Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

Background@#Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes.Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy. @*Methods@#We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control- or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes. @*Results@#OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity. @*Conclusion@#We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production.Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation

Adipose tissue inflammation is considered a major contributing factor in the development of obesity-associated insulin resistance and cardiovascular diseases. However, the cause of adipose tissue inflammation is presently unclear. The role of mitochondria in white adipocytes has long been neglected because of their low abundance. However, recent evidence suggests that mitochondria are essential for maintaining metabolic homeostasis in white adipocytes. In a series of recent studies, we found that mitochondrial function in white adipocytes is essential to the synthesis of adiponectin, which is the most abundant adipokine synthesized from adipocytes, with many favorable effects on metabolism, including improvement of insulin sensitivity and reduction of atherosclerotic processes and systemic inflammation. From these results, we propose a new hypothesis that mitochondrial dysfunction in adipocytes is a primary cause of adipose tissue inflammation and compared this hypothesis with a prevailing concept that “adipose tissue hypoxia” may underlie adipose tissue dysfunction in obesity. Recent studies have emphasized the role of the mitochondrial quality control mechanism in maintaining mitochondrial function. Future studies are warranted to test whether an inadequate mitochondrial quality control mechanism is responsible for mitochondrial dysfunction in adipocytes and adipose tissue inflammation.

Past and Current Status of Adult Type 2 Diabetes Mellitus Management in Korea: A National Health Insurance Service Database Analysis

Korea's National Healthcare Program, the National Health Insurance Service (NHIS), a government-affiliated agency under the Korean Ministry of Health and Welfare, covers the entire Korean population. The NHIS supervises all medical services in Korea and establishes a systematic National Health Information database (DB). A health information DB system including all of the claims, medications, death information, and health check-ups, both in the general population and in patients with various diseases, is not common worldwide. On June 9, 2014, the NHIS signed a memorandum of understanding with the Korean Diabetes Association (KDA) to provide limited open access to its DB. By October 31, 2017, seven papers had been published through this collaborative research project. These studies were conducted to investigate the past and current status of type 2 diabetes mellitus and its complications and management in Korea. This review is a brief summary of the collaborative projects between the KDA and the NHIS over the last 3 years. According to the analysis, the national health check-up DB or claim DB were used, and the age category or study period were differentially applied.

Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice

BACKGROUND: Non-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO) and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH), but underlying mechanisms of this prevention are largely unknown. METHODS: Seven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD) with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day), for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver. RESULTS: Statin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα) were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels. CONCLUSION: Statins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.

Data Analytic Process of a Nationwide Population-Based Study Using National Health Information Database Established by National Health Insurance Service

In 2014, the National Health Insurance Service (NHIS) signed a memorandum of understanding with the Korean Diabetes Association to provide limited open access to its databases for investigating the past and current status of diabetes and its management. NHIS databases include the entire Korean population; therefore, it can be used as a population-based nationwide study for various diseases, including diabetes and its complications. This report presents how we established the analytic system of nation-wide population-based studies using the NHIS database as follows: the selection of database study population and its distribution and operational definition of diabetes and patients of currently ongoing collaboration projects.

Serum Total Bilirubin Levels Provide Additive Risk Information over the Framingham Risk Score for Identifying Asymptomatic Diabetic Patients at Higher Risk for Coronary Artery Stenosis

BACKGROUND: The diagnosis of coronary artery disease (CAD) is often delayed in patients with type 2 diabetes. Serum total bilirubin levels are inversely associated with CAD. However, no studies have examined whether this can be used as a biochemical marker for identifying asymptomatic diabetic patients at higher risk for having obstructive CAD. METHODS: We performed a cross-sectional study of 460 consecutive asymptomatic patients with type 2 diabetes. All patients underwent coronary computed tomographic angiography, and their serum total bilirubin levels were measured. Obstructive CAD was defined as > or =50% diameter stenosis in at least one coronary artery. RESULTS: Serum total bilirubin tertiles showed an inverse association with the prevalence of obstructive CAD. In multivariate logistic regression analysis, the odds ratio for the highest versus the lowest tertile of total bilirubin was 0.227 (95% confidence interval [CI], 0.130 to 0.398), and an increment of 1 micromol/L in serum total bilirubin level was associated with a 14.6% decrease in obstructive CAD after adjustment for confounding variables. Receiver operating characteristic curve analysis showed that the area under the curve for the Framingham Risk Score (FRS) plus serum total bilirubin level was 0.712 (95% CI, 0.668 to 0.753), which is significantly greater than that of the FRS alone (P=0.0028). CONCLUSION: Serum total bilirubin level is inversely associated with obstructive CAD and provides additive risk information over the FRS. Serum total bilirubin may be helpful for identifying asymptomatic patients with type 2 diabetes who are at higher risk for obstructive CAD.

