Sung-Dae Moon

Long-Term Effect of the Internet-Based Glucose Monitoring System on HbA1c Reduction and Glucose Stability A 30-month follow-up study for diabetes management with a ubiquitous medical care system

OBJECTIVE—To investigate the long-term effectiveness of the Internet-based glucose monitoring system (IBGMS) on glucose control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted a prospective, randomized, controlled trial in 80 patients with type 2 diabetes for 30 months. The intervention group was treated with the IBGMS, while the control group made conventional office visits only. HbA1c (A1C) was performed at 3-month intervals. For measuring of the stability of glucose control, the SD value of A1C levels for each subject was used as the A1C fluctuation index (HFI). RESULTS—The mean A1C and HFI were significantly lower in the intervention group (n = 40) than in the control group (n = 40). (A1C [mean ± SD] 6.9 ± 0.9 vs. 7.5 ± 1.0%, P = 0.009; HFI 0.47 ± 0.23 vs. 0.78 ± 0.51, P = 0.001; intervention versus control groups, respectively). Patients in the intervention group with a basal A1C ≥7% (n = 27) had markedly lower A1C levels than corresponding patients in the control group during the first 3 months and maintained more stable levels throughout the study (P = 0.022). Control patients with a basal A1C <7% (n = 15) showed the characteristic bimodal distribution of A1C levels, whereas the A1C levels in the intervention group remained stable throughout the study with low HFI. CONCLUSIONS—Long-term use of the IBGMS has proven to be superior to conventional diabetes care systems based on office visits for controlling blood glucose and achieving glucose stability.

Clinical characteristics of diabetic ketoacidosis in Korea over the past two decades

Aims  The aim of this study was to investigate changes in the clinical characteristics of diabetic ketoacidosis (DKA) in Korea over the last two decades.

Diabetic Peripheral Neuropathy Is Associated With Increased Arterial Stiffness Without Changes in Carotid Intima–Media Thickness in Type 2 Diabetes

OBJECTIVE This study was conducted to investigate the association of diabetic peripheral neuropathy (DPN) with both arterial stiffness and intima–media thickness (IMT). RESEARCH DESIGN AND METHODS We conducted a cross-sectional analysis of 731 subjects with type 2 diabetes. DPN was diagnosed on the basis of neuropathic symptoms, insensitivity to a 10-g monofilament, abnormal pin-prick sensation, and abnormal current perception threshold. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI), and IMT was assessed by B-mode ultrasonography. RESULTS Patients with DPN had higher CAVI than those without DPN in multivariate-adjusted models, whereas no differences in IMT were observed between patients with and without DPN after adjustment for age and sex. In the multivariate analysis, CAVI was a significant determinant of DPN (odds ratio 1.36 [95% CI 1.13–1.65], P = 0.001). CONCLUSIONS DPN is significantly associated with arterial stiffness without carotid intimal changes in patients with type 2 diabetes.

Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by the combined occurrence of tumours of the parathyroid glands, pancreatic islet cells and anterior pituitary gland. Mutation analysis of the MEN1 gene has enabled the genetic diagnosis of patients with MEN1. Two MEN1‐related disorders – familial isolated hyperparathyroidism (FIHP) and familial pituitary adenoma – are considered to be variants of MEN1, or at least to be incompletely expressed variants. Germline mutations of the MEN1 gene have been reported in some with FIHP, but familial pituitary adenoma usually lacks the MEN1 mutation and has been described as a genetically distinct disorder. In this work, we investigated five Korean families with MEN1, one family with FIHP and one family with familial pituitary adenoma. Polymerase chain reaction (PCR)‐based single‐strand conformation polymorphism (PCR‐SSCP) analysis, denaturing high‐performance liquid chromatography (DHPLC) and sequencing were used to detect the MEN1 mutations. Screening of the genetic variations of the MEN1 gene revealed four germline mutations in five typical MEN1 families. All four germline mutations led to truncated proteins or a change in the amino acids of the functional domains. In this study, we identified three novel MEN1 germline mutations (969C >A, 973G >C and 1213C >T) and one previously reported mutation (200–201insAGCCC). The frequency of the MEN1 germline mutation in Korean MEN1 families (four of five; 80%) was similar to those reported previously. In accordance with previous studies, no MEN1 germline mutation was detected in two families with FIHP or familial pituitary adenoma.

Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes

Background Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Methods Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. Results After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05). Conclusion Dapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

Novel compound heterozygous mutations in the fructose-1,6-bisphosphatase gene cause hypoglycemia and lactic acidosis

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase 1 (FBP1) gene and results in impaired gluconeogenesis. We describe a male patient with typical FBPase deficiency who presented with hypoglycemia and lactic acidosis. The FBPase activity in his peripheral leukocytes and liver was very low. We amplified and sequenced the entire FBP1 coding region of the patient and his family members. Direct and allele-specific sequence analysis of the FBP1 gene revealed that the proband had a compound heterozygote for the G164S and 838delT, which he inherited from his carrier parents. His father and mother had heterozygous 838delT and G164S mutations, respectively, without any symptoms of hypoglycemia. Gene tracking within the family revealed that his elder sister had a heterozygous G164S mutation without symptoms of hypoglycemia. A G164S mutation of FBP1 in a heterozygous pattern (G164S and InsG960_961) has been reported previously, but the heterozygous 838delT mutation is novel. Transient transfection studies using COS-7 cells demonstrated that FBPase proteins with G164S or 838delT mutations were enzymatically inactive. In conclusion, we report a new case of molecular diagnosis of FBPase deficiency and provide evidence that impaired FBPase activity may be caused by novel compound heterozygous mutations in the FBP1 gene.

Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury.

Background Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic β-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic β-cells from high glucose-induced apoptosis. Methods Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations. Results CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP. Conclusion Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.

Proteomic analysis of differential protein expression in response to epidermal growth factor in neonatal porcine pancreatic cell monolayers

We have proposed that porcine neonatal pancreatic cell clusters (NPCCs) may be a useful alternative source of cells for islet transplantation, and that monolayer cultures might provide an opportunity to manipulate the cells before transplantation. In addition we previously identified 10 genes up‐regulated by epidermal growth factor (EGF) in cultured porcine NPCC monolayers. We have now analyzed the intracellular signaling pathways activated by EGF and searched for proteins differentially expressed following EGF treatment of the monolayers, using two‐dimensional gel electrophoresis (2‐DE) and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS). EGF treatment resulted in phosphorylation of both Erk 1/2 and Akt, as well as increased cell proliferation. Five unknown and 13 previously identified proteins were differentially expressed in response to EGF. EGF treatment increased the expression of several structural proteins of epithelial cells, such as cytokeratin 19 and plakoglobin, whereas vimentin, the intermediate filament protein of mesenchymal cells, and non‐muscle myosin alkali chain isoform 1, decreased. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 factor, which promotes epithelial cell proliferation, and hemoglobin alpha I & II also increased, whereas cyclin A1, immunoglobulin heavy chain, apolipoprotein A1, 5,10‐ethylenetetrahydrofolated reductase (5,10‐MTHFR), angiotensin‐converting enzyme 2 (ACE2), co‐lipase II precursor, and NAD+ isocitrate dehydrogenase (NAD+ IDH) alpha chain proteins decreased. Our results show that EGF stimulates proliferation of pancreatic epithelial cells by simultaneously activating the MAPK and PI‐3K pathways. HnRNP A2/B1, hemoglobin, cyclin A1, and ACE2 may play roles in the proliferation of epithelial cells in response to EGF.

The diagnosis of diabetes mellitus in Korea: a pooled analysis of four community-based cohort studies

