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Volume 39(5); October 2015
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Reviews
Interaction between Glucose and Lipid Metabolism: More than Diabetic Dyslipidemia
Klaus G. Parhofer
Diabetes Metab J. 2015;39(5):353-362.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.353
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AbstractAbstract PDFPubReader   

Glucose and lipid metabolism are linked to each other in many ways. The most important clinical manifestation of this interaction is diabetic dyslipidemia, characterized by elevated triglycerides, low high density lipoprotein cholesterol (HDL-C), and predominance of small-dense LDL particles. However, in the last decade we have learned that the interaction is much more complex. Hypertriglyceridemia and low HDL-C cannot only be the consequence but also the cause of a disturbed glucose metabolism. Furthermore, it is now well established that statins are associated with a small but significant increase in the risk for new onset diabetes. The underlying mechanisms are not completely understood but modulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA)-reductase may play a central role as genetic data indicate that mutations resulting in lower HMG CoA-reductase activity are also associated with obesity, higher glucose concentrations and diabetes. Very interestingly, this statin induced increased risk for new onset type 2 diabetes is not detectable in subjects with familial hypercholesterolemia. Furthermore, patients with familial hypercholesterolemia seem to have a lower risk for type 2 diabetes, a phenomenon which seems to be dose-dependent (the higher the low density lipoprotein cholesterol, the lower the risk). Whether there is also an interaction between lipoprotein(a) and diabetes is still a matter of debate.

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Obesity and Metabolic Syndrome
Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity
Miki Okada-Iwabu, Masato Iwabu, Kohjiro Ueki, Toshimasa Yamauchi, Takashi Kadowaki
Diabetes Metab J. 2015;39(5):363-372.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.363
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AbstractAbstract PDFPubReader   

Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified "AdipoRon" as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes.

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Clinical Care/Education
Dipeptidyl Peptidase 4 Inhibitors and the Risk of Cardiovascular Disease in Patients with Type 2 Diabetes: A Tale of Three Studies
Jang Won Son, Sungrae Kim
Diabetes Metab J. 2015;39(5):373-383.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.373
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AbstractAbstract PDFPubReader   

Dipeptidyl peptidase 4 (DPP4) inhibitors have been touted as promising antihyperglycemic agents due to their beneficial effects on glycemia without inducing hypoglycemia or body weight gain and their good tolerability. Beyond their glucose-lowering effects, numerous clinical trials and experimental studies have suggested that DPP4 inhibitors may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms or involving other substrates. Since 2008, regulatory agencies have required an assessment of cardiovascular disease (CVD) safety for the approval of all new anti-hyperglycemic agents, including incretin-based therapies. Three large prospective DPP4 inhibitor trials with cardiovascular (CV) outcomes have recently been published. According to the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) and EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) trials, DPP4 inhibitors, including saxagliptin and alogliptin, did not appear to increase the risk of CV events in patients with type 2 diabetes and established CVD or high risk factors. Unexpectedly, saxagliptin significantly increased the risk of hospitalization for heart failure by 27%, a finding that has not been explained and that requires further exploration. More recently, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial demonstrated the CV safety of sitagliptin, including assessments of the primary composite CV endpoint and hospitalization for heart failure in patients with type 2 diabetes and established CVD. The CV outcomes of an ongoing linagliptin trial are expected to provide new evidence about the CV effects of a DPP4-inhibitor in patients with type 2 diabetes.

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Editorial
Complications
Role of Bilirubin in Diabetic Vascular Complications: Can Bilirubin Predict More than Just Liver Disease?
Jun Sung Moon
Diabetes Metab J. 2015;39(5):384-386.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.384
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Original Articles
Epidemiology
Changing Clinical Characteristics according to Insulin Resistance and Insulin Secretion in Newly Diagnosed Type 2 Diabetic Patients in Korea
Jang Won Son, Cheol-Young Park, Sungrae Kim, Han-Kyu Lee, Yil-Seob Lee
Diabetes Metab J. 2015;39(5):387-394.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.387
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AbstractAbstract PDFPubReader   
Background

The role of increased insulin resistance in the pathogenesis of type 2 diabetes has been emphasized in Asian populations. Thus, we evaluated the proportion of insulin resistance and the insulin secretory capacity in patients with early phase type 2 diabetes in Korea.

