Kun-Der Lin

The association of diabetes mellitus with liver, colon, lung, and prostate cancer is independent of hypertension, hyperlipidemia, and gout in Taiwanese patients

Studies have shown an association between diabetes and cancer in Western countries; but this, as well as the influence of associated metabolic factors, must be confirmed by a prospective study in other population groups. This study aimed to investigate whether the strong association of cancer and diabetes is independent from the influence of hypertension, dyslipidemia, and gout in the Taiwanese population. A total of 985,815 study subjects were identified from the National Health Insurance in 1997 and followed up from 1998 to 2009. The demographic characteristics between patients with diabetes and cancer, including age, sex, hypertension, dyslipidemia, and gout, were analyzed using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risks of cancer. A total of 104,343 diabetic patients were followed up from 1998 to 2009. After adjusting for sex, age, hypertension, dyslipidemia, and gout, the incidences of cancer at any site and in the liver, colon, lungs, and prostate in diabetic patients were independently higher, with risk ratios of 1.56 (95% confidence interval [CI], 1.43-1.71), 1.67 (95% CI, 1.39-2.01), 1.75 (95% CI, 1.49-2.06), 1.54 (95% CI, 1.26-1.88), and 1.56 (95% CI, 1.19-2.04), respectively. Only breast cancer did not show any clinical significance. There was an increased incidence of cancer at any site in the diabetic patients compared with nondiabetic subjects. The most common cancers were liver, colon, lung, breast, and prostate cancer; and except for breast cancer, their incidences increased independently of hypertension, dyslipidemia, and gout in patients with diabetes.

Pathways of empowerment perceptions, health literacy, self-efficacy, and self-care behaviors to glycemic control in patients with type 2 diabetes mellitus.

OBJECTIVE To validate a hypothesized model exploring the influencing pathways of empowerment perceptions, health literacy, self-efficacy, and self-care behaviors to glycosylated hemoglobin (HbA1c) levels in patients with type 2 diabetes (T2DM). METHODS Overall, 295 patients with T2DM were recruited from five endocrine clinics in Taiwan through convenience sampling. Data regarding personal characteristics, empowerment perceptions, health literacy, self-efficacy, self-care behaviors, and HbA1c levels were collected. A structural equation modeling was used to validate the hypothesized model. RESULTS Significant direct pathways were determined from empowerment perceptions to health literacy, from health literacy to self-efficacy, from self-efficacy to self-care behaviors, and from self-care behaviors to HbA1c levels. CONCLUSIONS The empowerment perceptions and health literacy relatively influenced self-efficacy and self-care behaviors. Self-efficacy and self-care behaviors relatively influenced glycemic control in patients with T2DM. PRACTICE IMPLICATIONS Modifying self-care behaviors have been demonstrated to be the most essential for improving glycemic control. To improve self-care behaviors, healthcare providers should target improving self-efficacy, and enhancing health literacy can be considered to be a potential strategy for improving self-efficacy. To enhance health literacy, healthcare providers could use an empowerment approach rather than an authoritative approach that emphasizes patient compliance in managing patients with T2DM.

SUMO4 M55V Variant Is Associated With Diabetic Nephropathy in Type 2 Diabetes

OBJECTIVE—SUMO4 mRNA was recently found to be mainly expressed in the kidney, and the methionine-to-valine substitution at codon 55 (M55V) variant of SUMO4 may induce higher nuclear factor-κB (NF-κB) activity. Because NF-κB is known to mediate the development of diabetic nephropathy, we examined the association between the SUMO4 M55V variant and the severity of diabetic nephropathy. RESEARCH DESIGN AND METHODS—We recruited a total of 430 patients with type 2 diabetes. The M55V (rs237025, 163A→G) polymorphism of SUMO4 was genotyped by real-time PCR, and urine albumin concentration was measured by radioimmunoassay. RESULTS—The frequencies of SUMO4 AA, GA, and GG were 52.6, 40.7, and 6.7%, respectively, in the normoalbuminuric group; 45.5, 47.3, and 7.1% in the microalbuminuric group; and 36.9, 46.2, and 16.9% in the macroalbuminuric group. We detected a significant linear trend for SUMO4 genotype between the macroalbuminuric and normoalbuminuric groups. The mean urine albumin–to–creatinine ratio (42.3 ± 108.82 mg/mmol) in the GG group was significantly higher than in the AA (14.9 ± 51.49 mg/mmol) and GA (17.0 ± 43.74 mg/mmol) groups. Multivariate logistic regression analysis showed the SUMO4 M55V variant to be independently associated with the severity of diabetic nephropathy. CONCLUSIONS—This study indicates that the SUMO4 gene M55V variant is associated with severity of diabetic nephropathy in patients with type 2 diabetes.

