Author Correction: Adiponectin promotes muscle regeneration through binding to T-cadherin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adiponectin, a unique adipocyte-derived factor beyond hormones.

Visceral fat accumulation has a marked impact on atherosclerotic cardiovascular diseases and metabolic syndrome clustering diabetes, dyslipidemia, and hypertension. Adiponectin, an adipocyte-derived circulating protein, is a representative adipocytokine and uniquely possesses two major properties: 1) its circulating concentration is approximately 3-6 orders of magnitude greater than ordinary hormones and cytokines; 2) its concentration inversely correlates with body fat mass despite its adipocyte-specific production. Low serum levels of adiponectin correlate with cardiometabolic diseases. Extensive experimental evidence has demonstrated that adiponectin possesses multiple properties, such as anti-atherosclerotic, anti-diabetic, and anti-inflammatory activities. It has been shown to play a central role against the development of metabolic syndrome and its complications. However, even approximately 25 years after its discovery, the properties of adiponectin, including how and why it exerts multiple beneficial effects on various tissues and/or organs, remain unclear. Furthermore, the mechanisms responsible for the very high circulating concentrations of adiponectin in the bloodstream have not been elucidated. Several adiponectin-binding partners, such as AdipoR1/2, have been identified, but do not fully explain the multi-functional and beneficial properties of adiponectin. Recent advances in adiponectin research may resolve these issues. Adiponectin binds to and covers cell surfaces with T-cadherin, a unique glycosylphosphatidylinositol (GPI)-anchored cadherin. The adiponectin/T-cadherin complex enhances exosomal production and release, excreting cell-toxic products from cells, particularly in the vasculature. In this review, we discuss adiponectin and the role of the adiponectin/T-cadherin system in the maintenance of whole body homeostasis and cardiovascular protection.

Adiponectin promotes muscle regeneration through binding to T-cadherin.

Skeletal muscle has remarkable regenerative potential and its decline with aging is suggested to be one of the important causes of loss of muscle mass and quality of life in elderly adults. Metabolic abnormalities such as obesity were linked with decline of muscle regeneration. On the other hand, plasma levels of adiponectin are decreased in such metabolic conditions. However, plasma levels of adiponectin have been shown to inversely correlate with muscle mass and strength in elderly people especially with chronic heart failure (CHF). Here we have addressed whether adiponectin has some impact on muscle regeneration after cardiotoxin-induced muscle injury in mice. Muscle regeneration was delayed by angiotensin II infusion, mimicking aging and CHF as reported. Adiponectin overexpression in vivo decreased necrotic region and increased regenerating myofibers. Such enhanced regeneration by excess adiponectin was also observed in adiponectin null mice, but not in T-cadherin null mice. Mechanistically, adiponectin accumulated on plasma membrane of myofibers both in mice and human, and intracellularly colocalized with endosomes positive for a multivesicular bodies/exosomes marker CD63 in regenerating myofibers. Purified high-molecular multimeric adiponectin similarly accumulated intracellularly and colocalized with CD63-positive endosomes and enhanced exosome secretion in differentiating C2C12 myotubes but not in undifferentiated myoblasts. Knockdown of T-cadherin in differentiating C2C12 myotubes attenuated both adiponectin-accumulation and adiponectin-mediated exosome production. Collectively, our studies have firstly demonstrated that adiponectin stimulates muscle regeneration through T-cadherin, where intracellular accumulation and exosome-mediated process of adiponectin may have some roles.

Low muscle quality in Japanese type 2 diabetic patients with visceral fat accumulation.

BACKGROUND: Although obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated. METHODS: We enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation. RESULTS: The prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (-) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (-) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018). CONCLUSIONS: T2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.

Hypoxanthine Secretion from Human Adipose Tissue and its Increase in Hypoxia.

