Positive association between serum resistin and smoking was strongest in homozygotes of the G-A haplotype at c.-420 C>G and c.-358 G>A in RETN promoter: the Toon Genome Study.

Resistin is mainly expressed in human monocytes/macrophages and is associated with insulin resistance, inflammation, and atherosclerosis. Serum resistin is strongly correlated with the G-A haplotype defined by single nucleotide polymorphisms (SNPs) c.-420 C>G (SNP-420) (rs1862513) and c.-358 G>A (SNP-358) (rs3219175) in the promoter region of the human resistin gene (RETN). Smoking is also associated with insulin resistance. We investigated the association between smoking and serum resistin and the effect of the G-A haplotype on this association. Participants were recruited under the Toon Genome Study (an observational epidemiology research in the Japanese population). Of these, 1975 subjects genotyped for both SNP-420 and SNP-358 were analyzed for serum resistin by grouping them based on smoking status and G-A haplotype status. RETN mRNA, isolated from whole blood cells, was evaluated in smokers (n = 7) and age-, sex-, and BMI-matched non-smokers (n = 7) with the G-A haplotype homozygotes. Serum resistin tended to be higher in current smokers who smoked more cigarettes per day (P for trend < 0.0001). The positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes, followed by heterozygotes and non-carriers (interaction P < 0.0001). This positive association was stronger in the G-A homozygotes than the C-G homozygotes (interaction P < 0.0001). RETN mRNA was 1.40-fold higher in smokers than non-smokers with the G-A homozygotes (P = 0.022). Therefore, the positive association between serum resistin and smoking was strongest in the G-A haplotype homozygotes defined by RETN SNP-420 and SNP-358.

Resistin G-A haplotype at SNP-420/-358 is associated with the latent sarcopenic obesity index in the toon genome study.

AIM/INTRODUCTION: Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G-A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and - 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. MATERIALS AND METHODS: We cross-sectionally analyzed 567 community-dwelling Japanese participants attending annual medical check-ups in which the sarcopenic obesity index was evaluated. The age- and gender-matched normal glucose tolerance subjects with G-A homozygotes and those with C-G homozygotes were examined via RNA-sequencing and pathway analysis (each n = 3), and RT-PCR (each n = 8). RESULTS: In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G-A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G-A homozygotes compared with C-G homozygotes. RT-PCR revealed that TNF mRNA was higher in G-A homozygotes than in C-G homozygotes. CONCLUSIONS: The G-A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF-α.

Association of a SNP in the IAPP gene and hyperglycemia on ß-cell dysfunction in type 2 diabetes: the Toon Genome Study.

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on ß-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on ß-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

The fluctuation in sympathetic nerve activity around wake-up time was positively associated with not only morning but also daily glycemic variability in subjects with type 2 diabetes.

AIMS: It is known that autonomic nerve activity (ANA) affects glucose metabolism by regulating the secretion of insulin and glucagon. Sympathetic nerve stimulation results in increased blood glucose levels. ANA also showed a circadian variation, and sympathetic nerve activity was minimal at night and began to rise at arousal. Therefore, a drastic alteration in ANA around wake-up would be associated with glycemic variability (GV) known risk factor for cardiovascular disease. We investigated the relation between ANA around wake-up and either morning or daily GV. METHODS: We simultaneously performed Holter ECG and continuous glucose monitoring system in 41 patients with type 2 diabetes (T2D). ANA was assessed by heart rate variability (HRV) analysis. Delta (Δ) wake-up was defined as the difference between the maximum and minimum value during 1 h before and after wake-up time, before breakfast. RESULTS: Δ of low frequency/high frequency (LF/HF) around wake-up time (Δ LF/HF wake-up) was positively associated with Δ glucose wake-up, standard deviation (SD) glucose wake-up, the mean amplitude of glucose excursions (MAGE24h), and SD glucose24h after adjustment for age, sex, BMI, the duration of diabetes, and the prevalence of diabetic polyneuropathy (ß = 0.47, p = 0.011, ß = 0.48, p = 0.009, ß = 0.54, p = 0.002 and ß = 0.41, p = 0.0025, respectively). No association was found between Δ LF/HFwake-up and either mean blood glucose for 24 h, or HbA1c as parameters of chronic hyperglycemia. CONCLUSIONS: In T2D, the fluctuation in fasting sympathetic nerve activity around wake-up was positively associated with not only morning but also daily GV.