Serum osteoprotegerin and tumor necrosis factor related apoptosis inducing-ligand (TRAIL) are elevated in type 2 diabetic patients with albuminuria and serum osteoprotegerin is independently associated with the severity of diabetic nephropathy

Osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have recently been reported to be associated with diabetic nephropathy in an in vitro study. However, the literature regarding serum OPG and TRAIL in type 2 diabetes mellitus patients is scarce. To investigate the role of OPG/TRAIL in diabetic nephropathy, we measured the serum concentrations of OPG and TRAIL in type 2 diabetes mellitus patients with different stages of nephropathy by enzyme-linked immunosorbent assay. One hundred seventy-nine subjects with type 2 diabetes mellitus were studied and stratified according to urinary microalbumin and serum creatinine measurements. The serum concentrations of OPG and TRAIL were significantly elevated in patients with microalbuminuria (OPG, 2154.2 ± 922.1 pg/mL; TRAIL, 80.2 ± 24.1 pg/mL) and macroalbuminuria (OPG, 2251.5 ± 925.7 pg/mL; TRAIL, 88.1 ± 23.8 pg/mL) as compared with patients with normoalbuminuria (OPG, 1690.1 ± 627.2 pg/mL; TRAIL, 70.7 ± 23.3 pg/mL). Serum OPG and TRAIL levels were increased in parallel and were significantly associated with each other. Using multivariate stepwise regression analysis, serum OPG was found to be an independent factor associated with the severity of diabetic nephropathy. Our results suggested that serum OPG may be a marker for the severity of diabetic nephropathy. Further studies are necessary to investigate the role of elevated serum OPG in the pathogenesis of diabetic nephropathy.

Elevated serum retinol-binding protein 4 concentrations are associated with renal dysfunction and uric acid in type 2 diabetic patients

While some studies have reported that retinol‐binding protein 4 (RBP4) might induce insulin resistance, other studies have demonstrated that the presence of albuminuria in diabetic patients and increased uric acid are related to insulin resistance. Therefore, this study attempted to further investigate the relationship among serum RBP4, serum uric acid, and the severity of albuminuria in diabetic patients.

Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance

AbstractThe absorption efficiency of cholesterol is closely correlated to dietary phytosterol content and determined by genetic factors. The ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 act as a sterol efflux pump to regulate the absorption of cholesterol and phytosterol. The levels of cholesterol and phytosterol associated with a Chinese diet are very different from those associated with a Western diet. This study aims to explore the association between serum total cholesterol/LDL-C levels and ABCG5/ABCG8 polymorphisms in a Taiwanese population consuming an ordinary Chinese diet. A total of 1,046 subjects (894 men and 152 women) were recruited in a hospital-based health check-up center in Kaohsiung Medical University Hospital. Five nonsynonymous polymorphisms of Q604E (ABCG5), D19H, C54Y, T400 K and A632 V (ABCG8) were analyzed by TaqMan genotyping assay. Analysis showed that the D19H polymorphism of the ABCG8 gene was significantly associated with serum total cholesterol, LDL-C levels and HOMA-IR index. Adjusting for sex and age, subjects with the D19H (GC) genotype were significantly associated with a threefold higher risk of high cholesterol and LDL-C levels than subjects with D19 (GG). These results suggest that the D19H polymorphism of ABCG8 could be considered a susceptible gene marker indicating an increased likelihood of developing high cholesterol and LDL-C levels in Taiwanese consuming an ordinary Chinese diet. It is supposed that the coexistence of higher insulin resistance and hypercholesterolemia for carriers of the D19H polymorphism may result in a greater risk of cardiovascular disease.

The hOGG1 Ser326Cys gene polymorphism is associated with decreased insulin sensitivity in subjects with normal glucose tolerance.

AbstractIncreased oxidative stress has been observed to contribute the development of insulin resistance. Oxidative stress is known to increase the conversion of deoxyguanosine (dG) to 8-hydroxy-2′-deoxyguanosine (8-OHdG). Human 8-oxoguanine glycosylase (hOGG1) is the key component responsible for the removal of 8-OHdG from oxidatively damaged DNA. The repair activity of the hOGG1 Ser326Cys gene variant has been demonstrated to be lower than that of the hOGG1 Ser/Ser genotype. Therefore, the possible association of the hOGG1 Ser326Cys gene variant with insulin sensitivity was investigated in 279 normal glucose-tolerant subjects without history of cancer. Allele frequency was 21.5% for the Ser/Ser genotype (n=60), 45.9% for the Ser/Cys genotype (n=128), and 32.6% for the Cys/Cys genotype (n=91). Subjects carrying the Cys/Cys genotype had significantly lower insulin sensitivity levels, assessed by homeostasis model assessment-insulin resistance (HOMA-IR), compared with the Ser/Ser and Ser/Cys genotypes (P<0.001 and P<0.001, respectively). In a multiple linear regression analysis, the Cys/Cys genotype was a significant determinant of HOMA-IR, independent of age, sex, body mass index, fasting plasma cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, or hypertension. The present study indicates that the hOGG1 gene Cys/Cys variant is associated with a significant decrease in insulin sensitivity in subjects with normal glucose tolerance.