Clinical Features and Causes of Endogenous Hyperinsulinemic Hypoglycemia in Korea

BACKGROUND: Endogenous hyperinsulinemic hypoglycemia (EHH) is characterized by an inappropriately high plasma insulin level, despite a low plasma glucose level. Most of the EHH cases are caused by insulinoma, whereas nesidioblastosis and insulin autoimmune syndrome (IAS) are relatively rare. METHODS: To evaluate the relative frequencies of various causes of EHH in Korea, we retrospectively analyzed 84 patients who were diagnosed with EHH from 1998 to 2012 in a university hospital. RESULTS: Among the 84 EHH patients, 74 patients (88%), five (6%), and five (6%) were diagnosed with insulinoma, nesidioblastosis or IAS, respectively. The most common clinical manifestation of EHH was neuroglycopenic symptoms. Symptom duration before diagnosis was 14.5 months (range, 1 to 120 months) for insulinoma, 1.0 months (range, 6 days to 7 months) for nesidioblastosis, and 2.0 months (range, 1 to 12 months) for IAS. One patient, who was diagnosed with nesidioblastosis in 2006, underwent distal pancreatectomy but was later determined to be positive for insulin autoantibodies. Except for one patient who was diagnosed in 2007, the remaining three patients with nesidioblastosis demonstrated severe hyperinsulinemia (157 to 2,719 microIU/mL), which suggests that these patients might have had IAS, rather than nesidioblastosis. CONCLUSION: The results of this study suggest that the prevalence of IAS may be higher in Korea than previously thought. Therefore, measurement of insulin autoantibody levels is warranted for EHH patients, especially in patients with very high plasma insulin levels.

Background and Data Configuration Process of a Nationwide Population-Based Study Using the Korean National Health Insurance System

BACKGROUND: The National Health Insurance Service (NHIS) recently signed an agreement to provide limited open access to the databases within the Korean Diabetes Association for the benefit of Korean subjects with diabetes. Here, we present the history, structure, contents, and way to use data procurement in the Korean National Health Insurance (NHI) system for the benefit of Korean researchers. METHODS: The NHIS in Korea is a single-payer program and is mandatory for all residents in Korea. The three main healthcare programs of the NHI, Medical Aid, and long-term care insurance (LTCI) provide 100% coverage for the Korean population. The NHIS in Korea has adopted a fee-for-service system to pay health providers. Researchers can obtain health information from the four databases of the insured that contain data on health insurance claims, health check-ups and LTCI. RESULTS: Metabolic disease as chronic disease is increasing with aging society. NHIS data is based on mandatory, serial population data, so, this might show the time course of disease and predict some disease progress, and also be used in primary and secondary prevention of disease after data mining. CONCLUSION: The NHIS database represents the entire Korean population and can be used as a population-based database. The integrated information technology of the NHIS database makes it a world-leading population-based epidemiology and disease research platform.

Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3L1 adipocytes

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.

Response: The Prevalence of Peripheral Arterial Disease in Korean Patients with Type 2 Diabetes Mellitus Attending a University Hospital (Diabetes Metab J 2011;35:543-50)

No abstract available.

A Case of MELAS Syndrome Diagnosed in a Woman in Her 50s / 대한내과학회지

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, abbreviated to MELAS, syndrome is a common mitochondrial disease that can present with a wide range of clinical symptoms, including seizures, stroke-like episodes, neuropathy, myopathy, sensorineural hearing loss, and encephalopathy. Although more than 90% of patients present with stroke-like episodes before the age of 40 years, some reports have described patients presenting later in life. Here, we report MELAS syndrome diagnosed in a 52-year-old Korean woman admitted because of altered mentality. She had a history of diabetes, sensorineural hearing loss, and cardiomyopathy. The patient's mentality fluctuated and her lactic acid level was elevated in the hospital. Although she was in her 50s, her medical history, encephalopathy, and lactic acidosis made us strongly suspect MELAS syndrome. The diagnosis was confirmed when a test showed the A3243G mitochondrial DNA mutation.

