The recent epidemic of type 2 diabetes in Asia differs from that reported in other regions of the world in several key areas: it has evolved over a much shorter time, in an earlier stage of life, and in people with lower body mass indices. These phenotypic characteristics of patients strongly suggest that insulin secretory defects may perform a more important function in the development and progression of diabetes. A genetic element clearly underlies β-cell dysfunction and insufficient β-cell mass; however, a number of modifiable factors are also linked to β-cell deterioration, most notably chronic hyperglycemia and elevated free fatty acid (FFA) levels. Neither glucose nor FFAs alone cause clinically meaningful β-cell toxicity, especially in patients with normal or impaired glucose tolerance. Thus the term "glucolipotoxicity" is perhaps more appropriate in describing the phenomenon. Several mechanisms have been proposed to explain glucolipotoxicity-induced β-cell dysfunction and death, but its major factors appear to be depression of key transcription factor gene expression by altered intracellular energy metabolism and oxidative stress. Therefore, stabilization of metabolic changes induced by glucolipotoxicity in β-cells represents a new avenue for the treatment of type 2 diabetes mellitus.
β-cell dysfunction; Glucolipotoxicity; Glucotoxicity; Lipotoxicity
A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.
Adult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.
The adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.
These data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.
Ad-BETA2/NeuroD; Ad-MafA; Ad-PDX-1/VP16; Beta-cell; Neonatal pig cell clusters; Pancreatic exocrine cell; Transdifferentiation; Transplantation
AIM: To assess the efficacy and safety of vildagliptin/pioglitazone combination therapy in Korean patients with type 2 diabetes mellitus (T2DM).
METHODS: This was a post hoc analysis in Korean patients, from a 24-wk, randomized, active-controlled, double-blind, parallel-group, multicenter study. Eligible patients were aged between 18 and 80 years, drug naive, and had been diagnosed with T2DM [hemoglobin A1c (HbA1c): 7.5%-11.0% and fasting plasma glucose (FPG): < 270 mg/dL (< 15 mmol/L)]. Patients were randomized (1:1:1:1) to receive the vildagliptin/pioglitazone combination at 100/30 mg q.d. (high-dose) or 50/15 mg q.d. (low-dose), vildagliptin 100 mg q.d., or pioglitazone 30 mg q.d. monotherapies. The primary outcome measure was change in HbA1c from baseline to endpoint.
RESULTS: The distribution of baseline demographic and clinical parameters was well balanced between treatment groups. The overall mean age, body mass index, HbA1c, FPG, and duration of disease were 50.8 years, 24.6 kg/m2, 8.6%, 10.1 mmol/L, and 2.2 years, respectively. Adjusted mean changes (± standard error) in HbA1c from baseline (~8.7%) to week 24 endpoint were -2.03% ± 0.16% (high-dose, N = 34), -1.88% ± 0.15% (low-dose, N = 34), -1.31% ± 0.21% (vildagliptin, N = 36), and -1.52% ± 0.16% (pioglitazone, N = 36). The high-dose combination therapy demonstrated greater efficacy than monotherapies [vildagliptin (P = 0.029) and pioglitazone (P = 0.027)]. Percentage of patients achieving HbA1c < 7% and ≤ 6.5% was the highest in the high-dose group (76% and 68%) followed by low-dose (58% and 47%), vildagliptin (59% and 37%), and pioglitazone (53% and 28%) groups. The overall incidence of adverse events was comparable.
CONCLUSION: In Korean patients, first-line treatment with high-dose combination therapy improved glycemic control compared to pioglitazone and vildagliptin monotherapies, consistent with results published for the overall study population.
Type 2 diabetes mellitus; Vildagliptin; Pioglitazone
New diabetes management systems based on interactive communication have been introduced recently, accompanying rapid advances in information technology; these systems are referred to as "ubiquitous diabetes management systems." In such ubiquitous systems, patients and medical teams can communicate via Internet or telecommunications, with patients uploading their glucose data and personal information, and medical teams sending optimal feedback. Clinical evidence from both long-term and short-term trials has been reported by some researchers. Such systems appear to be effective not only in reducing the levels of HbA1c but also in stabilizing glucose control. However, most notably, evidence for the cost-effectiveness of such a system should be demonstrated before it can be propagated out to the general population in actual clinical practice. To establish a cost-effective model, various types of clinical decision supporting software designed to reduce the labor time of physicians must first be developed. A number of sensors and devices for monitoring patients' data are expected to be available in the near future; thus, methods for automatic interconnections between devices and web charts were also developed. Further investigations to demonstrate the clinical outcomes of such a system should be conducted, hopefully leading to a new paradigm of diabetes management.
