Objective: 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. Subjects and methods: 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 À2 ), 199 obese subjects with normal glucose tolerance (NGT, BMIX30 kg m À2 ) and 188 control subjects (NGT, BMIp26 kg m À2 ), were genotyped. Results: 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 BMIX30 kg m À2 (P ¼ 0.003 and 0.005). The significance was borderline in T2D patients with BMIo30 kg m À2 (P ¼ 0.051 and 0.084) and disappeared in T2D patients with BMIp26 kg m À2 . Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P ¼ 0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects. Conclusions: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.

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 traitmodifying 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. Diabetes 53:2137-2142, 2004 T he gene encoding insulin-degrading enzyme (IDE) is located on chromosome 10q23-q24, within a region linked to type 2 diabetes and related quantitative traits (1-4). IDE is the major enzyme responsible for insulin proteolysis in vitro (5) and shares structural and functional homology with bacterial protease III, which may function in the termination of the insulin response (6,7). In mice, IDE hypofunction induced by IDE gene disruption leads to hyperinsulinemia (8). Furthermore, IDE activity in the diabetic Goto-Kakizaki (GK) rat is reduced by ϳ30%, where polymorphism in IDE is likely to be the main contributing factor (9). Congruence of positional and functional data indicates that sequence variation in IDE may play a role in modifying insulin metabolism in human populations. Two recent genetic association studies investigated the IDE region in relation to type 2 diabetes. One produced significant evidence for effects on both type 2 diabetes and plasma glucose levels (10), whereas the other explored only case-control models and obtained no evidence of association (11). Neither of these studies, however, attempted to directly relate IDE variants to measures of insulin metabolism.To evaluate the potential influence of genetic variation in IDE on insulin levels and correlated quantitative traits, a haplotype-tagging stra...

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.

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