Jaechan Leem

Interaction between Mitochondria and the Endoplasmic Reticulum: Implications for the Pathogenesis of Type 2 Diabetes Mellitus

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated with β-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca2+ homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM.

Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: A 4 year retrospective longitudinal study

OBJECTIVE Bilirubin, a natural product of heme catabolism by heme oxygenase, one of key antioxidant enzymes, has been recognized as a substance with potent antioxidant and cytoprotective properties. Several studies have shown a significant negative relationship between serum bilirubin levels and the risk of metabolic disorders, including type 2 diabetes. However, longitudinal studies investigating the association of elevated serum bilirubin levels and type 2 diabetes are lacking. In the present study, we aimed to investigate the longitudinal effects of baseline serum bilirubin concentrations on the development of type 2 diabetes in healthy Korean men. MATERIALS AND METHODS This 4 year retrospective longitudinal observational study was conducted at the Asan Medical Center, Seoul, Republic of Korea. The study population consisted of 5960 men without type 2 diabetes who underwent routine health examinations in 2007 (baseline) and 2011 (follow-up). Baseline serum bilirubin concentrations were determined by the vanadate oxidation method. RESULTS During a 4 year period, 409 incident cases of diabetes (6.9 %) were identified. Incident type 2 diabetes decreased across the baseline bilirubin quartile categories (P for trend <0.001). In multivariable-adjusted model, the relative risk (RR) for the development of type 2 diabetes was significantly lower in the highest (i.e., 1.30-2.00 mg/dl) than in the lowest bilirubin quartile category (i.e., ≤ 0.90 mg/dl), even after adjustment for confounding variables (RR=0.69, 95% confidence interval 0.48-0.99, P for trend = 0.041). CONCLUSIONS The results indicate that serum total bilirubin level may provide additional information for predicting future development of type 2 diabetes in healthy subjects.

The Risk of Incident Type 2 Diabetes in a Korean Metabolically Healthy Obese Population: The Role of Systemic Inflammation

OBJECTIVE This study sought to investigate whether the metabolically healthy obese (MHO) phenotype is associated with an increased risk of incident type 2 diabetes in a Korean population and, if so, whether systemic inflammation affects this risk in MHO individuals. DESIGN AND METHODS The study population comprised 36 135 Koreans without type 2 diabetes. Participants were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). High-sensitive C-reactive protein (hsCRP) was used as a surrogate marker of systemic inflammation. Subjects were classified into low (ie, hsCRP < 0.5 mg/L) and high (ie, hsCRP ≥ 0.5 mg/L) systemic inflammation groups. RESULTS During a median followup of 36.5 months (range, 4.8-81.7 mo), 635 of the 36 135 individuals (1.8%) developed type 2 diabetes. The MHO group had a significantly higher risk of incident type 2 diabetes (multivariate-adjusted hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16-2.11) than the metabolically healthy nonobese (MHNO) group. However, the risk of the MHO group varied according to the degree of systemic inflammation. Compared with the MHNO/low systemic inflammation group, the risk of type 2 diabetes in the MHO/low systemic inflammation group was not significantly elevated (multivariate-adjusted HR, 1.61; 95% CI, 0.77-3.34). However, the MHO/high systemic inflammation group had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 3.73; 95% CI 2.36-5.88). CONCLUSIONS MHO subjects show a substantially higher risk of incident type 2 diabetes than MHNO subjects. The level of systemic inflammation partially explains this increased risk.

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.

Association of Serum C1q/TNF-Related Protein-9 Concentration With Arterial Stiffness in Subjects With Type 2 Diabetes

CONTEXT Although recent animal studies have suggested that C1q/TNF-related protein-9 (CTRP9) is more likely to be involved in the regulation of vascular function, more specifically atherosclerosis, in rodents, little is known about whether serum CTRP9 level is associated with atherosclerosis in humans. OBJECTIVE The aim of this study was to investigate whether serum CTRP9 concentration is associated with atherosclerosis by measuring brachial ankle pulse wave velocity (baPWV) in subjects with type 2 diabetes. In addition, we examined the clinical and biochemical variables associated with serum CTRP9 concentration. DESIGN AND METHODS We measured circulating CTRP9 and total adiponectin levels in 278 subjects (169 men and 109 women; mean age of 58.3 years) with type 2 diabetes. Measurements of baPWV were performed in all subjects. RESULTS Serum CTRP9 concentration was positively correlated with baPWV. This correlation was significant even after adjusting for total adiponectin levels. In multiple linear regression, serum CTRP9 concentration was independently associated with increased baPWV. Female gender, higher body mass index, and homeostatic model assessment of insulin resistance were significantly associated with elevated serum CTRP9 concentration in subjects with type 2 diabetes. CONCLUSIONS Serum CTRP9 concentration was significantly and positively associated with arterial stiffness in patients with type 2 diabetes, suggesting that CTRP9 might be important in the regulation of arterial stiffness in humans.

Association of metabolically healthy obesity with subclinical coronary atherosclerosis in a Korean population.

The degree of subclinical coronary atherosclerosis detected by coronary multidetector computed tomography (MDCT) in four groups defined by the state of metabolic health and obesity in an asymptomatic Korean population was compared.