OBJECTIVE: The production of uric acid in murine white adipose tissue (mWAT), and that such production was augmented in obese mice, was recently reported. However, little is known about the secretion of metabolites associated with purine catabolism in human WAT (hWAT). The present study analyzed this in hWAT. METHODS: Freshly isolated hWAT and mWAT were cultured. The secretion of metabolites associated with purine catabolism was measured. Tissue distribution profiles of genes associated with purine metabolism and metabolite profiling of adipocytes in hypoxia were analyzed. RESULTS: Secretion of hypoxanthine from hWAT was higher than those of xanthine and uric acid. On the other hand, secretion of uric acid was relatively higher than xanthine and hypoxanthine in mWAT. Xanthine oxidoreductase (XOR) mRNA expression levels in hWAT were markedly lower than that in the human liver. In murine tissues, XOR mRNA expression levels in mWAT were comparable with those in the liver. Cultured human adipocytes secreted hypoxanthine, and its secretion was increased under hypoxia. The metabolic analysis of human adipocytes showed that hypoxia increased metabolites associated with de novo biosynthesis of purine nucleotides. CONCLUSIONS: The present study revealed that hypoxanthine was secreted from human adipose tissue, and the secretion might be increased in local hypoxia.

Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release.

Adiponectin, an adipocyte-derived circulating protein, accumulates in vasculature, heart, and skeletal muscles through interaction with a unique glycosylphosphatidylinositol-anchored cadherin, T-cadherin. Recent studies have demonstrated that such accumulation is essential for adiponectin-mediated cardiovascular protection. Here, we demonstrate that the adiponectin/T-cadherin system enhances exosome biogenesis and secretion, leading to the decrease of cellular ceramides. Adiponectin accumulated inside multivesicular bodies, the site of exosome generation, in cultured cells and in vivo aorta, and also in exosomes in conditioned media and in blood, together with T-cadherin. The systemic level of exosomes in blood was significantly affected by adiponectin or T-cadherin in vivo. Adiponectin increased exosome biogenesis from the cells, dependently on T-cadherin, but not on AdipoR1 or AdipoR2. Such enhancement of exosome release accompanied the reduction of cellular ceramides through ceramide efflux in exosomes. Consistently, the ceramide reduction by adiponectin was found in aortas of WT mice treated with angiotensin II, but not in T-cadherin-knockout mice. Our findings provide insights into adiponectin/T-cadherin-mediated organ protection through exosome biogenesis and secretion.

Characteristics of sleep-wake cycle and sleep duration in Japanese type 2 diabetes patients with visceral fat accumulation.

Sleep pattern has been shown to be associated with type 2 diabetes mellitus. Here, we investigated the difference in bedtime, waking time and estimated sleep duration in type 2 diabetes mellitus patients with or without visceral fat accumulation, using a questionnaire on sleep patterns. The study participants were 59 Japanese type 2 diabetes mellitus patients (men/women 34/25, age 64.5 ± 12.1 years). Visceral fat accumulation was defined as estimated visceral fat area ≥100 cm2 . The patients with visceral fat accumulation (n = 40) showed significantly later bedtime (23.51 ± 01.27 h in the [+] group vs 22.49 ± 01.23 h in the [-] group) and shorter estimated sleep duration (6.6 ± 1.4 h in the [+] group vs 7.9 ± 1.0 h in the [-] group) on weekdays, compared with those without (n = 19). Later bedtime and shorter estimated sleep duration existed in the type 2 diabetes mellitus patients with visceral fat accumulation, compared with those without.

Association of Epicardial, Visceral, and Subcutaneous Fat With Cardiometabolic Diseases.

BACKGROUND: Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat.Methods and Results:Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm2) and was also reduced in the high EFV group (EFV ≥80 cm3). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis. CONCLUSIONS: Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.

Westernization of lifestyle affects quantitative and qualitative changes in adiponectin.