Methods

We performed a cross-sectional analysis of 1,314 drug-naive patients with newly diagnosed diabetes from primary care clinics nationwide. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an index to measure insulin resistance, which was defined as a HOMA-IR ≥2.5. Insulin secretory defects were classified based on fasting plasma C-peptide levels: severe (<1.1 ng/mL), moderate (1.1 to 1.7 ng/mL) and mild to non-insulin secretory defect (≥1.7 ng/mL).

Results

The mean body mass index (BMI) was 25.2 kg/m2; 77% of patients had BMIs >23.0 kg/m2. Up to 50% of patients had central obesity based on their waist circumference (≥90 cm in men and 85 cm in women), and 70.6% had metabolic syndrome. Overall, 59.5% of subjects had insulin resistance, and 20.2% demonstrated a moderate to severe insulin secretory defect. Among those with insulin resistance, a high proportion of subjects (79.0%) had a mild or no insulin secretory defect. Only 2.6% of the men and 1.9% of the women had both insulin resistance and a moderate to severe insulin secretory defect.

Conclusion

In this study, patients with early phase type 2 diabetes demonstrated increased insulin resistance, but preserved insulin secretion, with a high prevalence of obesity and metabolic syndrome.

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Epidemiology
The Association between Hypertension Comorbidity and Microvascular Complications in Type 2 Diabetes Patients: A Nationwide Cross-Sectional Study in Thailand
Cameron Hurst, Bandit Thinkhamrop, Hoang The Tran
Diabetes Metab J. 2015;39(5):395-404.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.395
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AbstractAbstract PDFPubReader   
Background

Type 2 diabetes mellitus (T2DM) is a global pandemic and its prevalence is rapidly increasing in developing countries, including Thailand. The most common comorbidity of T2DM is hypertension. T2DM with a hypertension comorbidity is likely to exacerbate the development of, or more severe microvascular complications. This study aims to determine the association between the hypertension comorbidity and microvascular complication among T2DM patients in Thailand.

Methods

The present study is a nationwide, multicenter, cross-sectional survey of T2DM outpatients across Thailand. Binary logistic mixed effect regression was used to investigate the effect of hypertension and other risk factors on the presence of microvascular complications. Imputation was used to investigate potential bias introduced by missing values.

Results

Of the 55,797 T2DM patients included in our sample, 55.35% were hypertensive. Prevalence of microvascular complication diagnosis in the last 12 months was higher in T2DM patients with hypertension than those without hypertension (12.12% vs. 9.80%, respectively). Patient with a hypertension comorbidity had 1.32 time the odds of developing microvascular complication (adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.20 to 1.46; P<0.001). Older age, longer diabetes duration had 1.07 and 1.21 times the odds of developing microvascular complication, per 10 years (age) and 5 years (duration), respectively (ORage, 1.07; 95% CI, 1.03 to 1.12; P<0.001; and ORduration, 1.12; 95% CI, 1.07 to 1.16; P<0.001; respectively). Minimal bias was introduced by missing values, and did not influence to the magnitude of effect of hypertension on the presence microvascular complication.

Conclusion

Hypertension comorbidity is highly associated with microvascular complication among T2DM patients. Patients with T2DM and physicians should pay attention to blood pressure control.

Citations

Citations to this article as recorded by  
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Clinical Care/Education
Increased Epicardial Adipose Tissue Thickness in Type 2 Diabetes Mellitus and Obesity
Do Kyeong Song, Young Sun Hong, Hyejin Lee, Jee-Young Oh, Yeon-Ah Sung, Yookyung Kim
Diabetes Metab J. 2015;39(5):405-413.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.405
  • 3,619 View
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AbstractAbstract PDFPubReader   
Background

Epicardial adipose tissue (EAT) is suggested to play an important role in the progression of metabolic syndrome. We aimed to establish a simple method to measure EAT and examine the differences in EAT thickness according to the presence of type 2 diabetes mellitus or obesity.

