Chang-Hsun Hsieh

Type 2 diabetes mellitus (T2DM) is an independent risk factor of knee osteoarthritis (KOA). This study was mainly based on data from the Taiwan National Health Insurance Database. Using big data analysis, we showed that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment is helpful for patients with T2DM who have a lower risk of KOA or total knee replacement (TKR). A total of 35,762 patients with T2DM were included in this study. We divided these patients into 988 patients with T2DM without KOA and 372 patients with T2DM with KOA who received GLP-1RA treatment and those who did not receive GLP-1RA treatment. The patients were matched for sex, age, and inclusion date by 1:1 propensity score, which was included in the control group. Cox proportional hazards analyses were performed to compare KOA risk and TKR rate during a maximum follow-up period of 5 years. There were 1976/744 patients with T2DM without/with KOA who received and did not receive GLP-1RA treatment, including 1052/322 men (53.24/43.28%) and 924/422 women (46.76/56.72%). At the end of follow-up, there were 46/39 (4.66/10.48%) patients with T2DM without/with KOA who received GLP-1RA treatment and underwent KOA/TKR were lower than those without GLP-1RA treatment 87/70 (8.81/18.82%). Cox proportional hazard regression analysis showed a lower rate of KOA/TKR among patients with GLP-1RA treatment (adjusted hazard ratio [HR] = .852; 95% confidence interval [CI] = .784–.930, P < .001/ adjusted HR = .913; 95% CI = .885–.977, P = .015, respectively). Kaplan–Meier analysis showed that the cumulative risk of KOA/TKR in patient with/without GLP-1RA was significantly different (log-rank test, P < .001/P < .001, respectively). This study aimed to provide clinicians with the option of GLP-1RA as a treatment for patients with T2DM with or without KOA to reduce the risk of KOA or TKR among such patients.

This study investigated the effect of a combination of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and basal insulin (BI) in poorly controlled type 2 diabetes mellitus previously treated with premixed insulin. The possible therapeutic benefit of the subject is mainly hoped to provide a direction for optimizing treatment options to reduce the risk of hypoglycemia and weight gain. A single-arm, open-label study was conducted. The antidiabetic regimen was switched to GLP-1 RA plus BI to replace previous treatment with premixed insulin in type 2 diabetes mellitus subjects. After 3 months of treatment modification, GLP-1 RA plus BI was compared for superior outcomes by continuous glucose monitoring system. There were 34 subjects at the beginning, 4 withdrew due to gastrointestinal discomfort, and finally 30 subjects completed the trial, of which 43% were male; the average age was 58 ± 9 years old, and the average duration of diabetes was 12 ± 6 years, the baseline glycated hemoglobin level was 8.6 ± 0.9 %. The initial insulin dose of premixed insulin was 61 ± 18 units, and the final insulin dose of GLP-1 RA + BI was 32 ± 12 units (P < .001). Time out of range (from 59%–42%), time-in-range (from 39%–56%) as well as glucose variability index including standard deviation also improved, mean magnitude of glycemic excursions, mean daily difference and continuous population in continuous glucose monitoring system, continuous overall net glycemic action (CONGA). Also noted was a decrease in body weight (from 70.9 kg–68.6 kg) and body mass index (all P values < .05). It provided important information for physicians to decide to modify therapeutic strategy as individualized needs.

The glucokinase regulator gene (GCKR) is located on chromosome 2p23. It plays a crucial role in maintaining plasma glucose homeostasis and metabolic traits. Recently, genome-wide association studies have revealed a positive association between hyperuricemia and GCKR variants in adults. This study investigated this genetic association in Taiwanese adolescents. Data were collected from our previous cross-sectional study (Taipei Children Heart Study). The frequencies of various genotypes (CC, CT, and TT) or alleles (C and T) of the GCKR intronic single-nucleotide polymorphism (SNP) rs780094 and the coding SNP rs1260326 (Pro446Leu, a common 1403C-T transition) were compared between a total of 968 Taiwanese adolescents (473 boys, 495 girls) with hyperuricemia or normal uric acid levels on the basis of gender differences. Logistic and linear regression analyses explored the role of GCKR in abnormal uric acid (UA) levels. Boys had higher UA levels than girls (6.68 ± 1.29 and 5.23 ± 0.95 mg/dl, respectively, p < 0.001). The analysis of both SNPs in girls revealed that the T allele was more likely to appear in patients with hyperuricemia than the C allele. After adjusting for confounders, the odds ratio (OR) for hyperuricemia incidence in the TT genotype was 1.75 (95% confidence interval [CI] 1.02–3.00), which was higher than that in the C allele carriers in rs1260326 in the girl population. Similarly, the TT genotypes had a higher risk of hyperuricemia, with an OR of 2.29 (95% CI 1.11–4.73) for rs1260326 and 2.28 (95% CI 1.09–4.75) for rs780094, than the CC genotype in girl adolescents. The T (Leu446) allele of GCKR rs1260326 polymorphism is associated with higher UA levels in Taiwanese adolescent girls.

