg once daily all in combination with metformin: 1 : 1 : 1 : 1). One subject withdrew immediately after randomization and before exposure. RESULTS: HbA1(c) was significantly reduced in all groups compared with baseline. Treatment with liraglutide 1.2 and 1.8 mg was non-inferior to glimepiride (mean HbA1(c) reduction: 1.36% points, 1.45% points and 1.39% points, respectively). No significant difference was shown in the percentage of subjects reaching American Diabetes Association HbA1(c) target <7% or American Association of Clinical Endocrinologists target ≤6.5% between liraglutide 1.2 and 1.8 mg and glimepiride. Liraglutide was associated with a 1.8-2.4 kg mean weight reduction, compared with a 0.1 kg mean weight gain with glimepiride. Liraglutide led to a significantly greater reduction in systolic blood pressure (SBP) compared with glimepiride. Two subjects in the glimepiride group reported major hypoglycaemia while none in the liraglutide groups. Liraglutide was associated with about 10-fold lower incidence of minor hypoglycaemia than glimepiride. Gastrointestinal disorders were the most common adverse events (AEs) for liraglutide, but were transient and resulted in few withdrawals. CONCLUSIONS: In Asian subjects with type 2 diabetes, once-daily liraglutide led to improvement in glycaemic control similar to that with glimepiride but with less frequent major and minor hypoglycaemia. Liraglutide also induced a significant weight loss and reduced SBP and was generally well tolerated. The most frequently reported AE was transient nausea. The effect of liraglutide in this Asian population is comparable to the effects seen in Caucasian, African American and Hispanic populations in global liraglutide phase 3 trials.

Transmission of G-protein beta3 subunit C825T alleles to offspring affected with end-stage renal disease.

BACKGROUND: Results of epidemiological studies have suggested that a hereditary predisposition to the development of chronic renal failure exists, and that such predisposition might be independent from underlying etiology of kidney disease. On the other hand, high blood pressure contributes substantially to a faster rate of progression of renal damage, regardless of underlying etiology of kidney disease. In this study we tested whether GNB3 C825T polymorphism, previously reported to be associated with hypertension, contributes to predisposition to end-stage renal disease (ESRD). METHODS: GNB3 polymorphism was genotyped in 247 family trios: offspring affected with ESRD and both parents, and transmission/disequilibrium test was used to establish the allele-phenotype association. Among the examined offspring, 47 patients had ESRD in the course of type 1 diabetes and diabetic nephropathy, 120 had primary glomerulonephritis and 80 had interstitial nephritis. We observed no significant differences between the GNB3 C and T allele transmission from heterozygous parents to affected offspring. RESULTS: In the overall group of examined patients, the C:T allele transmission (%) was 48:52, while in patients with diabetic nephropathy, chronic glomerulonephritis and chronic interstitial nephritis the transmission was (%) 50:50, 48:52 and 48:52, respectively. CONCLUSION: The results of our study suggest that GNB3 C825T polymorphism does not contribute substantially to the increased risk of the development of ESRD.

Human SA gene Pst1 polymorphism and chronic renal failure: results of the family-based study.

BACKGROUND: Because of the heterogeneous aetiology of kidney diseases, interactions between multiple genetic and environmental factors are thought to be involved in the process of progression to end-stage renal disease (ESRD). Raised blood pressure remains a well-established, independent risk factor for a more rapid decline of renal function in various kidney diseases. The aim of the study was to investigate the role of the human SA gene Pst1 polymorphism in the development and/or progression of chronic renal failure (CRF). METHODS: This polymorphism was genotyped in a group of 247 family trios (offspring affected with end-stage renal disease, and both parents): 120 with primary chronic glomerulonephritis, 80 with interstitial nephritis, and 47 with diabetic nephropathy. Transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: SA gene Pst1 allele transmission did not differ from random proportion of 50:50, with no significant variation in the slope of reciprocal serum creatinine over time between patients with SA Pst1 A1A1, A1A2, and A2A2 genotypes. In addition, no impact of this marker on the rate of progression of CRF in the course of diabetes mellitus, interstitial nephritis, and chronic glomerular nephritis was shown. CONCLUSION: Results of the study suggest no major role of SA gene polymorphism in promoting renal damage. However, the limited numbers of patients having both parents alive included in the analysis might have resulted in insufficient power to detect a minor impact of this polymorphism, especially if such effect is confined to a certain aetiology of CRF.

Role of GLUT1 gene in susceptibility to diabetic nephropathy in type 2 diabetes.

BACKGROUND: The XbaI polymorphism in the glucose transporter GLUT1 gene has been implicated in the development of diabetic nephropathy in Chinese type 2 diabetes patients. METHODS: To examine whether the XbaI polymorphism is involved in the development of diabetic nephropathy in Caucasian type 2 diabetes patients, a large case control study was performed. The study group of 444 patients with type 2 diabetes consisted of three subgroups: 162 patients with normoalbuminuria (only patients with duration of type 2 diabetes of at least 10 years after diagnosis); 150 with microalbuminuria; and 132 subjects with persistent proteinuria or chronic renal failure (CRF). The polymerase chain reaction (PCR)-based genotyping of the XbaI polymorphism was performed in each subject. RESULTS: The genotype distribution in the subgroups showed an increased frequency of the (+/+) genotype in patients with microalbuminuria (41%; OR 1.40, 95% CI, 0.89 to 2.24) and proteinuria/CRF (47%; OR 1.82, 95% CI, 1.13 to 2.93, P = 0.013) when compared with normoalbuminuria (33%). No difference in the genotype distribution was observed between type 2 diabetes patients and healthy controls. CONCLUSIONS: The results of this study in Caucasian patients with type 2 diabetes indicate that the XbaI(-) allele in the GLUT1 gene protects against the development of diabetic nephropathy. Our results are in contrast to the case control study in Chinese patients with type 2 diabetes in which the presence of the XbaI(-) allele appeared to have a strong association with the development of diabetic nephropathy.

Angiotensinogen M235T and chymase gene CMA/B polymorphisms are not associated with nephropathy in type II diabetes.

BACKGROUND: Several studies have suggested that the same genetic factors may be involved in the predisposition to both essential hypertension and diabetic nephropathy, but the molecular mechanism underlying this predisposition still remains unclear. In particular, the role of genes involved in blood-pressure regulation and angiotensin II action is still controversial. This study examines a possible association between angiotensinogen M235T and chymase gene CMA/B polymorphisms with the presence of nephropathy in type II diabetic Caucasians. METHODS: For the purposes of the study, 323 microalbuminuric and 127 overt proteinuric cases, together with 243 normoalbuminuric controls with long-duration diabetes were selected from a group of 941 type II diabetic patients with established renal status. RESULTS: No differences in the genotype distributions or allele frequencies of the examined polymorphisms between the study groups were observed. The study groups were also stratified by gender, diabetes duration, level of glycaemic control, body mass index, hypertension, and retinopathy status, but still no distortion in the distributions of genotypes of any of the examined polymorphisms in any of the strata was shown. CONCLUSIONS: Our study provided evidence against an association between angiotensinogen M235T or chymase gene CMA/B polymorphisms and the presence of incipient or overt nephropathy in Caucasian patients with type II diabetes.

G-Protein beta(3) subunit C825T variant, nephropathy and hypertension in patients with type 2 (Non-insulin-dependent) diabetes mellitus.

BACKGROUND: There is substantial evidence that hereditary factors contribute to the predisposition to diabetic nephropathy. On the other hand, it has been suggested that genetics of diabetic nephropathy and hypertension may overlap. Recently, a C to T substitution (C825T) in the gene encoding for the guanine-nucleotide-binding protein beta(3) subunit (GNB3) was identified, and this molecular variant was found to be associated with enhanced activation of G proteins and increased risk of the development of hypertension. The aim of the study was to test whether GNB3 C825T polymorphism contributes to the development of incipient or overt nephropathy or hypertension in type 2 diabetic patients. METHODS: GNB3 genotype was determined in 130 type 2 diabetic patients with overt proteinuria or chronic renal failure, 155 diabetic patients with microalbuminuria and 163 control subjects with normoalbuminuria and known type 2 diabetes duration of at least 10 years. RESULTS: No differences in GNB3 genotype distributions or allele frequencies between the study groups were found. Also, no differences between normotensive and hypertensive patients were demonstrated. CONCLUSION: The study provided evidence against the major impact of the GNB3 C825T polymorphism on the increased risk of the development of nephropathy or hypertension in type 2 diabetic patients.

Angiotensin I-converting enzyme gene insertion/deletion and angiotensinogen M235T polymorphisms: risk of chronic renal failure. End-Stage Renal Disease Study Group.

BACKGROUND: Chronic renal failure (CRF) is a complex phenotype that results from an underlying kidney disease and superimposing environmental and genetic factors. The aim of our study was to evaluate the role of polymorphisms in the genes encoding for components of the renin-angiotensin system (RAS) in the development and/or progression of CRF. METHODS: Two hundred forty-seven family trios (patients with CRF and both parents; 120 with primary chronic glomerulonephritis, 80 with interstitial nephritis, and 47 with type 1 diabetes with nephropathy) were examined, and transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: The D allele of the angiotensin I-converting enzyme (ACE) gene insertion/deletion polymorphism was transmitted significantly more frequently than expected for no association among all examined trios and in the subgroup of patients with interstitial nephritis. The angiotensinogen 235T allele was transmitted significantly more frequently to patients with CRF than expected for no association, but the effect was seen only in patients with interstitial nephritis. The presence of the DD or ID genotype was associated with a faster rate of decline of renal function, which was not observed for the angiotensinogen M235T polymorphism. For chymase gene and angiotensin II receptor type 1 gene, allele transmission did not deviate significantly from a random proportion of 50:50%. CONCLUSIONS: The results of this study suggest that ACE gene insertion/deletion and angiotensinogen M235T polymorphisms contribute to the increased risk for the development of CRF, but the magnitude of the effect within subsets of patients with specific etiologies of CRF must be evaluated further.

Ultrasound picture of gastroesophageal junction in children with reflux disease.

The assessment of gastroesophageal junction morphology is very important in children with reflux disease. Authors present ultrasonographic measurements of subdiaphragmatic part of the esophagus and His angle. In children with reflux disease, marked shortening of subdiaphragmatic part of esophagus and completely obtuse His angle were found. Ultrasound imaging of gastroesophageal junction is valuable part of ultrasound diagnostics of reflux and may be helpful in establishing the etiology and choosing the treatment method.

Angiotensin II type 1 receptor gene A1166C polymorphism is associated with the increased risk of pregnancy-induced hypertension.

OBJECTIVE: The aim of our study was to evaluate the relation of parental history of hypertension to the development of PIH, and to assess the potential role of plausible candidate loci in the susceptibility to PIH. STUDY DESIGN: Five polymorphisms: ACE gene I/D and Pst1 RFLP polymorphism, AGT gene M235T polymorphism, AGTR1 gene A1166C polymorphism, and chymase gene CMA/B polymorphism were studied in 126 women suffering from PIH in comparison with 150 healthy pregnant women. Genotyping was performed using methods based on polymerase chain reaction. RESULTS: Among the PIH patients, positive parental history of hypertension (hypertension in both parents, in mother alone or in father alone) was significantly more frequent than in healthy pregnant women. Having a hypertensive father or mother statistically significantly increased the risk of PIH (odds ratio 4.34, 95% CI, 1.86-10.13, and 2.33, 95% CI, 1.29-4.12 respectively). CC genotype was significantly more frequent in women with PIH as compared with healthy controls and the C allele frequency was also significantly higher among the cases compared to controls. Having a CC genotype increased the risk of development of PIH 2.74 times (95% CI, 1.08-6.97). We observed no significant differences in genotype distributions or the allele frequencies of other examined polymorphisms. CONCLUSION: On the basis of the results of our study, we may suggest that AGTR1 gene A1166C polymorphism may predispose women to the development of PIH. It seems that ACE gene I/D and Pst1 RFLP polymorphism, AGT gene M235T polymorphism, and finally chymase gene CMA/B polymorphism do not play any significant role in the pathogenesis of PIH in Caucasian women.

[The role of angiotensin I converting enzyme (ACE) Pst 1 polymorphism in the development of chronic renal failure]. / Znaczenie polimorfizmu Pst 1 genu enzymu konwertujacego angiotensyne I (ACE) w rozwoju przewleklej niewydolnosci nerek.

Chronic renal failure (CRF) is a complex phenotype, which results from the underlying kidney disease and superimposing environmental and genetic factors. The aim of the study was to evaluate the role of angiotensin converting enzyme gene Pst 1 polymorphism in the development and/or progression of CRF. 247 family trios (patients with CRF and both parents): 120 with primary chronic glomerulonephritis, 80 with interstitial nephritis and 47 with diabetic nephropathy were examined, and transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected off-spring. No significant deviation from random transmission of the examined ACE gene Pst 1 alleles was observed, as well as no impact of this marker on the rate of progression of chronic renal failure.

