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Background: Diabetic patients have an elevated risk of infection, but the optimal level of glycemic control with the lowest infection risk remains unclear, especially among the elderly. We conducted a cohort study to investigate the relation between fasting plasma glucose (FPG) level and risk of infection-related morbidity and mortality. Methods: Data of participants from a community-based health screening program in Taiwan during 2005-2008 (n=118,645) were analyzed. Incidence of hospitalization for infection and infection-related death was ascertained from the National Health Insurance Database and National Death Registry. Cox proportional hazards regression modelling was used to estimate the hazard ratio (HR) between FPG and risk of infection, adjusting for major risk factors of infection. Separate analyses were also performed to evaluate the risk of hospitalization among the elderly (> 65 years). Results: During a median follow-up of 8.13 years, 14,372 cases of hospitalization for infection and 422 infection-related deaths occurred. The incidence rate of hospitalization for any infection was 36.33 and 14.26 per 1,000 person-years among diabetics and nondiabetics in the total study population, but increased to 70.02 and 45.21 per 1,000 person-years in the elderly. In the Cox regression analysis, the adjusted HR comparing diabetics to nondiabetics was 1.59 (95% CI: 1.52-1.67) for any hospitalization for infection and 1.71 (95% CI: 1.36-2.16) for infection-related mortality. The hazard for infection morbidity and mortality was higher at both extremes (200 mg/dl) of FPG. The above relations were consistently observed in older people and across different sites of infection. Conclusion: The U-shape association between glycemic control and infection risk suggested that very tight glucose control may not provide additional benefits in risk reduction. In older adults, the absolute risk of infection associated with diabetes was high. Disclosure C. Chang: None. J. Wang: None. L. Wu: None. L. Chuang: None. H. Lin: None. Funding Taiwan Ministry of Science and Technology (MOST105-2628-B-002-025-MY3)

Objective: Previous research has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-γ) may play an important role in immunomodulation. We examined whether PPAR-γ agonists (thiazolidinediones) were associated with the incidence of bacterial abscess among patients with type 2 diabetes. Research Design and Methods: This retrospective cohort study included 46,986 propensity-matched patients diagnosed with type 2 diabetes between 2000 and 2010. We compared the incidence of bacterial abscess and the incidences of two subclasses: liver and non-liver abscesses, between groups treated with either metformin plus a thiazolidinedione (M+T, N=7831) or metformin plus a sulfonylurea (M+S, N=39,155). Data were retrieved from a population-based Taiwanese database. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox proportional hazard regression models. Results: During a median follow-up of 4.5 years, the adjusted rate of incident bacterial abscess was lower with M+T than with M+S treatment (1.89 vs. 3.15 per 1000 person-years). M+T was associated with a reduced risk of bacterial abscess (adjusted HRs: 0.58, 95% CI: 0.42-0.80 for bacterial abscess; 0.54, 95% CI: 0.28-1.07 for liver abscess; and 0.59, 95% CI: 0.41-0.85 for non-liver abscess). The results did not change materially, after accounting for unmeasured confounding factors and differential censoring between the two treatment groups. Rosiglitazone and pioglitazone, in combination with metformin, produced similar reductions in risk for all abscess outcomes. Conclusions: We found that M+T had a substantial protective effect in reducing the incidence of bacterial abscesses. These findings merit further investigation. Disclosure C. Chang: None. J. Wang: None. Y. Dong: None. W. Ko: None. L. Wu: None. L. Chuang: None. P. Chen: None.

OBJECTIVE Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10-year survival in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan. RESULTS The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17–4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A1c, diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17–28.97) for cardiovascular mortality, 6.32 (95% CI 1.25–32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57–65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly. CONCLUSIONS Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors.

OBJECTIVE—Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene is one of the few validated genetic variants with large effects on the risk of type 2 diabetes in the populations of European ancestry. In this study, we aimed to explore the effect of the TCF7L2 polymorphisms in a Han Chinese population. RESEARCH DESIGN AND METHODS—We genotyped 20 single nucleotide polymorphisms (SNPs) across the TCF7L2 gene in 1,520 unrelated subjects from a Han Chinese population in Taiwan. The associations of SNPs and haplotypes with type 2 diabetes and linkage disequilibrium (LD) structure of the TCF7L2 gene were analyzed. RESULTS—The previously reported SNPs rs7903146 T- and rs12255372 T-alleles of the TCF7L2 gene were rare and were not associated with type 2 diabetes in a Chinese population, which may attribute to the low frequencies of these two SNPs. SNP rs290487 located in an LD block close to the 3′ end of the gene was associated with type 2 diabetes (allele-specific P = 0.0021; permuted P = 0.03). The odds ratio was 1.36 for the CT genotype (95% CI 1.08−1.71; P = 0.0063) and 1.51 for the CC genotype (1.10 −2.07; P = 0.0085) compared with the TT genotype, corresponding to a population attributable risk fraction of 18.7%. The haplotypes composed of rs290487 were also significantly associated with type 2 diabetes (global P = 0.012). CONCLUSIONS—We identified a novel risk-conferring genetic variant of TCF7L2 for type 2 diabetes in a Chinese population. Our data suggested that the TCF7L2 genetic polymorphisms are major determinants for risk of type 2 diabetes in the Chinese population.

