Bo-Wan Kim

Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner.

Prolonged elevations of glucose concentration have deleterious effects on β-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose–induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1–and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of β-cell dysfunction induced by glucotoxicity.

Factors that Affect Medication Adherence in Elderly Patients with Diabetes Mellitus

Background This study was conducted to evaluate the factors affecting medication adherence in geriatric diabetic patients treated at private clinics and tertiary hospitals. We compared the factors affecting medication adherence between these two patient groups. Methods We included 108 diabetic patients older than 65 years treated at one tertiary hospital and 157 patients older than 65 years treated at two private clinics. We conducted an interview survey based on the Health Belief Model, and used a questionnaire that included the self-efficacy variable. For the medication adherence, Moriskys self-report was used. Results The medication adherence based on Moriskys self-report was significantly higher in tertiary hospital patients (61.1%) compared to private clinic patients (43.2%) (P < 0.01). The results showed that drug storage and self-efficacy were factors affecting adherence to medication in tertiary hospital patients (P < 0.05). The adherence was high in cases of proper drug storage (odds ratio [OR], 5.401) and in cases with high self-efficacy (OR, 13.114). In private clinic patients, financial level (P < 0.05), recognition of the seriousness of diabetes complications (P < 0.05) and self-efficacy (P < 0.01) were associated with medication adherence. The medication adherence was significantly lower in patients whose financial state were moderate than those with lower (OR, 0.410), and medication adherence was significantly higher in patients who had higher perceived severity (OR, 2.936) and in patients with higher self-efficacy (OR, 4.040). Conclusion Different strategies should be used to increase medication adherence in geriatric diabetic patients, depending on institutions whether they are treated.

TGF‐β‐induced protein βig‐h3 is upregulated by high glucose in vascular smooth muscle cells

TGF‐β‐induced gene‐h3 (βig‐h3) is an adhesive molecule that interacts with integrins. Because TGF‐β plays an important role in diabetic complications and βig‐h3 serves as a cell substrate, we hypothesized that diabetic conditions might increase βig‐h3 synthesis in vascular smooth muscle cells (VSMCs), which may subsequently contribute to the pathogenesis of diabetic angiopathy. The concentrations of βig‐h3 and TGF‐β were measured in conditioned media using an enzyme‐linked immunosorbent assay. An immunohistochemical study showed that βig‐h3 was expressed in the VSMCs and the matrix of rat aortas. TGF‐β stimulated βig‐h3 production, and high glucose induced βig‐h3 as well as TGF‐β production in the VSMCs. The high glucose‐induced βig‐h3 expression was almost entirely blocked by an anti‐TGF‐β antibody. βig‐h3 protein mediated the adhesion, spreading, migration, and proliferation of rat VSMCs. These results suggest that the high glucose‐induced βig‐h3 in VSMCs regulates VSMC functions and may play an important role in diabetic angiopathy.

Impact of ENPP1 and MMP3 gene polymorphisms on aortic calcification in patients with type 2 diabetes in a Korean population

AIMS We investigated whether gene polymorphisms of Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and matrix metalloproteinase 3 (MMP3) are associated with increased vascular calcification in patients with type 2 diabetes (T2D) and evaluated whether serum MMP3 and osteoprotegerin (OPG) levels are related to calcification. METHODS This study included 464 subjects: 269 patients with T2D and 195 healthy controls in South Korea. We genotyped subjects for four single nucleotide polymorphisms (SNPs): ENPP1 K121Q, ENPP1 A/G+1044TGA, MMP3 -709A>G and MMP3 -1475G>A. The presence or absence of calcifications in the aortic arch was assessed by plain chest radiography. RESULTS The SNPs ENPP1 K121Q and MMP3 -709A>G showed significant associations with T2D (P=0.001 and P=0.004). The SNP ENPP1 K121Q showed a significant association with aortic arch calcification in T2D (P=0.036). Serum OPG levels were significantly higher in T2D patients than in the control group (P<0.001). However, serum MMP3 levels were significantly lower in T2D patients than in the control group (P<0.001). CONCLUSIONS Our study demonstrates that the ENPP1 K121Q and MMP3 -709A>G polymorphisms are associated with T2D, and that the ENPP1 Q allele is associated with increased aortic arch calcification in a Korean population.

Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injury

Increased expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues is a potential factor linking diabetes to restenosis after percutaneous coronary intervention. Recent studies have shown that cilostazol, a selective type 3 phosphodiesterase inhibitor, prevents neointimal hyperplasia and in-stent thrombosis in patients with diabetes after coronary angioplasty and stent implantation. However, the molecular mechanism of this drug has not been fully elucidated. We examined whether cilostazol inhibits PAI-1 expression in vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. We found that cilostazol effectively inhibits angiotensin II-, high glucose- and TGF-beta-stimulated PAI-1 expression in vivo and in vitro. Cilostazol attenuated PAI-1 expression in neointimal regions and inhibited neointimal hyperplasia after balloon injury. Cilostazol inhibited PAI-1 expression by multiple mechanisms including downregulation of TGF-beta, JNK and p38 signaling pathways. Cilostazol also inhibited transactivating activity at the PAI-1 promoter by Smad3, leading to a suppression of PAI-1 gene transcription. Taken together with its antiproliferative effect on VSMCs, this may explain how cilostazol exerts its antithrombogenic effects after angioplasty and stent implantation.

Trend analysis of diabetic prevalence and incidence in a rural area of South Korea between 2003–2008

Aims/Introduction:  This study determined the change in prevalence of diabetes and prediabetes over a period of 5 years in South Korea. The incidence of diabetes and prediabetes and risk factors associated with the development of diabetes were also investigated.