BACKGROUND: Although Japanese-Americans and native Japanese share the same genetic predispositions, they live different lifestyles, resulting in insulin resistance in Japanese-Americans. We investigated whether the quantitative and qualitative changes in adiponectin (APN) due to differences in lifestyle contribute to the development of insulin resistance. METHODS: We evaluated 325 native Japanese in Hiroshima, Japan and 304 Japanese-Americans in Los Angeles, the United States, who were aged between 30 and 70 years and underwent medical examinations between 2009 and 2010. All participants underwent a 75-g oral glucose tolerance test (OGTT) to assess their glucose tolerance. The insulin response to oral glucose load, the Matsuda index, total APN levels, and C1q-APN/total-APN ratios were compared between native Japanese and Japanese-Americans. RESULTS: Compared with the native Japanese, the Japanese-Americans had significantly lower Matsuda index and higher area under the curve values for serum insulin concentration during OGTT in the normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) groups, but not in the diabetes mellitus (DM) group. Furthermore, the Japanese-Americans had significantly lower total APN levels and higher C1q-APN/total-APN ratios than the native Japanese in the NGT and IGT groups, but not in the DM group. CONCLUSIONS: This study suggested that, in Japanese people, the westernization of their lifestyle might affect quantitative and qualitative changes in APN and induce insulin resistance.

Multiple Gouty Tophi with Bone Erosion and Destruction: A Report of an Early-onset Case in an Obese Patient.

A 27 year-old severely obese man (BMI, 35.1) had hyperuricemia and multiple gouty tophi with bone erosion and destruction, resulting in gait disturbance for 6 years after the early onset of gout at 21 years of age. His hyperuricemia was associated with hyperinsulinemia in obesity and a genetic variant of the ABCG2 gene. In addition, multiple gouty tophi with bone erosion and destruction might have been caused by hypoadiponectinemia and the elevation of the patient' s pro-inflammatory cytokine (IL-1ß) level with the accumulation of visceral fat. In this case, bone and Ga-67 scintigraphy were useful for detecting the location and magnitude of gouty tophi.

The unique prodomain of T-cadherin plays a key role in adiponectin binding with the essential extracellular cadherin repeats 1 and 2.

Adiponectin, an adipocyte-derived circulating protein, accumulates in the heart, vascular endothelium, and skeletal muscles through an interaction with T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored cadherin. Recent studies have suggested that this interaction is essential for adiponectin-mediated cardiovascular protection. However, the precise protein-protein interaction between adiponectin and T-cad remains poorly characterized. Using ELISA-based and surface plasmon analyses, we report here that T-cad fused with IgG Fc as a fusion tag by replacing its glycosylphosphatidylinositol-anchor specifically bound both hexameric and larger multimeric adiponectin with a dissociation constant of ∼1.0 nm and without any contribution from other cellular or serum factors. The extracellular T-cad repeats 1 and 2 were critical for the observed adiponectin binding, which is required for classical cadherin-mediated cell-to-cell adhesion. Moreover, the 130-kDa prodomain-bearing T-cad, uniquely expressed on the cell surface among members of the cadherin family and predominantly increased by adiponectin, contributed significantly to adiponectin binding. Inhibition of prodomain-processing by a prohormone convertase inhibitor increased 130-kDa T-cad levels and also enhanced adiponectin binding to endothelial cells both by more preferential cell-surface localization and by higher adiponectin-binding affinity of 130-kDa T-cad relative to 100-kDa T-cad. The preferential cell-surface localization of 130-kDa T-cad relative to 100-kDa T-cad was also observed in normal mice aorta in vivo In conclusion, our study shows that a unique key feature of the T-cad prodomain is its involvement in binding of the T-cad repeats 1 and 2 to adiponectin and also demonstrates that adiponectin positively regulates T-cad abundance.

Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy.

This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-ß, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.

Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. In vitro, knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.

Significant Association of Serum Adiponectin and Creatine Kinase-MB Levels in ST-Segment Elevation Myocardial Infarction.