Polymorphisms in the genes encoding for human kinin receptors and the risk of end-stage renal failure: results of transmission/disequilibrium test. The End-Stage Renal Disease Study Group.

There is evidence that environmental factors and genetic predisposition affect the development of end-stage renal disease (ESRD). The role of kinin peptides in renal pathology has been also suggested, and a nephroprotective effect of kinins, mediated by B1 and B2 kinin receptors, has been postulated. Recently, two novel sequence differences in the B1R gene were identified, and the C allele of the G-->C substitution at position -699 in the promoter region of the B1R gene was found to be less frequent among patients with ESRD compared with healthy control subjects. In this study, the association between B1R and B2R polymorphisms and ESRD was examined using a family-based study design: transmission/disequilibrium test. B1R gene G-->C substitution at position -699 in the promoter region and B2R gene C-->T transition at position 181 in exon 2 were genotyped in 247 family trios: offspring affected with ESRD and both parents. The less common alleles of both polymorphisms (B1R C allele and B2R T allele) were transmitted from heterozygous parents to offspring affected with ESRD less frequently than expected (37 and 36%, respectively; P < 0.05). In conclusion, results obtained in this study support a hypothesis of the protective role of bradykinin receptor gene polymorphisms in the development of ESRD.

The role of aldose reductase gene in the susceptibility to diabetic nephropathy in Type II (non-insulin-dependent) diabetes mellitus.

The dinucleotide repeat polymorphism (5'-ALR2) in the promoter region of the aldose reductase gene on chromosome 7q35 has been implicated in the development of diabetic nephropathy in Type I (insulin-dependent) diabetes mellitus, and markers flanking the aldose reductase locus have given evidence suggestive of a linkage between diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus in Pima Indians. To examine whether the 5'-ALR2 polymorphism in the aldose reductase gene is involved in the development of diabetic nephropathy in Caucasians with Type II diabetes, we carried out a large association study. Patients with Type II diabetes from one outpatient clinic were screened for diabetic nephropathy and divided into three groups according to the degree of this disease: 179 patients with normoalbuminuria, 225 patients with microalbuminuria and 70 patients with proteinuria. Patients with normoalbuminuria were included in the study only if they had had Type II diabetes for 10 or more years. DNA from all patients was genotyped for the 5'-ALR2 polymorphism using a previously established polymerase chain reaction protocol. The frequency of the putative risk allele Z-2 was 34.6%, 34.2% and 33.6% in the normoalbuminuria, microalbuminuria and proteinuria groups, respectively. Similarly no difference among groups was found for the frequency of the putative protective allele Z + 2. In conclusion, the results of our association study in Caucasian patients with Type II diabetes do not support the hypothesis that the 5'-ALR2 polymorphism in the aldose reductase gene contributes to susceptibility to diabetic nephropathy.

The C825T polymorphism in the human G-protein beta3 subunit gene is not associated with diabetic nephropathy in Type I diabetes mellitus.

In Type I (insulin-dependent) diabetes mellitus a genetic predisposition exists to nephropathy and is related to parental hypertension. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in Type I diabetic subjects with nephropathy. This enhanced G-protein activation has been associated with a genetic variant in the G-protein beta3 subunit, GNB3. A C-->T polymorphism at position 825 in exon 10 is associated with G-protein activation, the T allele associated with enhanced activity. Furthermore the T allele was observed more frequently in a group with essential hypertension. In this report we have analysed the role of the C825T polymorphism in the predisposition to diabetic nephropathy in Type I diabetes. We have investigated the frequency of this polymorphism in a large case-control study and found no association of the T allele with diabetic nephropathy. Specifically carriage of the T allele as CT or TT was observed in 49% of 200 Type I diabetic control subjects with normoalbuminuria (diabetes duration 24 years) compared with 53% of 216 Type I diabetic subjects with nephropathy (overt proteinuria or end-stage renal failure). Within this group we have also examined the inheritance of C825T alleles in a family study and found no evidence for excess transmission of the T allele to Type I diabetic offspring with nephropathy (T allele transmitted to 51% of nephropathy offspring, C allele transmitted to 49% of nephropathy offspring, p = 0.79). In none of the Type I diabetic datasets examined was there any effect of genotype on variation in systolic or diastolic blood pressure. In conclusion we can find no evidence for the C825T polymorphism of the beta3 G-protein subunit as a major gene in the susceptibility to diabetic nephropathy in Type I diabetes.