To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045–4.5 μmol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 μmol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.

Insulin receptor substrate-1 is a major substrate of insulin receptor Tyr kinase. We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. Human IRS-1 cDNA encodes a 1242 amino acid sequence that is 88% identical with rat liver IRS-1. The 14 potential Tyr phosphorylation sites include 6 Tyr-Met-X-Met motifs and 3 Tyr-X-X-Met motifs that are completely conserved in human IRS-1. Human IRS-1 has >50 possible Ser/Thr phosphorylation sites and one potential ATP-binding site close to the NH2-terminal. The human IRS-1 gene contains the entire 5ʹ-untranslated region and protein coding region in a single exon and was localized on chromosome 2 q36–37 by in situ hybridization. By Northern blot analysis, IRS-1 mRNA is rare and consists of two species of 6.9 and 6 kilobase. By using quantitative polymerase chain reaction after reverse transcription of total RNA from human fetal tissues, IRS-1 mRNA could be identified in all tissues. When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000–180,000 Mr in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. Thus, IRS-1 is widely expressed and highly conserved across species and tissues. Compared with rat protein, human IRS-1 contains more potential Ser/Thr phosphorylation sites and only one nucleotide binding site. The entire protein coding sequence is contained within a single exon.

OBJECTIVE The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders. RESEARCH DESIGN AND METHODS Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies. RESULTS Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2–9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. CONCLUSIONS There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.

OBJECTIVE— Genetic variants in the fat mass and obesity-associated (FTO) gene have been linked with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO genetic variants in obesity and type 2 diabetes in the Chinese population. RESEARCH DESIGN AND METHODS— We genotyped 19 single-nucleotide polymorphisms (SNPs) spanning from the 3′ end of the neighboring RPGRIP1L gene to the 5′ flanking region of the FTO gene. We analyzed their associations with obesity (638 case and 1,610 control subjects), type 2 diabetes (759 case and 784 control subjects), and obesity-related traits in nondiabetic subjects. RESULTS— Among the 19 SNPs, the rs9939609 A allele was strongly associated with obesity (P = 7.0 × 10−4) and BMI (P = 0.0024) in the Chinese population. The odds ratio for obesity was 2.60 (95% CI 1.24–5.46) (P = 0.011) for the AA genotype and 1.32 (1.05–1.66) (P = 0.018) for the AT genotype compared with the TT genotype. Each additional copy of the rs9936609 A allele was associated with a BMI increase of ∼0.37 kg/m2. The rs9939609 A allele was substantially less common in the Chinese population than in the European population (12.6 vs. 45%). We did not find significant associations of the 19 SNPs with type 2 diabetes or other obesity-related traits. CONCLUSIONS— Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. The risk variant is less common in the Chinese population, but its effect size on BMI is comparable with that in the European population.

Type 2 diabetes is a complex disease involving both genetic and environmental components. Abnormalities in insulin secretion and insulin action usually precede the development of type 2 diabetes and can serve as good quantitative measures for genetic mapping. We therefore undertook an autosomal genomic search to locate the quantitative trait locus (QTL) linked to these traits in 1,365 nondiabetic Chinese subjects from 411 nuclear families. Residuals of these log-transformed quantitative traits were analyzed in multipoint linkage analysis using a variance-components approach. The most significant QTL for fasting insulin, which coincides with the QTL for homeostasis model assessment of insulin resistance, was located at 37 cM on chromosome 20, with a maximum empirical logarithm of odds (LOD) score of 3.01 (empirical P = 0.00006) when adjusted for age, sex, BMI, antihypertensive medications, recruitment centers, and environmental factors. In the same region, a QTL for fasting glucose was identified at 51 cM, with an empirical LOD score of 2.03 (empirical P = 0.0012). There were other loci with maximum empirical LOD scores ≥1.29 located on chromosomes 1q, 2p, 5q, 7p, 9q, 10p, 14q, 18q, and 19q for different diabetes-related traits. These loci may harbor genes that regulate glucose homeostasis either independently or via interactions of the genes within these regions.

We appreciate the comments from Ku et al. (1). Although previously genome-wide linkage studies were and, currently, genome-wide association studies are the preferred approaches for the search of genetic causes of complex diseases, such as type 2 diabetes, the candidate gene approach remains a very useful tool as a supplement to the …