Delivery of healthcare; Diabetes mellitus; Internet
The aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes.
In this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics.
Ultimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (ΔHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P<0.05). Of the variables, initial HbA1c levels (P=0.032) and history of sulfonylurea use (P=0.026) were independently associated with responsiveness to vildagliptin treatment.
Vildagliptin was effective when it was used in subjects with poor glycemic control. It controlled fasting plasma glucose levels as well as sulfonylurea treatment in Korean type 2 diabetic subjects.
Diabetes mellitus; Dipeptidyl peptidase 4; Dipeptidyl peptidase 4 inhibitor; Vildagliptin
While many studies have shown the good efficacy and safety of exenatide in patients with diabetes, limited information is available about exenatide in clinical practice in Korean populations. Therefore, this retrospective cohort study was designed to analyze the effects of exenatide on blood glucose level and body weight in Korean patients with type 2 diabetes mellitus.
We reviewed the records of the patients with diabetes who visited Seoul St. Mary's Hospital and for whom exenatide was prescribed from June 2009 to October 2011. After excluding subjects based on their race/ethnicity, medical history, whether or not they changed more than 2 kinds of oral hypoglycemic agents with exenatide treatment, loss to follow-up, or whether they stopped exenatide therapy within 6 months, a total of 52 subjects were included in the final analysis.
The mean glycated hemoglobin (HbA1c) level and weight remarkably decreased from 8.5±1.7% to 6.7±1.0% (P<0.001) and from 82.3±15.8 kg to 78.6±16.3 kg (P<0.001), respectively. The multiple regression analysis indicated that the reduction in HbA1c level was significantly associated with a shorter duration of diabetes, a higher baseline HbA1c level, and greater weight reduction, whereas weight loss had no significant correlation with other factors. No severe adverse events were observed.
These results suggest that a 6-month exenatide injection therapy significantly improved patients' HbA1c levels and body weights without causing serious adverse effects in Korean patients with type 2 diabetes.
Diabetes mellitus, type 2; Exenatide; Glucagon-like peptide 1; Treatment outcome
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.
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).
DPN is significantly associated with arterial stiffness without carotid intimal changes in patients with type 2 diabetes.
There is controversy regarding definition of vitamin D inadequacy. We analyzed threshold 25-hydroxyvitamin D (25[OH]D) below which intact parathyroid hormone (iPTH) increases, and examined age- and sex-specific changes of 25(OH)D and iPTH, and association of 25(OH)D and iPTH with bone mineral density (BMD) in elderly Koreans. Anthropometric parameters, serum 25(OH)D and iPTH, lumbar spine and femur BMD by dual-energy radiography absorptiometry (DXA) were measured in 441 men and 598 postmenopausal women. iPTH increased below serum 25(OH) of 36.7 ng/mL in men, but failed to reach plateau in women. Femur neck BMD above and below threshold differed when threshold 25(OH)D concentrations were set at 15-27.5 ng/mL in men, and 12.5-20 ng/mL in postmenopausal women. Vitamin D-inadequate individuals older than 75 yr had higher iPTH than those aged ≤ 65 yr. In winter, age-associated iPTH increase in women was steeper than in summer. In conclusion, vitamin D inadequacy threshold cannot be estimated based on iPTH alone, and but other factors concerning bone health should also be considered. Older people seemingly need higher 25(OH)D levels to offset age-associated hyperparathyroidism. Elderly vitamin D-inadequate women in the winter are most vulnerable to age-associated hyperparathyroidism.
Vitamin D; Intact Parathyroid Hormone; Bone Density; Age; Sex
Recent studies have shown the importance of postprandial glucose (PPG) in the development of diabetes complications. This study was conducted in order to survey the perceptions of clinicians and diabetic patients with respect to PPG management and the current status of diabetes education.