Methods

A total of 94 patients (42.6% type 2 diabetes mellitus, 53.2% obese, mean age 61±13) who underwent multidetector computed tomography were enrolled. Thickness of EAT was measured on the parasternal short and horizontal long axis view. Epicardial fat area (EFA) was measured at the level of left main coronary artery (LMCA).

Results

All EAT thicknesses were correlated with EFA at the LMCA level (r=0.235 to 0.613, all Ps<0.05), and EAT thickness in the left atrioventricular groove (LAVG) had the highest correlation coefficient (r=0.613). EFA, and EAT thicknesses in the LAVG and the left ventricular apex were higher in the group with type 2 diabetes mellitus than in the group without type 2 diabetes mellitus when adjusted only for body mass index. When adjusted only for type 2 diabetes mellitus, EFA, and EAT thicknesses in the LAVG and the right atrioventricular groove were higher in obese group than in nonobese group.

Conclusion

In conclusion, EAT thickness can be easily measured and represent EFA. EAT thickness, especially in LAVG, was higher in groups with type 2 diabetes mellitus and obesity independently. These findings implicate that EAT thickness may be a useful indicator for type 2 diabetes mellitus and obesity.

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Complications
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
Jaechan Leem, Eun Hee Koh, Jung Eun Jang, Chang-Yun Woo, Jin Sun Oh, Min Jung Lee, Joon-Won Kang, Tae-Hwan Lim, Chang Hee Jung, Woo Je Lee, Joong-Yeol Park, Ki-Up Lee
Diabetes Metab J. 2015;39(5):414-423.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.414
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AbstractAbstract PDFPubReader   
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 ≥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 µmol/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.

Citations

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Pathophysiology
The Preventive Effects of 8 Weeks of Resistance Training on Glucose Tolerance and Muscle Fiber Type Composition in Zucker Rats
Ji-yeon Kim, Mi Jung Choi, Byunghun So, Hee-jae Kim, Je Kyung Seong, Wook Song
Diabetes Metab J. 2015;39(5):424-433.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.424
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AbstractAbstract PDFPubReader   
Background

We investigated the therapeutic effects of resistance training on Zucker rats before and after the onset of diabetes to understand the importance of the timing of exercise intervention. We assessed whether 8 weeks of resistance training ameliorated impaired glucose tolerance and altered muscle fiber type composition in Zucker rats.

Methods

Five-week-old male Zucker rats were divided into Zucker lean control (ZLC-Con), non-exercised Zucker diabetic fatty (ZDF-Con), and exercised Zucker diabetic fatty (ZDF-Ex) groups. The ZDF-Ex rats climbed a ladder three times a week for 8 weeks. Intraperitoneal glucose tolerance tests (IPGTT) were performed on the 1st and 8th weeks of training, and grip strength was measured during the last week. We also measured glucose transporter 4 (GLUT4) expression by Western blot and immunofluorescence. Moreover, immunohistochemistry was performed to assess muscle fiber type composition.

Results

Fasting glucose levels and area under the curve responses to IPGTTs gradually increased as diabetes progressed in the ZDF-Con rats but decreased in the ZDF-Ex rats. Grip strength decreased in the ZDF-Con rats. However, resistance training did not improve grip strength in the ZDF-Ex rats. GLUT4 expression in the ZLC-Con and the ZDF-Con rats did not differ, but it increased in the ZDF-Ex rats. The proportions of myosin heavy chain I and II were lower and higher, respectively, in the ZDF-Con rats compared to the ZLC-Con rats. Muscle fiber type composition did not change in the ZDF-Ex rats.

Conclusion

Our results suggest that regular resistance training initiated at the onset of diabetes can improve glucose tolerance and GLUT4 expression without changing muscle morphology in Zucker rats.

Citations

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Brief Reports
Epidemiology
Relationship between Biological Markers, Metabolic Components, Lifestyles, and Impaired Fasting Glucose in Male Workers
Tomoyuki Kawada
Diabetes Metab J. 2015;39(5):434-438.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.434
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AbstractAbstract PDFPubReader   
Background

Confirmation regarding the association between impaired fasting glucose (IFG) and biomarkers in addition to metabolic components and lifestyle factors are required in the occupational filed for preventing diabetes mellitus.