The association of pioglitazone and urinary tract disease in type 2 diabetic Taiwanese: bladder cancer and chronic kidney disease.

Objective Although studies have shown an association between pioglitazone and bladder cancer, the associated factors have not been identified. The aim of this study was to investigate the factors that may link pioglitazone to bladder cancer. Materials and Methods In total, 34,970 study subjects were identified from the National Health Insurance Research Database in 2003 with follow-up from 2005 to 2009. The demographic characteristics of patients who had used and had never used pioglitazone, including age, sex, diabetes duration, urinary tract disease, nephropathy, bladder cancer, and cumulative dose and duration of pioglitazone therapy, were analyzed using the χ2 test. Cox proportional hazard regression models were used to determine the independent effects of pioglitazone on bladder cancer and newly developed chronic kidney disease. Results Among 3,497 ever users and 31,473 never users of pioglitazone, the respective incident cases of bladder cancer were 12 (0.4%) and 72 (0.2%), and for newly developed chronic kidney disease 245 (8.1%) and 663 (2.3%), respectively. Ever use of pioglitazone [1.59(1.32–1.91)], cumulative dose of pioglitazone <10,500 mg [1.69 (1.37–2.01)] and >10,500 mg [1.34 (1.04–1.73)], and duration of therapy <12 months [1.68 (1.36–2.08)] and >12 months [1.39 (1.09–1.76)] were associated with the development of chronic kidney disease. Conclusions There was no association of pioglitazone use with bladder cancer development, however, there was an association with an increased risk of newly developed chronic kidney disease.

Serum retinol-binding protein 4 is inversely correlated with disease severity of chronic hepatitis C☆

BACKGROUND/AIMS Hepatitis C virus (HCV) infection carries a significant risk for development of insulin resistance (IR) and/or diabetes mellitus. Recently, retinol-binding protein 4 (RBP4) has been reported as a protein contributing to IR. This study aimed to assess the correlation between RBP4 and disease severity of chronic HCV infection (CHC). METHODS Serum RBP4 was measured in 105 treatment-nai ve CHC patients and its correlation with the homeostasis model assessment of insulin resistance index (HOMA-IR), liver histology, virology and metabolic factors was investigated. Patients were stratified into different stages of glucose tolerance by oral glucose tolerance test. RESULTS There was a significant decreasing linear trend of RBP4 dependent on both histological grading (from 35.8+/-16.5 microg/mL of minimal to 19.2+/-12.5 microg/mL of severe, P=0.002) and staging (from 34.2+/-10.0 microg/mL of F0 to 22.2+/-11.9 microg/mL of F3-4, P=0.02) progression, whilst a significant increment of HOMA-IR was found. Multivariate regression analysis showed BMI (1.1, 95% CI 0.44 ~ 1.77, P=0.001), HDL-C (-0.40, 95% CI -0.73 ~ -0.06, P=0.02), and LDL-C (0.31, 95% CI 0.02 ~ 0.61, P=0.04) were the significant variables for prediction of RBP4. CONCLUSIONS Disease severity may limit the role of RBP4 as a predictor of IR in CHC.

Increased Unbound Retinol-binding Protein 4 Concentration Induces Apoptosis through Receptor-mediated Signaling

Background: An increase of apo- to holo-RBP4 concentration in plasma is observed in subjects with renal dysfunction and is supposed to induce cell damage. Results: Increased apo-/holo-RBP4 ratio affects STRA6 signaling, which activates JAK2/STAT5 and then induces apoptosis. Conclusion: Increased apo-RBP4 concentration can affect vitamin A signaling, leading to cell death. Significance: This study establishes a direct relationship between increased apo-RBP4 concentration and apoptosis. The increase of apo-/holo-retinol-binding protein 4 (RBP4) concentrations has been found in subjects with renal dysfunction and even in diabetic patients with microalbuminuria. Holo-RBP4 is recognized to possess cytoprotective function. Therefore, we supposed that the relative increase in apo-RBP4 might induce cell damage. In this study, we investigated the signal transduction that activated apoptosis in response to the increase of apo-/holo-RBP4 concentration. We found that increase of apo-/holo-RBP4 concentration ratio delayed the displacement of RBP4 with “stimulated by retinoic acid 6” (STRA6), enhanced Janus kinase 2 (JAK2)/STAT5 cascade, up-regulated adenylate cyclase 6 (AC6), increased cAMP, enhanced JNK1/p38 cascade, suppressed CRBP-I/RARα (cellular retinol-binding protein/retinoic acid receptor α) expression, and led to apoptosis in HK-2 and human umbilical vein endothelial cells. Furthermore, STRA6, JAK2, STAT5, JNK1, or p38 siRNA and cAMP-PKA inhibitor reversed the repression of CRBP-I/RARα and apoptosis in apo-RBP4 stimulation. In conclusion, this study indicates that the increase of apo-/holo-RBP4 concentration may influence STRA6 signaling, finally causing apoptosis.