This was a cross-sectional study involving face-to-face interviews and an open questionnaire survey conducted in Korea. A total of 300 patients and 130 clinicians completed questionnaires, which included current education status, self monitoring of blood glucose (SMBG), criteria of diagnosis and management, and perceptions relating to PPG management.
While there was a significantly higher perceived need for diabetes education, the sufficiency of the current education was considered to be severely lacking. Fasting plasma glucose (FPG), PPG, and glycosylated hemoglobin (HbA1c) were all important considerations for clinicians when making a diagnosis of diabetes, although PPG was considered less important than FPG or HbA1c in the treatment of diabetes. Most clinicians and patients were aware of the importance of PPG, but actual education on the importance of PPG was not actively being delivered.
Our study showed that the current status of diabetes education is insufficient to meet the needs of the Korean population. A considerable gap was found to exist between awareness and what was actually taught in the current education program in regard to the importance of PPG. These results suggest that clinicians need to be more active in patient education, especially in regard to the importance of PPG.
Diabetes education; Diabetes mellitus, type 2; Perception; Postprandial glucose
This study aims to investigate the discrepancy between clinicians' perceptions and actual achievement rates of low density lipoprotein cholesterol (LDL-C) in Korean patients with diabetes according to updated American Diabetes Association (ADA)/American College of Cardiology Foundation (ACC) recommendations.
This is a multi-center, retrospective, non-interventional, observational study. Diabetic patients aged 18 years or older were eligible if they had been diagnosed with hypercholesterolemia or were receiving a lipid-lowering therapy between May 2010 and August 2010. The information was obtained by reviewing medical records and using a self-completed questionnaire to examine physician perceptions.
A total of 2,591 subjects who satisfied the inclusion criteria were enrolled. Highest-risk and high-risk patients accounted for 61.9% and 38.1% of the patients, respectively. Although most (96.3%) underwent a statin monotherapy or a statin-based combination therapy, just 47.4% of patients attained the LDL-C target. However, the physicians' perceptions on target achievement rate (70.6%) were different from the actual results (47.4%). Many patients (65.3%) remained on the starting doses of statins, despite evidence of poor achievement of lipid goals.
Only less than half of patients with diabetes attained the LDL-C goal. The surveys showed that poor physician performance might be due to the lack of recognition on ADA/ACC consensus causing a low LDL-C target attainment rate. Therefore, changes in doctor perception are needed to attain target LDL-C level and reduce cardiovascular risk in Korean patients with diabetes.
Diabetes mellitus, type 2; Hypercholesterolemia; Surveys
As in other countries, type 2 diabetes is major health concern in Korea. A dramatic increase in the prevalence of type 2 diabetes and its chronic complications has led to an increase in health costs and economic burdens. Early detection of high risk individuals, hidden diabetic patients, and improvement in the quality of care for the disease are the first steps to mitigate the increase in prevalence. The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the '3rd Clinical Practice Guidelines' at the end of 2010. In the guidelines, the committee recommended active screening of high risk individuals for early detection and added the hemoglobin A1c level to the diagnostic criteria for type 2 diabetes based on clinical studies performed in Korea. Furthermore, the committee members emphasized that integrating patient education and self-management is an essential part of care. The drug treatment algorithm based on the degree of hyperglycemia and patient characteristics were also updated.
Clinical practice guideline; Diabetes mellitus, type 2; Diagnosis; Treatment
We aimed to determine the characteristics affecting insulin resistance in non-obese middle-aged adults in a rural community.
A total of 1,270 non-diabetic adults aged between 40 and 64 years old with body mass index (BMI) less than 25 kg/m2 were analyzed. Subjects with insulin resistance were defined as those who had the highest quartile value of the homeostasis model assessment of insulin resistance (HOMA-IR) in a non-diabetic population.
A total of 217 subjects (20.6%) had insulin resistance. Prevalence of metabolic syndrome was significantly higher in insulin-resistant subjects in both men (29.3% vs. 10.3%) and women (34.1% vs. 15.6%). Among metabolic syndrome components, elevated waist circumference and elevated triglyceride were higher in insulin-resistant subjects in both genders. After being controlled for socioeconomic status and lifestyle related covariates, the association between insulin resistance and BMI was statistically significant in the category of 23.0-24.9 kg/m2 in men (adjusted OR, 4.63; 95% confidence interval [95% CI], 1.77-12.15) using the category of 18.5-20.9 kg/m2 as a reference. In addition, the association between insulin resistance and abdominal obesity was statistically significant only for men (adjusted OR, 2.57; 95% CI, 1.29-5.11).