AIMS: Adiponectin, an adipocyte-specific secretory protein, abundantly exists in the blood stream while its concentration paradoxically decreases in obesity. Hypoadiponectinemia is one of risks of cardiovascular diseases. However, impact of serum adiponectin concentration on acute ischemic myocardial damages has not been fully clarified. The present study investigated the association of serum adiponectin and creatine kinase (CK)-MB levels in subjects with ST-segment elevation myocardial infarction (STEMI). METHODS: This study is a physician-initiated observational study and is also registered with the University Hospital Medical Information Network (Number: UMIN 000014418). Patients were admitted to Senri Critical Care Medical Center, given a diagnosis of STEMI, and treated by primary percutaneous coronary intervention (PCI). Finally, 49 patients were enrolled and the association of serum adiponectin, CK-MB, and clinical features were mainly analyzed. RESULTS: Serum adiponectin levels decreased rapidly and reached the bottom at 24 hours after recanalization. Such reduction of serum adiponectin was inversely correlated with the area under the curve (AUC) of serum CK-MB (p=0.013). Serum adiponectin concentrations were inversely correlated with AUC of serum CK-MB. In multivariate analysis, serum adiponectin concentration on admission (p=0.002) and collateral (p=0.037) were significantly and independently correlated with serum AUC of CK-MB. CONCLUSION: Serum AUC of CK-MB in STEMI subjects was significantly associated with serum adiponectin concentration on admission and reduction of serum adiponectin levels from baseline to bottom. The present study may provide a possibility that serum adiponectin levels at acute phase are useful in the prediction for prognosis after PCI-treated STEMI subjects.

Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue: IN VIVO METABOLIC TURNOVER ANALYSIS.

Obesity is closely associated with various metabolic disorders. However, little is known about abnormalities in the metabolic change of obese adipose tissue. Here we use static metabolic analysis and in vivo metabolic turnover analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of the TCA cycle were increased in the white adipose tissue (WAT) of ob/ob and diet-induced obesity mice but not in the liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that these glucose-derived metabolites were dynamically and specifically produced in obese WAT compared with lean WAT. Glutamate rise in obese WAT was associated with down-regulation of glutamate aspartate transporter (GLAST), a major glutamate transporter for adipocytes, and low uptake of glutamate into adipose tissue. In adipocytes, glutamate treatment reduced adiponectin secretion and insulin-mediated glucose uptake and phosphorylation of Akt. These data suggest that a high intra-adipocyte glutamate level potentially relates to adipocyte dysfunction in obesity. This study provides novel insights into metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.

Impact of visceral fat on gene expression profile in peripheral blood cells in obese Japanese subjects.

BACKGROUND: Visceral fat plays a central role in the development of metabolic syndrome and atherosclerotic cardiovascular diseases. The association of visceral fat accumulation with cardio-metabolic diseases has been reported, but the impact of visceral fat on the gene expression profile in peripheral blood cells remains to be determined. The aim of this study was to determine the effects of visceral fat area (VFA) and subcutaneous fat area (SFA) on the gene expression profile in peripheral blood cells of obese subjects. METHODS: All 17 enrolled subjects were hospitalized to receive diet therapy for obesity (defined as body mass index, BMI, greater than 25 kg/m2). VFA and SFA were measured at the umbilical level by computed tomography (CT). Blood samples were subjected to gene expression profile analysis by using SurePrint G3 Human GE Microarray 8 × 60 k ver. 2.0. The correlation between various clinical parameters, including VFA and SFA, and peripheral blood gene expression levels was analyzed. RESULTS: Among the 17 subjects, 12 had normal glucose tolerance or borderline diabetes, and 5 were diagnosed with type 2 diabetes without medications [glycated hemoglobin (HbA1c); 6.3 ± 1.3%]. The mean BMI, VFA, and SFA were 30.0 ± 5.5 kg/m2, 177 ± 67 and 245 ± 131 cm2, respectively. Interestingly, VFA altered the expression of 1354 genes, including up-regulation of 307 and down-regulation of 1047, under the statistical environment that the parametric false discovery rate (FDR) was less than 0.1. However, no significant effects were noted for SFA or BMI. Gene ontology analysis showed higher prevalence of VFA-associated genes than that of SFA-associated genes, among the genes associated with inflammation, oxidative stress, immune response, lipid metabolism, and glucose metabolism. CONCLUSIONS: Accumulation of visceral fat, but not subcutaneous fat, has a significant impact on the gene expression profile in peripheral blood cells in obese Japanese subjects.