Angiotensin I-converting enzyme gene polymorphisms: relationship to nephropathy in patients with non-insulin dependent diabetes mellitus.

Nephropathy is a frequent complication of long-term diabetes. Strong evidence exists that genetic predisposition plays a major role in the development of diabetic nephropathy. The role of the angiotensin I-converting enzyme gene (ACE) in the susceptibility to nephropathy in diabetes, especially in non-insulin dependent diabetes mellitus (NIDDM), remains unclear. This study examines the association of two ACE polymorphisms: a 287-bp insertion/deletion (I/D) in intron 16 and PstI (A/G substitution in intron 7; alleles P/M) with renal complications in 941 NIDDM patients. From this group, for further analysis 127 patients were selected with overt proteinuria or chronic renal failure, 335 patients with microalbuminuria, and a control group of 254 normoalbuminuric patients with a diabetes duration of at least 10 yr. No significant differences in the distribution of ACE I/D and PstI genotypes or allele frequencies were observed between the examined groups. The results of this study strongly suggest that there is no association between the ACE gene I/D and PstI polymorphisms and nephropathy in NIDDM.

[Lack of relationship between angiotensinogen gene m235t polymorphism and gene insertion/deletion (I/D-intron 16) and Pst I RFLP (P/M-intron 7) polymorphisms of the angiotensin I converting enzyme(ACE) gene and the development of H-gestosis. Preliminary results]. / Brak zwiazku polimorfizmu m235t genu angiotensynogenu i polimorfizmów insercja/delecja (I/D-intron 16) oraz Pst I RFLP (P/M-intron 7) genu enzymu konwertujacego angiotensyne I (ACE) z wystepowaniem H-gestozy. Doniesienie wstepne.

Genetic and familial factors may predispose to H-gestosis. The aim of our study was to answer the question if angiotensinogen gene m235t polymorphism, and ACE gene I/D and Pst I RFLP polymorphisms may be markers of genetic predisposition to the H-gestosis. 246 pregnant women (median age 26 years) were studied (the studied group consisted of 116 women with H-gestosis and the control group consisted of 130 healthy pregnant women). Genotyping was performed using polymerase chain reaction method. Statistical analysis was done by means of Statistica for Windows. Genotype distribution was analyzed using chi 2 test. P < 0.05 was considered as statistically significant. In our study we did not receive statistically significant differences in ACE and angiotensinogen genes genotype distributions and allele frequencies between the investigated groups. Based on results of the study we may suggest that I/D and Pst I RFLP ACE gene polymorphism and angiotensinogen gene m235t polymorphism do not play any significant role in the pathogenesis of H-gestosis.

[Is PstI polymorphism of the angiotensin I converting enzyme gene associated with nephropathy development in non-insulin-dependent diabetes mellitus (preliminary study)]. / Czy polimorfizm PstI genu enzymu konwertujacego laczy sie ze zwiekszonym ryzykiem zapadalnosci na nefropatie u chorych na cukrzyce insulino-niezalezna (doniesienie wstepne).

Nephropathy is a frequent complication of long term diabetes. Diabetic nephropathy is the major determinant of premature morbidity and mortality both in insulin-dependent (IDDM) and in non-insulin dependent-diabetes mellitus (NIDDM). There is good evidence that genetic predisposition plays a major role in development of diabetic nephropathy. This hypothesis is based on the observation that diabetic nephropathy clusters within families, both in IDDM and NIDDM. Components of the renin-angiotensin system (RAS) are plausible candidate genes to examine for a association with microalbuminuria and diabetic nephropathy. In this study we compared the distribution of PstI melting polymorphism at the ACE locus among NIDDM patients with diabetic nephropathy and in patients who, despite long duration of NIDDM, remain without this complication. The 220 NIDDM patients for whom DNA was available were classified into two groups according to their renal status: normoalbuminuric control subjects (n = 80) who are NIDDM patients with an A/C ratio < 2.5 and nephropathy cases (n = 140) who are NIDDM patients with A/C ratio > 2.5. Albumin excretion rate was assayed by radioimmunoassay. HbA1c was assayed using HPLC methods, creatinine--using Jaffe methods and DNA analysis using PCR reaction, and then after the amplification product was digested with PstI enzyme. The study revealed that PstI sequence differences ("+/= and -") in the ACE gene do not contribute to genetic susceptibility to diabetic nephropathy in NIDDM.