Insulin resistance appears to be highly associated with high BMI and abdominal obesity, even in non-obese, non-diabetic middle-aged men.
Abdominal obesity; BMI; Insulin resistance
In the 2-acetylaminofluorene (2-AAF)/70% partial hepatectomy (PHx) model, the mechanism underlying the differentiation of activated hepatic oval cells (HOCs) into hepatocytes and bile ductile cells is unclear. We investigated the role of cyclooxygenase-2 (COX-2) in HOCs and the relationship between COX-2 and extracellular matrix proteins in cellular proliferation.
Reverse transcription-polymerase chain reaction, immunohistochemical staining, and Western blotting were used to assess COX-2 expression. The co-localization of COX-2 with Thy1, c-Met, epithelial cell adhesion molecule, and α-smooth muscle actin was also examined. Additionally, we investigated whether connective tissue growth factor (CTGF), fibronectin (FN), extracellular signal-regulated kinase 1/2 (P-ERK1/2), and AKT were expressed in HOCs.
The expression of COX-2, prostaglandin E2 receptors, and c-Met was upregulated in HOCs. However, HOCs treated with the COX-2 inhibitor NS398 showed decreased COX-2, CTGF, FN, and AKT expression, whereas P-ERK1/2 was unaffected. Additionally, NS398 inhibited HOC proliferation, but not the proliferation of HOCs cultured on FN-coated dishes. Furthermore, the proliferative response of HOCs treated with NS398 was reversed by hepatic growth factor treatment.
These results suggest that HOC proliferation is mediated through COX-2, extracellular FN expression, and AKT activation. Thus, COX-2 plays an important role in HOC proliferation following acute injury.
Hepatic oval cells; Cyclooxygenase-2; Liver generation
This study was aimed to investigate the prevalence of diabetic retinopathy and its associated factors in rural Korean patients with type 2 diabetes. A population-based, cross-sectional diabetic retinopathy survey was conducted from 2005 to 2006 in 1,298 eligible participants aged over 40 yr with type 2 diabetes identified in a rural area of Chungju, Korea. Diabetic retinopathy was diagnosed by a practicing ophthalmologist using funduscopy. The overall prevalence of diabetic retinopathy in the population was 18% and proliferative or severe non-proliferative form was found in 5.0% of the study subjects. The prevalence of retinopathy was 6.2% among those with newly diagnosed type 2 diabetes and 2.4% of them had a proliferative or severe non-proliferative diabetic retinopathy. The odds ratio of diabetic retinopathy increased with the duration of diabetes mellitus (5-10 yr: 5.2- fold; > 10 yr: 10-fold), postprandial glucose levels (> 180 mg/dL: 2.5-fold), and HbA1c levels (every 1% elevation: 1.34-fold). The overall prevalence of diabetic retinopathy in rural Korean patients was similar to or less than that of other Asian group studies. However, the number of patients with proliferative or severe non-proliferative diabetic retinopathy was still high and identified more frequently at the time of diagnosis. This emphasizes that regular screening for diabetic retinopathy and more aggressive management of glycemia can reduce the number of people who develop diabetic retinopathy.
Diabetic Retinopathy; Prevalence; Risk Factors
Hypertension is common in patients with type 2 diabetes, affecting up to 60% of patients. The Korean Diabetes Association performed a nationwide survey about prevalence, awareness and control of hypertension among diabetic Koreans.
The current survey included 3,859 diabetic patients recruited from 43 hospitals in Korea. Age, gender, height, weight and blood pressure (BP) were measured by standard methods. Data on fasting plasma glucose, glycosylated hemoglobin (HbA1c), awareness of hypertension, and compliance of antihypertensive medication were collected via interview and reviewed using patient medical records.