Treatment of Mitochondrial Diabetes with a Peroxisome Proliferator-activated Receptor (PPAR)-gamma Agonist.

The 3243 A>G mutation in mitochondrial DNA is the most common cause of monogenic diabetes mellitus in Japan. A 45-year-old woman with mitochondrial diabetes and significant insulin resistance presented with hypoadiponectinemia despite a normal amount of visceral fat. Three months of treatment with pioglitazone (PIO) improved her blood glucose profile and response to the 75-g oral glucose tolerance test. These changes were accompanied by the amelioration of her insulin resistance and the impairment of early-phase insulin secretion. Her serum adiponectin levels increased to the normal range. In this case of mitochondrial diabetes, PIO was effective for glycemic control.

E-selectin ligand-1 (ESL-1) is a novel adiponectin binding protein on cell adhesion.

BACKGROUND: Adiponectin (APN) is an adipocyte-derived bioactive molecule with anti-diabetic and anti-atherogenic properties. Although anti-diabetic effects are mostly mediated by the adiponectin receptors AdipoR1 and AdipoR2, the anti-atherogenic mechanisms have not been fully elucidated. METHODS AND RESULTS: In this study, we identified E-selectin ligand (ESL)-1 as a novel APN-binding protein by mass spectrometry analysis of HepG2 cell-derived immunoprecipitant with an anti-APN antibody. Cell adhesion assays using fluorescence-labelled monocyte cell line THP-1 cells and human umbilical vein endothelial cells (HUVECs) revealed that APN-pre-treated THP-1 cells had reduced binding ability to HUVECs. This APN-mediated suppressive effect on monocyte binding to endothelial cells was partially abrogated by targeting ESL-1 with shRNA in THP-1 cells. In addition, serial mutagenesis analysis disclosed that five extracellular amino acids close to the N-terminus of ESL-1 were essential for binding with APN. CONCLUSION: Our results highlight the fact that interaction between APN and ESL-1 could provide a fundamental mechanism underlying the anti-atherogenic properties of APN.

A case of glucocorticoid-induced diabetes in which the efficacy between sitagliptin and metformin was compared.

To date, promising strategies for treating glucocorticoid (GC)-induced diabetes with antidiabetic drugs have not been established. We herein report the case of a woman with GC-induced diabetes in which we compared the efficacy of two kinds of orally administered antidiabetic drugs sitagliptin and metformin by continuous glucose monitoring (CGM) and meal-challenge test (MCT). As a result, CGM showed that daily fluctuation of blood glucose levels was reduced during administration of metformin but not during administration of sitagliptin. On the other hand, MCT showed that administration of metformin reduced plasma glucose levels accompanied by the decrease of plasma insulin levels and the increase of plasma glucagon levels, whereas administration of sitagliptin had little effects on these parameters. This case is the first report to compare the efficacy between sitagliptin and metformin in glucose homeostasis by CGM and MCT in a patient with GC-induced diabetes.

CDH13 Polymorphisms are Associated with Adiponectin Levels and Metabolic Syndrome Traits Independently of Visceral Fat Mass.

AIM: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels. METHODS: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals. RESULTS: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P ＜ 1 × 10 (-14)), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) scores, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels, similar to increasing VFA and decreasing adiponectin levels. CONCLUSION: These results suggested that CDH13 SNPs cause an adiponectin-resistant status to compensate for increasing adiponectin levels and could result in the deterioration of metabolic syndrome traits.