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

Background: Recent genome-wide association studies revealed a positive association between hyperuricemia and variants of the glucokinase regulator (GCKR) gene in adults. This study replicated the genetic association in a Taiwanese adolescent population. Methods: The frequencies of different genotypes or alleles of the GCKR rs780094 and rs1260326 single-nucleotide polymorphism (SNP) were compared between 962 subjects (468 boys, 494 girls) with hyperuricemia (HUA) and normal uric acid (NUA) levels relative to gender. Logistic regression analysis was carried out to explore the genetic role in abnormal uric acid (UA) concentrations. Results: Boys had higher UA levels than girls (6.68 ± 0.06 and 5.23 ± 0.04 mg/dl, respectively, p < 0.001). The T allele had a higher HUA frequency than the C allele in both SNPs in girls; the rest of the frequencies of alleles and genotypes did not differentiate between subjects with HUA and NUA groups in both genders. However, after adjusting for confounding factors, the odds ratio for hyperuricemia incidence in TT genotype carriers was 1.75 (95% confidence interval [CI]: 1.02 to 3.00) and higher than the C-carrier genotype in rs1260326 of the girl population. Conclusion: The GCKR rs1260326 polymorphism is associated with higher UA concentrations in Taiwanese girl adolescents.

Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up (p = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691–0.972, p = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.

Obesity and regional adiposity are important risk factors for cardiometabolic disorders. The aim of this study is to compare 7-site skinfold (SF) measurement to dual-energy x-ray absorptiometry (DXA) as the reference method for estimating body fat percentage (BF%) and regional adiposity in diabetic outpatients. A total of 59 diabetic patients (36 females and 23 males) aged 28.5–78 years (median 67.7 years) with BMI 18.8–40.6 kg/m² (median: 25.5 kg/m²) were enrolled. 7-site skinfold measurement and DXA were performed at the same visit day and biochemistry data were collected. Our results demonstrate the BF% calculated via Jackson & Pollock 7-site skinfold equation presents a strong correlation (r = 0.672, p < 0.001 in females; r = 0.885, p < 0.001 in males) with that measured by DXA, but the means of BF% between these two methods are significantly different in both sexes (paired t-test, p < 0.001). The Bland-Altman analysis showed the mean differences (DXA-SF) of BF% were positive for female (8.74%) and male (7.22%), suggesting Jackson & Pollock 7-site skinfold equation tends to underestimate the BF%. Besides, regional SF thicknesses of 7-site skinfold measurement were significantly correlated with the matched regional adiposity quantified by DXA. Furthermore, truncal and android SF thicknesses were notably positively correlated with several cardiometabolic risk factors in gender-specific manner. Our data indicate the 7-site skinfold measurement is not an interchangeable method for precisely measuring BF%, but might be practical for evaluating the cardiometabolic risks in Taiwanese diabetic outpatients.

Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia—including Alzheimer’s disease, vascular dementia, and other dementia types—between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681–0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404–0.681; p < 0.001), but not in Alzheimer’s disease (HR 0.891; 95% CI 0.712–1.265; p = 0.297). The Kaplan–Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer’s disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.

Background: Evidence of low-dose aspirin as the primary prevention strategy for cardiovascular disease (CVD) in diabetes are unclear. This study was designed to evaluate the effect of low-dose aspirin use for the primary prevention of CVD in diabetes. Methods: We collected randomized controlled trials of low-dose aspirin for the primary prevention of CVD in adults with diabetes lasting at least 12 months from Medline, Embase, and the Cochrane Library up to 10 November 2018. Two reviewers extracted data and appraised the reporting quality according to a predetermined protocol (CRD4201811830). This review was conducted using Cochrane standards, trial sequential analysis, and the Grading of Recommendation. The primary outcomes were major adverse cardiovascular events (MACE, including non-fatal myocardial infarction, ischemia stroke, and cardiovascular death) and an incidence of major hemorrhage (major intracranial hemorrhage and major gastrointestinal bleeding). Results: In this primary prevention (number = 29,814 participants) meta-analysis, low-dose aspirin use reduced the risk of MACE by 9% and increased the risk of major hemorrhage by 24%. The benefits were only observed in subjects of age ≥ 60 years while reducing the same risk of MACE. In efficacy, it reduced the risk of stroke but not myocardial infarction. No increase in all-cause mortality or cardiovascular death was observed. Conclusions: We suggested the use of low-dose aspirin as the primary prevention strategy for CVD in diabetes, particularly in an older population. The absolute benefits were largely counterbalanced by the bleeding hazard.

Little is known about iodine nutritional status in island countries in the Pacific Ocean. The primary objective of this study was to report for the first time the iodine nutritional status of people in Nauru. In addition, sources of iodine nutrition (i.e., water and salt) were investigated. A school-based cross-sectional survey of children aged 6–12 years was conducted in three primary schools of Nauru. Urinary iodine concentration (UIC) was determined by spot urine samples. Available water and salt samples in Nauru were collected for the measurement of iodine content. A food frequency questionnaire was conducted. The median UIC was 142 μg/L, and 25.2% and 7.4% of the population had median UIC below 100 μg/L and 50 μg/L, respectively. Natural iodine-containing foods such as seaweeds and agar were rare. Iodine was undetectable in Nauruan tank water, filtered tap water, and raindrops. Of the analyzed salt products, five kinds were non-iodized, and three were iodized (iodine content: 15 ppm, 65 ppm, and 68 ppm, respectively). The results indicate that the iodine status in Nauruan school children is adequate. Iodized salt may serve as an important source of iodine nutrition in Nauru.