A total of 57.5% of all patients were >60 years old. Their mean HbA1c was 7.6±1.5%. Among antihypertensive medication users, 39.9% had <130 mm Hg and <80 mm Hg, whereas 60.1% had ≥130 mm Hg or ≥80 mm Hg. The answer "BP is under good control" was given by 75.1% of the antihypertensive medication users. Out of these patients, 26.4% had <130 mm Hg and <80 mm Hg, whereas 73.6% had ≥130 mm Hg or ≥80 mm Hg. A total of 75.5% of antihypertensive medication users answered that they had taken their antihypertensive medication every day for the past 2 weeks. "Forgetfulness" was most frequently the reason of non-compliance for patients that did not take their antihypertensive medication regularly.
Approximately one third of the patients with diabetes were found to reach target blood pressure control in the 43 hospitals across Korea. Stricter control is needed to reduce severe complications of diabetes in Korea.
Blood pressure; Diabetes mellitus; Hypertension
Attempts to introduce telemedicine in South Korea have failed mostly, leaving critical questions for service developers and providers about whether patients would be willing to pay for the service and how the service should be designed to encourage patient buy-in. In this study, we explore patients' valuations and preferences for each attribute of telemedicine service for diabetes management and evaluate patient willingness to pay for specific service attributes.
Materials and Methods
We conducted a conjoint survey to collect data on patients' stated preferences among telemedicine service alternatives. The alternatives for diabetes-related service differed in 10 attributes, including those related to price, type of service provider, and service scope. To estimate the relative importance of attributes, patients' willingness to pay for each attribute, and their probable choice of specific alternatives, we used a rank-ordered logit model. A total of 118 respondents participated in the survey.
All 10 attributes significantly affected patients' valuations and preferences, and demographic and disease characteristics, such as existence of complications and comorbidities, significantly affected patients' valuations of the attributes. Price was the most important attribute, followed by comprehensive scope of service, the availability of mobile phone-based delivery, and large general-hospital provided services.
The study findings have significant implications for adoption policy and strategy of telemedicine in diabetes management care. Further, the methodology presented in this study can be used to draw knowledge needed to formulate effective policy for adoption of the necessary technology and for the design of services that attract potential beneficiaries.
telemedicine; ubiquitous healthcare; patient preferences; diabetes management; conjoint analysis
Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated.
We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels.
HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group.
The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.
Diabetes mellitus, type 2; Glimepiride; Metformin; Rosiglitazone
Previously, we reported that neonatal porcine pancreatic cells transfected with hepatocyte growth factor (HGF) gene in an Epstein-Barr virus (EBV)-based plasmid (pEBVHGF) showed improved proliferation and differentiation compared to those of the control. In this study, we examined if pancreatic cells transfected repeatedly with pEBVHGF can be successfully grafted to control blood glucose in a diabetes mouse model.
Neonatal porcine pancreatic cells were cultured as a monolayer and were transfected with pEBVHGF every other day for a total of three transfections. The transfected pancreatic cells were re-aggregated and transplanted into kidney capsules of diabetic nude mice or normal nude mice. Blood glucose level and body weight were measured every other day after transplantation. The engraftment of the transplanted cells and differentiation into beta cells were assessed using immunohistochemistry.
Re-aggregation of the pancreatic cells before transplantation improved engraftment of the cells and facilitated neovascularization of the graft. Right before transplantation, pancreatic cells that were transfected with pEBVHGF and then re-aggregated showed ductal cell marker expression. However, ductal cells disappeared and the cells underwent fibrosis in a diabetes mouse model two to five weeks after transplantation; these mice also did not show controlled blood glucose levels. Furthermore, pancreatic cells transplanted into nude mice with normal blood glucose showed poor graft survival regardless of the type of transfected plasmid (pCEP4, pHGF, or pEBVHGF).
For clinical application of transfected neonatal porcine pancreatic cells, further studies are required to develop methods of overcoming the damage for the cells caused by repeated transfection and to re-aggregate them into islet-like structures.
Diabetes mellitus; Hepatocyte growth factor; Porcine neonatal pancreatic cells; Transfection
The present study was designed to develop criteria for screening patients with type 2 diabetes mellitus (T2DM) for asymptomatic coronary artery disease (CAD).
A total of 213 patients with T2DM without typical angina or chest pain were studied between 2002 and 2007. We also evaluated 53 patients with T2DM who had reported chest discomfort using an exercise treadmill test (ETT).