Elevated Serum Ferritin Level Is Associated with the Incident Type 2 Diabetes in Healthy Korean Men: A 4 Year Longitudinal Study

Background Elevated ferritin concentration has been implicated in the etiology of type 2 diabetes. Accumulating evidence, mostly from studies conducted on western populations, has demonstrated a strong association between the elevated ferritin concentrations and incident type 2 diabetes. In Asian populations, however, the longitudinal studies investigating the association of elevated serum ferritin levels and type 2 diabetes are lacking. In present study, we aimed to determine whether elevated serum ferritin levels are related to the incident type 2 diabetes in healthy Korean men. Methodology/Principal Findings This 4 year longitudinal observational study was conducted at the Asan Medical Center, Seoul, Republic of Korea. The study population consisted of 2,029 men without type 2 diabetes who underwent routine health examination in 2007 (baseline) and 2011 (follow-up). Baseline serum ferritin concentrations were measured by chemiluminescent two-site sandwich immunoassay. In multiple-adjusted model, the relative risk (RR) for incident type 2 diabetes was significantly higher in highest compared with the lowest ferritin quartile category, even after adjusting for confounding variables including homeostasis model assessment of insulin resistance (RR = 2.17, 95% confidence interval 1.27–3.72, P for trend = 0.013). Conclusions/Significance These results demonstrated that elevated level of serum ferritin at baseline was associated with incident type 2 diabetes in an Asian population.

Time-dependent changes in lipid metabolism in mice with methionine choline deficiency-induced fatty liver disease

Methionine and choline-deficient diet (MCD)-induced fatty liver is one of the best-studied animal models of fatty liver disease. The present study was performed to clarify the relative contributions of individual lipid metabolic pathways to the pathogenesis of MCD-induced fatty liver. Hepatic lipogenesis mediated by the sterol regulatory element-binding protein (SREBP-1c) was increased at 1 week, but not at 6 weeks, of MCD feeding. On the other hand, 14C-palmitate oxidation did not change at 1 week, but significantly decreased at 6 weeks. This decrease was associated with increased expression of fatty acid translocase, a key enzyme involved in fatty acid uptake. Expression of endoplasmic reticulum stress markers was increased in mice given MCD for both 1 and 6 weeks. These findings suggest the presence of time-dependent differences in lipid metabolism in MCD-induced fatty liver disease: SREBP-1c-mediated lipogenesis is important in the early stages of fatty liver disease, whereas increased fatty acid uptake and decreased fatty acid oxidation become more important in the later stages.

Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes.

BackgroundAlthough recent animal studies have suggested that angiopoietin-like protein 2 (ANGPTL2), a novel inflammatory adipokine, is likely to be involved in the pathogenesis of atherosclerosis, in rodents, little is known regarding whether serum ANGPTL2 level is also associated with atherosclerosis in humans, especially in patients with type 2 diabetes. The aim of this study was to investigate whether serum ANGPTL2 concentration is associated with atherosclerosis by measuring carotid intima-media thickness (IMT) in subjects with type 2 diabetes without previous history of cardiovascular diseases. In addition, we examined the clinical and biochemical variables associated with serum ANGPLT2 concentration.MethodsWe measured the circulating ANGPTL2 level in 166 subjects (92 men and 74 women; mean age of 60.0 years) with type 2 diabetes. Measurements of carotid IMT were performed in all subjects.ResultsSerum ANGPTL2 concentration was positively correlated with carotid IMT (r = 0.220, p = 0.004). In multiple linear regression, serum ANGPTL2 concentration was independently associated with increased carotid IMT along with older age, male gender, and higher systolic blood pressure. Higher levels of hemoglobin A1c and high-sensitivity C-reactive protein were significantly associated with elevated serum ANGPTL2 concentration in subjects with type 2 diabetes.ConclusionsSerum ANGPTL2 concentration was significantly and positively associated with carotid atherosclerosis in patients with type 2 diabetes, suggesting that ANGPTL2 may be important in the atherosclerosis in humans.

Serum Ceruloplasmin Level as a Predictor for the Progression of Diabetic Nephropathy in Korean Men with Type 2 Diabetes Mellitus

Background Oxidative stress is known to be associated with progression of diabetic kidney disease. Ceruloplasmin acts as a pro-oxidant under conditions of severe oxidative stress. Thus, we conducted a longitudinal observational study to evaluate whether the serum ceruloplasmin level is a predictive biomarker for progression of diabetic nephropathy. Methods A total of 643 Korean men with type 2 diabetes mellitus were enrolled. Serum ceruloplasmin was measured using a nephelometric method. Progression of diabetic nephropathy was defined as transition in albuminuria class (i.e., normoalbuminuria to microalbuminuria, microalbuminuria to macroalbuminuria, or normoalbuminuria to macroalbuminuria) and/or a greater than 2-fold increase of serum creatinine at follow-up compared with the baseline value. Results During the follow-up period (median, 2.7 years; range, 0.3 to 4.4 years), 49 of 643 patients (7.6%) showed the progression of diabetic nephropathy and three patients (0.5%) developed end-stage renal disease. Baseline ceruloplasmin levels were higher in the progressors than in the nonprogressors (262.6±40.9 mg/L vs. 233.3±37.8 mg/L, P<0.001). Kaplan-Meier analysis showed a significantly higher incidence of nephropathy progression according to ceruloplasmin tertile (log-rank test, P<0.001). The hazard ratio (HR) for progression of diabetic nephropathy was significantly higher in the highest ceruloplasmin tertile category compared with the lowest ceruloplasmin tertile category, even after adjusting for confounding variables (HR, 3.32; 95% confidence interval, 1.28 to 8.61; P=0.003). Conclusion Baseline serum ceruloplasmin is an independent predictive factor for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus.