Search

Adenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion.

ObjectiveThe distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.DesignOne sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.MethodsGenotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.ResultsThe C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249–5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.ConclusionsThe present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

Objective: Previously, it has been demonstrated that receptor protein tyrosine phosphatase σ (RPTPσ) is involved in glucose homeostasis and insulin signaling in several animal models. The aim of this study was to evaluate whether polymorphisms in this gene influence the development of type 2 diabetes (T2D) in humans. Design: We investigated how genetic variations in the RPTPσ gene influence susceptibility to impaired glucose tolerance (IGT) and T2D, in Swedish men and women. Methods: Genotyping of single nucleotide polymorphisms (SNPs) was performed by dynamic allele-specific hybridization in a total of 1057 Swedish Caucasians including 497 subjects with normal glucose tolerance (NGT), 262 subjects with IGT, and 298 patients with T2D. Results: SNPs rs1143699, rs4807015, and rs1978237 were found to be associated with T2D. SNP rs1143699 was associated with male T2D patients when compared with NGT controls (odds ratio; OR = 1.57; P = 0.029). SNP rs4807015 showed association with T2D patients when compared with NGT controls (OR = 1.32; P = 0.025). Finally, SNP rs1978237 was associated with T2D patients when compared with NGT controls (OR = 1.59; P = 0.002). Logistic regression analysis demonstrated that for SNP rs1143699 in men, C/C homozygosity conveys an increased risk of T2D (OR = 2.19; P = 0.035), while SNP rs4807015 was associated with an increased risk of T2D in both men and women (OR = 1.74; P = 0.029). SNP rs1978237 also demonstrated a risk of T2D in men and women (OR = 1.59; P = 0.026). Conclusions: This study provides evidence for association of SNPs in the RPTPσ gene with T2D in Swedish Caucasians. SNPs rs1143699, rs4807015, and rs1978237 confer an increased risk of developing T2D.

TCF7L2, HHEX and IDE on chromosome 10q23-25 reside within the linkage region for type 2 diabetes (T2D). Previous studies including ours have demonstrated that genetic polymorphisms in these three loci are associated with T2D, respectively. But, it is unclear whether TCF7L2, independently or interactively with HHEX and IDE, confer the susceptibility to T2D. In the present study, we first replicated genetic association study of the TCF7L2 gene in a Swedish cohort including 528 non-diabetic healthy controls and 243 T2D patients and then evaluated combining effect from common risk polymorphisms in TCF7L2-HHEX-IDE loci. T2D patients were diagnosed in the intermediate study time. To avoid influence from anti-diabetic treatment, baseline data in all T2D patients were used for analysis. We found that SNPs rs7901695, rs4506565, rs7903146 and rs12255372 in the TCF7L2 gene were strongly associated with T2D (p

Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects.Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m(-2)), 199 obese subjects with normal glucose tolerance (NGT, BMIor =30 kg m(-2)) and 188 control subjects (NGT, BMIor =26 kg m(-2)), were genotyped.A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMIor =30 kg m(-2) (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI30 kg m(-2) (P=0.051 and 0.084) and disappeared in T2D patients with BMIor =26 kg m(-2). Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects.The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.

The neuropeptide Y (NPY) is a neuropeptide with a role in the regulation of satiety and energy balance of body weight, insulin release, cardiovascular and central endocrine systems. In order to evaluate whether the NPY gene variations contribute to development of type 2 diabetes (T2DM), we have performed a genetic association study for Leu7Pro (T1128 C) polymorphism of the NPY gene in impaired glucose tolerance (IGT) and T2DM. Genotyping experiments for this non-synonymous single nucleotide polymorphism (SNP) in 263 patients with T2DM, 309 subjects with IGT and 469 non-diabetic healthy individuals in Swedish Caucasians were performed by using Dynamic Allele Specific Hybridisation (DASH). We found that the frequencies of the "risk" allele C in the subjects with IGT and the patients with T2DM in Swedish men were 13 % (p = 0.002, OR = 3.70, 1.65 - 8.29 95 % CI) and 10 % (p = 0.007, OR = 4.80, 1.47 - 11.33 95 % CI) respectively, which were significantly higher than the C allele frequency in non-diabetic controls (6 %). Furthermore, we found that the carriers with TC and CC genotypes in the subjects with IGT in Swedish men had significantly higher fasting plasma glucose in comparison with the TT carriers (5.6 +/- 0.7 mmol/l vs. 5.2 +/- 0.7 mmol/l, p = 0.021). The present study thus provides the evidence that Leu7Pro polymorphism in the NPY gene is associated with IGT and T2DM in Swedish men, and indicates that the NPY gene variations contribute to development of T2DM. Questions of gender specificity may be explained by genetic backgrounds, sense of coherence for stress and other factors in environment.

Insulin-degrading enzyme (IDE) plays a principal role in the proteolysis of several peptides in addition to insulin and is encoded by IDE, which resides in a region of chromosome 10q that is linked to type 2 diabetes. Two recent studies presented genetic association data on IDE and type 2 diabetes (one positive and the other negative), but neither explored the fundamental question of whether polymorphism in IDE has a measurable influence on insulin levels in human populations. To address this possibility, 14 single nucleotide polymorphisms (SNPs) from a linkage disequilibrium block encompassing IDE have been genotyped in a sample of 321 impaired glucose tolerant and 403 nondiabetic control subjects. Analyses based on haplotypic genotypes (diplotypes), constructed with SNPs that differentiate common extant haplotypes extending across IDE, provided compelling evidence of association with fasting insulin levels (P = 0.0009), 2-h insulin levels (P = 0.0027), homeostasis model assessment of insulin resistance (P = 0.0001), and BMI (P = 0.0067), with effects exclusively evident in men. The strongest evidence for an effect of a single marker was obtained for rs2251101 (located near the 3′ untranslated region of IDE) on 2-h insulin levels (P = 0.000023). Diplotype analyses, however, suggest the presence of multiple interacting trait-modifying sequences in the region. Results indicate that polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits, but questions of sex specificity and allelic heterogeneity will need to be taken into consideration as the molecular basis of the observed phenotypic effects unfolds.