Thirty-one of the 213 asymptomatic patients had positive ETT results. We performed coronary angiography on 23 of the 31 patients with a positive ETT and found that 11 of them had significant coronary stenosis. The main differences between the patients with significant stenosis and those with a negative ETT were age (63.1±9.4 vs. 53.7±10.1 years, P=0.008) and duration of diabetes (16.0±7.5 vs. 5.5±5.7 years, P<0.001). The positive predictive value (PPV) of the ETT was calculated to be 47.8%. The PPV of the ETT increased to 87.5% in elderly patients (≥60 years) with a long duration of diabetes (≥10 years). The latter value is similar to that of patients with T2DM who presented with chest discomfort or exertional dyspnea. The PPV of the ETT in symptomatic patients was 76.9%.
In the interest of cost-effectiveness, screening for asymptomatic CAD could be limited to elderly patients with a duration of diabetes ≥10 years.
Diabetes mellitus; Duration of diabetes; Exercise treadmill test; Silent myocardial ischemia
We aimed at determining the cutoff value of waist circumference with respect to its ability to reflect insulin resistance in a Korean population.
Materials and Methods
A total of 8,817 subjects aged 40 years and over were analyzed. Insulin resistant individuals were defined as those who had the highest quartile value of the homeostasis model assessment of insulin resistance (HOMA-IR) in a non-diabetic population. Receiver operating characteristic (ROC) curve analysis and multiple logistic regression analysis were applied.
The cutoff value of waist circumference reflecting insulin resistance from the ROC analysis was 84.4 cm for men and 80.6 cm for women. Sensitivity and specificity were 70.0% and 54.2% in men and 71.1% and 59.3% in women, respectively. After being controlled for other covariates, the odds ratio for the risk of insulin resistance using < 70 cm of waist circumference as a reference increased significantly in the category of 85.0-89.9 cm for men and 80.0-84.9 cm for women. In addition, statistically significant associations were consistently observed over the category of 85.0-89.9 cm for men and 80.0-84.9 cm for women.
The optimal cutoff value for waist circumference reflecting insulin resistance is considered to be 85 cm for men and 80 cm for women, suggesting that the Asian criterion of abdominal obesity (90 cm for men and 80 cm for women) as a component of metabolic syndrome (MetS) might not be applicable for middle-aged to older men in Korea.
Metabolic syndrome; waist circumference; insulin resistance
OBJECTIVE—We investigated whether cardiovascular autonomic dysfunction was associated with glycemic control status over time in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS—From 1999 to 2000, cardiovascular autonomic nerve function testing (AFT) was performed on patients with type 2 diabetes (n = 1,021) and was followed-up in 2006 and February 2008. Tests for cardiovascular autonomic functions measured heart rate variability parameters (expiration-to-inspiration [E/I] ratio, responses to the Valsalva maneuver, and standing). AFT scores were determined from the results of the each test as follows: 0 for normal and 1 for abnormal. We began with those who had a score of 0 and assessed the changes in total score along with biannual A1C levels.
RESULTS—At follow-up, the development of cardiovascular autonomic dysfunction was 34.5% (E/I ratio 21.9%, Valsalva maneuver 77.8%, and posture 58.9%; n = 783). The development of cardiovascular autonomic dysfunction was higher in older patients (P < 0.001); in those with longer duration of diabetes (P < 0.001); of hypertension (P = 0.005), and of diabetic retinopathy (P < 0.001); and in those who had higher levels of microalbuminuria (P = 0.002). Logistic regression analysis revealed that the development of cardiovascular autonomic dysfunction was strongly associated with the mean A1C level during the follow-up period (mean A1C >9.0% vs. ≤7.0%, odds ratio 2.984, 95% CI 1.177–7.561; P = 0.021).
CONCLUSIONS—The development of cardiovascular autonomic dysfunction was independently associated with microvascular complications and glycemic control status during this 7.5-year follow-up in patients with type 2 diabetes.
Thiazolidinediones reduce urinary albumin excretion and may prevent the development of renal injury. We evaluated the long-term effects of rosiglitazone on the progression of renal dysfunction in patients with type 2 diabetes mellitus.
We enrolled patients with type 2 diabetes mellitus who initially had normal or mildly impaired renal function, defined as an estimated glomerular filtration rate (eGFR) of 60-120 mL/min per 1.73 m2, and normoalbuminuria. Patients were divided into two groups according to their use of rosiglitazone during 3 years of follow-up: those treated with rosiglitazone (rosiglitazone group, n=52) and those treated without rosiglitazone (control group, n=85). Progression of renal dysfunction was defined as a decrease in eGFR of ≥9 mL/min per 1.73 m2 after 3 years.
A greater difference was observed in the decrease in eGFR between the rosiglitazone and control groups after 3 years (3.8±9.9 vs. 12.6±10.5 mL/min per 1.73 m2, p<0.001). Seventeen of 52 (32.7%) patients in the rosiglitazone group and 53 of 85 (62.3%) patients in the control group showed progression of renal dysfunction (p=0.001). The progressors had a longer duration of diabetes (6.7±5.9 vs. 3.9±4.1 years, p=0.002), higher HbA1c levels (7.4±1.8 vs. 6.8±1.3%, p=0.023), and less frequent use of rosiglitazone (24.2 vs. 52.2%, p<0.001) compared to non-progressors. Multiple logistic regression analysis revealed that the use of rosiglitazone was a significant and independent predictor of the progression of renal dysfunction.
This study suggests that rosiglitazone theatment slows the progressive deterioration of renal function in patients with type 2 diabetes.
Diabetic nephropathies; Rosiglitazone; Renal insufficiency
Astragalus Membranaceus (AM) is a useful Korean herb that has been clinically prescribed for stress-related illness. The objective of the present study was to examine the anti-stress effects of AM on repeated stress-induced alterations of anxiety, learning and memory in rats. Restraint stress was administered for 14 days (2h/day) and AM (400mg/kg) given by oral administration, in the AM group, for the same period. Starting on the eighth day, the rats were tested for spatial memory on the Morris water maze test (MW) and for anxiety on the elevated plus maze (EPM). Changes of expression on immunohistochemistry were studied for cholineacetyl transferase (ChAT) and tyrosine hydroxylase (TH) in the brain. The results showed that the rats treated with AM had significantly reduced stress-induced deficits on learning and memory on the spatial memory tasks. In addition, the ChAT immunoreactivities were increased. In the EPM, treatment with AM increased the time spent in the open arms (p<0.001) compared to the control group. In addition, AM treatment also normalized increases of TH expression in the LC (p<0.001). In conclusion, administration of AM improved spatial learning and memory and reduced stress-induced anxiety. Thus, the present results suggest that AM is able to recover behavioral and neurochemical impairments induced by stress.
Astragalus Membranaceus; Morris water maze; Elevated plus maze
The bone marrow contains stem cells that have the potential to differentiate into a variety of organ-specific mature cells, including the liver and the pancreas. Recently, the origin of hepatic progenitors and hepatocytes was identified to be the bone marrow. However, evidence that describes which cells, among all bone marrow cells, differentiate into hepatocytes, has not yet been presented. Based on recent reports, hematopoietic and hepatic stem cells share characteristic markers such as CD34, c-kit, and Thy1. In particular, both hematopoietic and hepatic stem cells express the Thy1 antigen. We investigated whether rat Thy1-positive bone marrow cells express liver-specific genes in vitro, and whether transplanted Thy1 BM cells differentiate into mature hepatocytes in vivo. For collection of Thy1 cells from bone marrow, FITC-conjugated anti-Thy1.1 monoclonal antibody was used with a Fluorescence-Activated Cell Sorter system. A coculture system of 2 separate layers was used for culture of Thy bone marrow cells. Cultured Thy1 cells expressed albumin protein, which was analyzed by immunofluorescent staining. Thy1 bone marrow cells obtained from wild-type dipeptidyl peptidase IV (DPPIV(+)) male rat were directly transplanted into the injured liver of DPPIV mutant (DPPIV(−)) Fisher 344 female rats and differentiated into mature hepatocytes in recipient liver on 60 days. Donor-derived hepatocytes were confirmed by DPPIV staining and Y-chromsome in situ hybridization. Our results suggest that Thy1-positive bone marrow cells have the potential to generate liver-specific genes in vitro and can differentiate into mature hepatocytes in adult liver in vivo. Thy1-positive bone marrow stem cells may represent preexisting hepatocyte-specific stem cells.
Thy1 antigens; Bone marrow; Stem cells; Hepatocyte