In 1997, the American Diabetes Association (ADA) proposed that the cut-off point for fasting plasma glucose (FPG) for diabetes should be reduced from 7.8 to 7.0 mmol/l. Since this report, several studies have shown poor agreement between criteria based on FPG and postchallenge 2-h plasma glucose (2-h PG). The association of FPG with 2-h PG may vary between populations due to different environmental or genetic backgrounds. The Committee of the Korean Diabetes Association on the Diagnosis and Classification of Diabetes Mellitus selected four of the community-based epidemiological studies in Korea that (i) were population based, (ii) were performed after 1990, (iii) included both men and women, (iv) studied patients who were at least 30 years of age, and (v) used a standard 2-h 75-g oral glucose tolerance test (OGTT). Using these four studies, we examined the diagnostic equivalence of FPG values to 2-h PG values of 7.8 and 11.1 mmol/l. The study subjects were 6234 (2473 in Yonchon [1], 774 in Mokdong [2], 1106 in Chongup [3] and 1881 in Ansan [4]). Yonchon and Chongup counties are rural communities, Mokdong is a residential district in metropolitan Seoul and Ansan is an urban area near Seoul. For statistical analysis, receiver operating characteristics (ROC) analysis was performed to reveal the optimal cut-off point of FPG to diagnose diabetes with a 2-h PG value ≥ 11.1 mmol/l, and impaired glucose tolerance (IGT) with a 2-h PG value ≥ 7.8 mmol/l. The mean age and body mass index of study subjects were 51.9 ± 13.7 years and 23.7 ± 3.2 kg/m 2 , respectively. The resulting ROC curve showed the optimal cut-off point of FPG values for the diagnosis of diabetes was 6.1 mmol/l, with sensitivity and specificity of 76.4% and 92.2%, respectively (Fig. 1). The sensitivity and specificity of the currently applied cut-off point for the diagnosis of diabetes, 7.0 mmol/l, were 56.5% and 98.8%, respectively. From the ROC curve, the optimal cut-off point of FPG values to diagnose IGT was 5.4 mmol/l, with 57.5% sensitivity and 71.0% specificity. There have been many reports that the optimal cut-off point of FPG for diabetes diagnosis is lower than that of the ADA recommendation, a result consistent with this study. In the DECODA study, the optimal FPG cut-off point corresponding to a 2-h PG of ≥ 11.1 mmol/l was 5.8 mmol/l by ROC analysis [5]. Chang et al . have also suggested that in a Taiwanese population the optimal FPG as a screening criterion for diabetes is 6.25 mmol/l, with sensitivity and specificity of 57.6% and 96.1%, respectively [6]. Recently, Miyazaki et al . reported that in a Japanese population, the optimal cut-off FPG level for the diagnosis of diabetes was 6.4 mmol/l. They showed a dramatic increase of retinopathy at this point [7]. Thus, the optimal cut-off point of FPG for the diagnosis of diabetes varies substantially between ethnic groups, and is slightly lower (range 5.6–6.4 mmol/l) in Asian than in Western populations. In this study, a FPG cut-off of 6.1 mmol/l corresponded to a 2-h PG value of 11.1 mmol/l. If this new cut-off value were used to diagnose diabetes, 11.3% of subjects would be classified as having diabetes, which is about two times higher than when a 2-h PG value of 11.1 mmol/l is used (5.1%). In this case, as the sensitivity increases, the specificity and positive predictive value decrease accordingly. As there have been no prospective cohort data of mortality to define the appropriate criteria for diagnosing diabetes in Korea and international comparison is important, it is prudent to retain the current fasting glucose value of 7.0 mmol/l as the cut-off for diagnosing diabetes in Korean adults.

Clinical significance of serum bilirubin and gamma- glutamyltransferase levels on coronary atherosclerosis assessed by multidetector computed tomography

BACKGROUND AND AIMS Low bilirubin and high gamma-glutamyltransferase (GGT), which are endogenous markers of oxidative stress, confer a higher risk of cardiovascular disease (CVD). We investigated associations between serum concentrations of bilirubin, GGT and coronary atherosclerosis. METHODS AND RESULTS A cross-sectional analysis was performed on 1520 subjects who underwent multidetector computed tomography scans. Coronary atherosclerosis was assessed by coronary artery calcium score (CACS) and obstructive coronary artery disease (OCAD), was defined as the presence of coronary artery stenosis of ≥50%. Total bilirubin (TB) level was negatively correlated with CACS and coronary stenosis whereas GGT level was positively correlated with CACS in men. However, there was no correlation between TB, GGT levels and either CACS or coronary artery stenosis in women. In a multivariate-adjusted model, TB level was inversely associated with a CACS > 100 [odds ratio (OR) per log standard deviation (SD), 0.67; 95% confidence interval (CI), 0.52-0.87], and OCAD (OR per log SD, 0.77; 95% CI, 0.62-0.95) in men. By contrast, GGT level was positively associated with a CACS > 100 (OR per log SD, 1.35; 95% CI, 1.05-1.73) but not with OCAD. Adding TB and GGT to the conventional risk factors increased predictive accuracy for CACS > 100 (net reclassification improvement index [NRI] = 13.1%, P = 0.026; integrated discrimination index [IDI] = 0.024, P = 0.001) and for OCAD (NRI = 12.6%, P = 0.026; IDI = 0.010, P = 0.013). CONCLUSIONS Low TB and high GGT levels were concomitantly associated with coronary atherosclerosis in Korean men. Future studies are needed to elucidate the causal associations of TB and GGT with CVD.