The Prevalence of Peripheral Arterial Disease in Korean Patients with Type 2 Diabetes Mellitus Attending a University Hospital

BACKGROUND: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. Diabetes is known to increase the risk of PAD two- to four-fold. The prevalence of PAD in Korean diabetic patients has not been established. In this study, we investigated the prevalence of PAD in Korean patients with type 2 diabetes attending a large university hospital and analyzed the factors associated with PAD. METHODS: A total of 2,002 patients with type 2 diabetes who underwent ankle-brachial index (ABI) measurement in an outpatient clinic were enrolled. PAD was defined as an ABI < or =0.9. Clinical characteristics of 64 patients with PAD were compared with those of 192 age- and sex-matched control patients without PAD. RESULTS: Of the 2,002 type 2 diabetic patients, 64 (3.2%) were diagnosed as having PAD. PAD was associated with higher prevalences of retinopathy, nephropathy, neuropathy, cerebrovascular and coronary artery disease. Patients with PAD had higher systolic blood pressure and serum triglyceride level and reported higher pack-years of smoking. Multivariate analysis showed that the presence of micro- and macrovascular complications and high systolic blood pressure are factors independently associated with PAD. CONCLUSION: The prevalence of PAD in diabetic patients was 3.2%, suggesting that the prevalence in Korean diabetic patients is lower than that of patients in Western countries.

The Primary Biliary Cirrhosis Presenting with Raynaud's Disease and Digital Necrosis

Necrosis of the upper extremity occurs rarely in type 2 diabetic patients compared to lower extremity necrosis. We report a 69-year-old woman with type 2 diabetes mellitus who presented with necrosis of the left 5th finger tip. The patient had primary biliary cirrhosis accompanied by necrosis of the fingertip due to severe Raynaud's phenomenon. Primary biliary cirrhosis (PBC) is a typical autoimmune disease, which can in rare cases be accompanied by autoimmune symptoms including sicca symptom and Raynaud's phenomenon. Furthermore, autoimmune diseases, such as systemic sclerosis, rheumatoid arthritis and undifferentiated connective tissue disease (UCTD) can be associated. Although every type of vascular etiology should be considered as a cause of digital necrosis, Raynaud's phenomenon is usually not considered in diabetes. We report this case of finger tip necrosis due to severe Raynaud's phenomenon accompanied by PBC and UCTD in a diabetic patient.

A Case of Familial Multiple Endocrine Neoplasia Type 1 with a Novel Mutation in the MEN1 Gene

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of multiple tumors in the parathyroid gland, pancreatic islet, and pituitary gland. This condition is caused by mutations of MEN1, a tumor suppressor gene. Thus far, 565 different germline and somatic mutations of the MEN1 gene have been reported. Herein, we describe the case of a 23-year-old woman who suffered from a repetitive loss of consciousness. After workup, the patient was diagnosed with MEN1 with insulinoma, hyperparathyrodism due to parathyroid adenoma, and non-functioning pituitary microadenoma. She underwent a partial parathyroidectomy and distal pancreatectomy. Familial screening of MEN1 revealed that her brother had prolactinoma, hyperparathyroidism, pancreatic gastrinoma and non-functioning adrenal adenoma. Her father had hyperparathyroidism, pancreatic tumor, and adrenal adenoma. Upon genetic analysis of the MEN1 gene, a novel mutation in the MEN1 gene (exon 1, c.251del; p.Ser84LuefsX35) was detected in the patient, as well as her father and brother.

Lack of Association between Serum Cystatin C Levels and Coronary Artery Disease in Diabetic Patients / 당뇨병

BACKGROUND: Serum cystatin C level is a more sensitive marker of renal dysfunction than serum creatinine level. Serum cystatin C level was recently reported to predict the development of cardiovascular disease. This study was performed to evaluate whether the cystatin C level is associated with coronary artery disease (CAD), independent of diabetic nephropathy. METHODS: We conducted a case-control study to assess the relationship between serum cystatin C level and coronary artery disease in diabetic patients. Among 460 diabetic patients, 38 diabetic patients had CAD. The control group consisted of 38 diabetic patients who were matched to cases by age, sex, and presence/absence of diabetic nephropathy. Serum cystatin C level was measured in stored samples. RESULTS: Serum cystatin C level was significantly higher in patients with diabetic nephropathy, both in CAD and non-CAD patients. However, serum cystatin C level did not differ between CAD and non-CAD patients, regardless of diabetic nephropathy. CONCLUSION: Serum cystatin C level is a marker of renal dysfunction, but not coronary artery disease, in diabetic patients.