Methods

The study was performed in working men aged 30 to 60 years old, who were not taking medication for any metabolic diseases. The author measured the serum levels of high-sensitivity C-reactive protein (CRP), uric acid, and plasma fibrinogen as potential biomarkers of IFG.

Results

The mean serum uric acid, log-transformed serum CRP, and plasma fibrinogen levels were higher in the subjects with IFG than in those without IFG. Multivariate analysis revealed significant associations between the presence of IFG and age, log-transformed value of serum CRP, increased waist circumference, hypertension, and hypertriglyceridemia, with odds ratios of 1.1 (95% confidence interval [CI], 1.08 to 1.1; P<0.001), 1.8 (95% CI, 1.4 to 2.3; P<0.001), 1.3 (95% CI, 1.09 to 1.7; P<0.01), 1.9 (95% CI, 1.6 to 2.3; P<0.001), and 1.3 (95% CI, 1.04 to 1.6; P<0.05), respectively, for the presence of IFG.

Conclusion

Serum CRP, age, and three metabolic components were associated with IFG. In contrast, there were no significant associations between IFG and lifestyle factors, serum uric acid or plasma fibrinogen.

Genetics
Identification of Two Cases of Ciliopathy-Associated Diabetes and Their Mutation Analysis Using Whole Exome Sequencing
Min Kyeong Kim, Soo Heon Kwak, Shinae Kang, Hye Seung Jung, Young Min Cho, Seong Yeon Kim, Kyong Soo Park
Diabetes Metab J. 2015;39(5):439-443.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.439
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AbstractAbstract PDFPubReader   
Background

Alström syndrome and Bardet-Biedl syndrome are autosomal recessively inherited ciliopathies with common characteristics of obesity, diabetes, and blindness. Alström syndrome is caused by a mutation in the ALMS1 gene, and Bardet-Biedl syndrome is caused by mutations in BBS1-16 genes. Herein we report genetically confirmed cases of Alström syndrome and Bardet-Biedl syndrome in Korea using whole exome sequencing.

Methods

Exome capture was done using SureSelect Human All Exon Kit V4+UTRs (Agilent Technologies). HiSeq2000 system (Illumina) was used for massive parallel sequencing. Sanger sequencing was used for genotype confirmation and familial cosegregation analysis.

Results

A 21-year old Korean woman was clinically diagnosed with Alström syndrome. She had diabetes, blindness, obesity, severe insulin resistance, and hearing loss. Whole exome sequencing revealed a nonsense mutation in exon 10 of ALMS1 (c.8776C>T, p.R2926X) and a seven base-pair deletion resulting in frameshift mutation in exon 8 (c.6410_6416del, p.2137_2139del). A 24-year-old Korean man had Bardet-Biedl syndrome with diabetes, blindness, obesity, and a history of polydactyly. Whole exome sequencing revealed a nonsynonymous mutation in exon 11 of the BBS1 gene (c.1061A>G, p.E354G) and mutation at the normal splicing recognition site of exon 7 of the BBS1 gene (c.519-1G>T).

Conclusion

We found novel compound heterozygous mutations of Alström syndrome and Bardet-Biedl syndrome using whole exome sequencing. The whole exome sequencing successfully identified novel genetic variants of ciliopathy-associated diabetes.

Citations

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    Brais Bea-Mascato, Diana Valverde
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Letter
Response
Response: Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2015;39:342-7)
Shusuke Yagi, Ken-ichi Aihara, Masataka Sata
Diabetes Metab J. 2015;39(5):446-447.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.446
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Erratum
Erratum: Figure Correction: Probiotics as Complementary Treatment for Metabolic Disorders
Mélanie Le Barz, Fernando F. Anhê, Thibaut V. Varin, Yves Desjardins, Emile Levy, Denis Roy, Maria C. Urdaci, André Marette
Diabetes Metab J. 2015;39(5):448-449.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.448
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