Adenine Nucleotide Translocator as a Regulator of Mitochondrial Function: Implication in the Pathogenesis of Metabolic Syndrome / 당뇨병

Mitochondria play key roles in energy production and intracellular reactive oxygen species (ROS) generation. Lines of evidence have shown that mitochondrial dysfunction contributes to the development of metabolic syndrome. The causes of mitochondrial dysfunction are complex, but overnutrition and sedentary living are among the best known causes of mitochondrial dysfunction. ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT) to provide a continuous supply of ADP to mitochondria. We recently found that ANT function is essential for peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha)'s action on endothelial cells. PGC-1alpha is a transcriptional coactivator of nuclear receptors, playing an important role in fatty acid oxidation and mitochondrial biogenesis. Recent studies have shown that PGC-1alpha decreases intracellular ROS generation by increasing the expression of antioxidant genes. In our study, PGC-1alpha reduced cell apoptosis and ROS generation in endothelial cells by increasing ATP/ADP translocase activity of ANT and ANT1 expression. Here we review the role of ANT in maintaining proper mitochondrial function, and possible role of ANT dysfunction in the pathogenesis of metabolic syndrome.

Homocysteine as a Risk Factor for Development of Microalbuminuria in Type 2 Diabetes / 당뇨병

BACKGROUND: Kidney function is critical in homocysteine clearance, and plasma homocysteine level is frequently increased in patients with renal failure. On the other hand, recent studies in animals have shown that hyperhomocysteinemia induces renal injury. In this study, we determined whether hyperhomocysteinemia can be a risk factor for the development of microalbuminuria in patients with type 2 diabetes. METHODS: A nested case-control study. Of 887 patients with type 2 diabetes who did not have microalbuminuria at baseline, 76 developed microalbuminuria during follow-up (mean, 36.0 +/- 11.7 months; range, 18 to 76 months). The control group consisted of 152 age- and sex-matched subjects who did not develop microalbuminuria. Baseline plasma homocysteine concentrations were measured in stored samples. RESULTS: Baseline plasma homocysteine concentrations and mean HbA1C levels during follow-up were significantly higher in patients who developed microalbuminuria than in those who remained normoalbuminuric. Multivariate logistic regression analysis showed that baseline plasma homocysteine level and mean HbA1C were independent predictors of microalbuminuria in type 2 diabetes. CONCLUSION: Hyperhomocysteinemia was associated with increased risk of microalbuminuria in patients with type 2 diabetes supporting the concept that hyperhomocysteinemia has an etiologic role in the pathogenesis of diabetic nephropathy.

Response: Lack of Association between Serum Cystatin C Levels and Coronary Artery Disease in Diabetic Patients (Korean Diabetes J 2010;34:95-100) / 당뇨병

No abstract available.

Variable Association between Components of the Metabolic Syndrome and Electrocardiographic Abnormalities in Korean Adults

BACKGROUND/AIMS: Resting electrocardiogram (ECG) abnormalities have been strongly associated with cardiovascular disease mortality. Little is known, however, about the association between individual components of metabolic syndrome and ECG abnormalities, especially in Asian populations. METHODS: We examined clinical and laboratory data from 31,399 subjects (age 20 to 89 years) who underwent medical check-ups. ECG abnormalities were divided into minor and major abnormalities based on Novacode criteria. Ischemic ECG findings were separately identified and analyzed. RESULTS: The overall prevalence rates of ECG abnormalities were significantly higher in subjects with than in those without metabolic syndrome (p < 0.01). Ischemic ECG was strongly associated with metabolic syndrome in all age groups of both sexes, except for younger women. In multiple logistic regression analysis, metabolic syndrome was independently associated with ischemic ECG (odds ratio, 2.30 [2.04 to 2.62]; p < 0.01), after adjusting for sex, age, smoking, and family history of cardiovascular disease. Of the metabolic syndrome components, hyperglycemia in younger subjects and hypertension in elderly subjects were major factors for ischemic ECG changes, whereas hypertriglyceridemia was not an independent risk factor in any age group. The association between ischemic ECG findings and central obesity was weaker in women than in men. CONCLUSIONS: Metabolic syndrome was strongly associated with ECG abnormalities, especially ischemic ECG findings, in Koreans. The association between each component of metabolic syndrome and ECG abnormalities varied according to age and sex.

Orphan nuclear receptor small heterodimer partner inhibits angiotensin II-stimulated PAI-1 expression in vascular smooth muscle cells

Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-beta signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad-SHP) in VSMCs inhibited angiotensin II- and TGF-beta-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-beta- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP-/- mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-beta/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis.