Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations.

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. MATERIALS AND METHODS: We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2 , F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. CONCLUSIONS: Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Adiponectin Paradox More Evident in Non-Obese Than in Obese Patients with Diabetic Microvascular Complications.

Aims/Introduction: Adiponectin is generally regarded as a beneficial molecule, protecting against insulin resistance and atherosclerosis, and its serum levels are low in individuals with obesity as well as in those with type 2 diabetes (T2DM). However, several clinical studies have shown associations between high adiponectin values and major health concerns. These conflicting findings are termed the "adiponectin paradox". Similarly, these paradoxical adiponectin elevations were observed in patients with diabetic microvascular complications. This cross-sectional study aimed to identify differences in factors, including adiponectin, related to diabetic vascular complications between non-obese and obese patients. Materials and Methods: Study patients with T2DM were non-obese (n=197) or obese (n=197), matched by a propensity score model adjusted with age and gender. Independent factors for each of the microvascular complications were determined using multivariate logistic regression analyses. Results: The prevalence of nephropathy was high in obese T2DM patients. In addition to long diabetes duration, elevated adiponectin was a common characteristic of patients with microvascular complications. Logistic regression analyses for microvascular complications revealed adiponectin to be highly related to retinopathy (odds ratio [OR], 1.138; 95%confidence intervals [CI], 1.004-1.289, p<0.001), nephropathy (OR, 1.192; CI, 1.077-1.319, p<0.001) and neuropathy (OR, 1.217; CI, 1.071-1.384, p<0.001), in non-obese patients. In contrast, the association between adiponectin values and complications was modest in obese patients. Conclusion: Adiponectin regulation in response to vascular damage differed between non-obese and obese patients, suggesting that adiponectin regulation is compromised by fat accumulation. Assuming that paradoxical elevation of adiponectin in vascular damage is a compensatory response, we speculate that responsive upregulation might be insufficient in obese patients. These newly-recognized differences in adiponectin values might lead to novel insights into adiponectin regulation and our understanding of the adiponectin paradox.

Evaluation of High Intracranial Plaque Prevalence in Type 2 Diabetes Using Vessel Wall Imaging on 7 T Magnetic Resonance Imaging.

BACKGROUND: While type 2 diabetes (T2D) is a major risk for ischemic stroke, the associated vessel wall characteristics remain essentially unknown. This study aimed to clarify intracranial vascular changes on three-dimensional vessel wall imaging (3D-VWI) using fast spin echo by employing 7Tesla (7T) magnetic resonance imaging (MRI) in T2D patients without advanced atherosclerosis as compared to healthy controls. METHODS: In 48 T2D patients and 35 healthy controls, the prevalence of cerebral small vessel diseases and intracranial plaques were evaluated by 3D-VWI with 7T MRI. RESULTS: The prevalence rate of lacunar infarction was significantly higher in T2D than in controls (n = 8 in T2D vs. n = 0 in control, p = 0.011). The mean number of intracranial plaques in both anterior and posterior circulation of each subject was significantly larger in T2D than in controls (2.23 in T2D vs. 0.94 in control, p < 0.01). In T2D patients, gender was associated with the presence of intracranial plaques. CONCLUSION: This is the first study to demonstrate the high prevalence of intracranial plaque in T2D patients with neither confirmed atherosclerotic disease nor symptoms by performing intracranial 3D-VWI employing 7TMRI. Investigation of intracranial VWI with 7T MRI is expected to provide novel insights allowing early intensive risk management for prevention of ischemic stroke in T2D patients.

The Effects of Imeglimin on the Daily Glycemic Profile Evaluated by Intermittently Scanned Continuous Glucose Monitoring: Retrospective, Single-Center, Observational Study.

INTRODUCTION: Imeglimin is a novel antidiabetic drug that amplifies glucose-stimulated insulin secretion (GSIS) and improves insulin sensitivity. Several randomized clinical studies have shown the efficacy of imeglimin for glycemic control in patients with type 2 diabetes (T2D). We aimed to evaluate the short-term effects and safety of imeglimin in terms of glycemic control, as assessed by intermittently scanned continuous glucose monitoring (isCGM). METHODS: This retrospective and observational study of 32 patients who were administered imeglimin in addition to existing treatment regimens was designed to evaluate glycemic profiles. The patients were monitored for more than 4 weeks, including the day of starting imeglimin. The changes in glycemic indices, including mean glucose level, coefficient of variation (CV), time in range (TIR) and time above range (TAR), before and after imeglimin administration were analyzed, and data on adverse effects were collected by interview. RESULTS: Imeglimin administration significantly improved the mean values of glucose (from 159.0 ± 27.5 mg/dL to 141.7 ± 22.1 mg/dL; p < 0.001), TIR (from 67.9 ± 17.0% to 79.5 ± 13.3%; p < 0.001) and TAR (from 29.4 ± 17.5% to 17.9 ± 13.7%; p < 0.001) and tended to improve CV (from 29.0 ± 6.1 to 27.4 ± 5.58; p = 0.058). The curves of 24-h mean glucose level for all 32 subjects were shifted downward from the baseline after imeglimin administration. The high mean glucose level, high TAR, low TIR, low body mass index and low C-peptide were related to the efficacy of imeglimin for glycemic control. The main adverse effects were gastrointestinal disorders, and the incidence of hypoglycemia was increased in cases receiving a combination of imeglimin plus insulin or a glinide agent. CONCLUSION: Imeglimin clearly shifted the daily glucose profile into an appropriate range in Japanese T2D patients, indicating improvement of short-term glycemic control. Imeglimin is thought to be a promising therapeutic agent for T2D patients, especially those with a low insulin secretory capacity, which is a common phenotype in East-Asian subjects with glucose intolerance.

Japanese Type 1 Diabetes Database Study (TIDE-J): rationale and study design.

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients.

Serum C-X-C motif chemokine ligand 14 levels are associated with serum C-peptide and fatty liver index in type 2 diabetes mellitus patients.

AIMS/INTRODUCTION: Recent studies have suggested C-X-C motif chemokine ligand 14 (CXCL14), secreted from adipose tissue, to play an important role in the pathogenesis of metabolic syndrome. However, the clinical significance of CXCL14 in humans has not been elucidated. This study aimed to assess correlations between serum CXCL14 levels and clinical parameters in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In total, 176 individuals with type 2 diabetes mellitus were recruited. Serum CXCL14 concentrations were determined by enzyme-linked immunosorbent assay. We examined the associations of serum CXCL14 levels with laboratory values, abdominal computed tomography image information, surrogate markers used for evaluating the pathological states of diabetes, obesity and atherosclerosis. RESULTS: Serum CXCL14 levels correlated positively with body mass index, waist circumference, subcutaneous and visceral fat areas, and serum alanine transaminase, uric acid, total cholesterol, low-density lipoprotein cholesterol, triglycerides and C-peptide (CPR) levels. In contrast, CXCL14 levels correlated inversely with age, pulse wave velocity and serum adiponectin levels. Multiple linear regression analysis showed serum levels of CPR (ß = 0.227, P = 0.038) and the fatty liver index (ß = 0.205, P = 0.049) to be the only parameters showing independent statistically significant associations with serum CXCL14 levels. CONCLUSIONS: Serum CXCL14 levels were independently associated with serum CPR and fatty liver index in patients with type 2 diabetes mellitus. In these patients, a high serum CPR concentration might reflect insulin resistance rather than ß-cell function, because CXCL14 showed simple correlations with obesity-related parameters. Collectively, these data suggested that serum CXCL14 levels in type 2 diabetes patients might be useful predictors of elevated serum CPR and hepatic steatosis.

High Prevalence of Cerebral Small Vessel Disease on 7T Magnetic Resonance Imaging in Familial Hypercholesterolemia.

AIM: It remains unclear whether elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cerebral vascular disease. Familial hypercholesterolemia (FH) is the most appropriate model for understanding the effects of excess LDL-C because affected individuals have inherently high levels of circulating LDL-C. To clarify the effects of hypercholesterolemia on cerebral small vessel disease (SVD), we investigated cerebrovascular damage in detail due to elevated LDL-C using high resolution brain magnetic resonance imaging (MRI) in patients with FH. METHODS: Twenty-eight patients with FH and 35 healthy controls underwent 7T brain MRI. The prevalence of SVD and arterial structural changes were determined in each group. RESULTS: The prevalence of periventricular hyperintensity (PVH) was significantly higher (control, 0% vs. FH, 14.2%, p=0.021) and deep white matter intensity tended to be more frequent in FH patients than in controls. The prevalence of SVD in patients with forms of cerebral damage, such as lacunar infarction, PVH, deep white matter hyperintensities (DWMH), microbleeding, and brain atrophy, was significantly higher among FH patients (control, n=2, 5.7% vs. FH, n=7, 25.0%, p＜0.001, chi-square test). The tortuosity of major intracranial arteries and the signal intensity of lenticulostriate arteries were similar in the two groups. In FH patients, as the grade of PVH progressed, several atherosclerosis risk factors, such as body mass index, blood pressure, and triglyceride level, showed ever worsening values. CONCLUSION: These results obtained from FH patients revealed that persistently elevated LDL-C leads to cerebral PVH. It is necessary in the management of FH to pay attention not only to the development of coronary heart disease but also to the presence of cerebral SVD.

Evaluation of Lenticulostriate Arteries Changes by 7 T Magnetic Resonance Angiography in Type 2 Diabetes.

AIM: Progress in neuroimaging techniques allows us to investigate the microvasculature characteristics including lenticulostriate arteries (LSA), which are closely associated with lacunar infarction. Because ischemic stroke is a more critical health problem in East Asian than in other populations, in order to clarify pathological changes underlying cerebral small vessel disease (SVD), we projected an imaging analysis of LSA using high-resolution brain magnetic resonance imaging (MRI) in middle-aged Japanese subjects with type 2 diabetes. METHODS: Twenty-five subjects with type 2 diabetes and 25 non-diabetic control subjects underwent 7 Tesla (7 T) brain MRI. The prevalences of SVD and LSA structural changes were determined in each group. RESULTS: SVD prevalence did not differ significantly between the type 2 diabetes and control groups. The average numbers of stems, as well as numbers of branches, of LSA were significantly smaller in diabetic subjects than non-diabetic control subjects. The signal intensity of LSA was markedly decreased, indicating reduced blood flow in type 2 diabetes. CONCLUSION: In spite of the prevalence of SVD being similar, structural changes and decreased signal intensity of LSA were highly detected in diabetic subjects compared with non-diabetic controls, suggesting that 7 T MRA enables us to determine LSA impairment prior to the development of SVD. Early detection of LSA impairment allows us earlier interventions aimed at the prevention of atherosclerotic events.

Association of epicardial adipose tissue with serum level of cystatin C in type 2 diabetes.

OBJECTIVE: Accumulation of epicardial adipose tissue (EAT) is considered to be a cardiovascular risk factor independent from visceral adiposity, obesity, hypertension and diabetes. We explored the parameters related to EAT accumulation, aiming to clarify the novel pathophysiological roles of EAT in subjects with type 2 diabetes (T2DM). METHODS: We examined the laboratory values, including cystatinC, and surrogate markers used for evaluating atherosclerosis. EAT was measured as the sum of the adipose tissue area, obtained by plain computed tomography scans in 208 subjects with T2DM but no history of coronary artery disease. RESULTS: EAT correlated positively with age, body mass index (BMI), visceral fat area, leptin, cystatin C and C-peptide, while correlating negatively with adiponectin, estimated glomerular filteration rate (eGFR) and the liver-to-spleen ratio. Multiple linear regression analysis revealed serum cystatin C (ß = 0.175), leptin (ß = 0.536), BMI (ß = 0.393) and age (ß = 0.269) to be the only parameters showing independent statistically significant associations with EAT. When cystatin C was replaced with eGFR, eGFR showed no significant correlation with EAT. In reverse analysis, serum cystatin C was significantly associated with EAT after adjustment in multivariate analysis. DISCUSSION: EAT accumulation and elevated cystatin C have been independently regarded as risk factors influencing atherosclerosis. The strong association between EAT and cystatin C demonstrated herein indicates that EAT accumulation may play an important role in Cystatin C secretion, possibly contributing to cardiometabolic risk in T2DM patients.

Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence.

AIM: Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. METHODS: In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. RESULTS: Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nε-(carboxymethyl) lysine and 3-deoxyglucosone. CONCLUSION: Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects.

Non-Islet Cell Tumor Hypoglycemia Is Caused by Big IGF-II in a Patient with a Carcinosarcoma of the Uterus.

We report a 72-year-old Japanese woman with severe hypoglycemia. The laboratory data, which revealed the suppression of serum insulin, suggested the existence of non-islet cell tumor hypoglycemia (NICTH). Abdominal computed tomography demonstrated the presence of a huge uterine tumor. The patient was treated with a continuous infusion of glucose, but died of sepsis on day 46. An autopsy revealed the pathological diagnosis to be a carcinosarcoma of the uterus. Interestingly, an immunohistochemical study discovered the expression of insulin-like growth factor (IGF)-II in both the carcinoma and sarcoma cells. In addition, an immunoblot analysis of blood samples revealed the presence of circulating big IGF-II. Therefore, this is a novel case of NICTH that was caused by a uterine carcinosarcoma.

Response to the dipeptidyl peptidase-4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin-6 promoter region under a certain level of physical activity.

AIMS/INTRODUCTION: Muscle-derived interleukin-6 (IL-6) has been reported to promote glucagon-like peptide-1 (GLP-1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL-6 promoter region with the responsiveness to dipeptidyl peptidase-4 inhibitors (DPP-4Is), drugs that increase circulating GLP-1. MATERIALS AND METHODS: The present observational study enrolled Japanese patients with type 2 diabetes who took a DPP-4I over 3 months, and most of the clinical information was collected retrospectively. We defined non-responders as those having less than a 0.2% decrease of the glycated hemoglobin level at 3 or 4 months after starting DPP-4I treatment. Physical activity was retrospectively estimated by the Japanese short version of International Physical Activity Questionnaire. RESULTS: We studied 316 patients whose physical activity corresponding to the season of the DPP-4I administration was estimated. The non-responder rate was 29.7%. We analyzed rs1800796 and rs2097677, both are suggested to be functional in Japanese. Multivariate analysis for all patients showed that the adjusted odds ratio for the non-responder risk of the diplotype rs1800796 G/*-rs2097677 A/* against C/C-G/G (OR_G*A*) was 0.445 (P = 0.068). When patients were stratified by the International Physical Activity Questionnaire into low (n = 149) and moderate/high (n = 167) activity groups, however, OR_G*A* in each group was 1.58 (P = 0.615) and 0.153 (P = 0.003), respectively. CONCLUSIONS: The diplotype rs1800796 G/*-rs2097677 A/* might contribute to responsiveness to DPP-4Is in Japanese patients with type 2 diabetes under a certain level of physical activity. However, further investigation is warranted to confirm this.

Association of coronary artery calcification with MDA-LDL-C/LDL-C and urinary 8-isoprostane in Japanese patients with type 2 diabetes.

OBJECTIVE: Oxidative stress has been implicated in the development of coronary artery calcification (CAC). However, there are few reports on this issue in Japanese patients with diabetes. In this study, we examined the association of the CAC score (CACS) with oxidative stress markers. METHODS: The study subjects were 163 Japanese patients with type 2 diabetes (75 men and 88 women). The CACS (Agatston unit: AU) was measured by multi-detector computed tomography (MDCT), and the oxidative stress markers, such as the urinary 8-isoprostane and 8-hydroxydeoxyguanosine (8-OHdG) and serum malondialdehyde (MDA)-LDL cholesterol were measured. The relationships between CACS and oxidative stress markers were statistically analyzed. RESULTS: Compared with the CACS 0-400 AU group (n=132), the age, duration of diabetes, urinary 8-isoprostane levels, serum MDA-LDL-C/LDL-C and maximum intima media thickness (IMT) were higher, and body mass index and HbA1c level were lower, in the CACS >400 AU group (n=31). The multiple logistic regression analysis showed that a CAC >400 AU was independently associated with the urinary 8-isoprostane (>median) (OR=2.54, 95% CI=1.03-6.32, p=0.044), MDA-LDL-C/LDL-C (>median) (OR=2.62, 95% CI=1.07-6.40, p=0.035) and HbA1c (>median) (OR=0.32, CI=0.12-0.87, p<0.025). Focusing on oxidative stress, a higher MDA-LDL-C/LDL-C (p=0.026) and a higher urinary 8-isoprostane level (p=0.074) were associated with the CACS. CONCLUSION: The CACS was found to be independently associated with the MDA-LDL-C/LDL-C and urinary 8-isoprostane levels in Japanese patients with type 2 diabetes.

Different susceptibility to insulin resistance and fatty liver depending on the combination of TNF-α C-857T and adiponectin G+276T gene polymorphisms in Japanese subjects with type 2 diabetes.

The C-857T promoter polymorphism of TNF-α gene is associated with obese type 2 diabetes, while the adiponectin G+276T gene polymorphism in intron 2 may influence the fat accumulation in the liver. In this study, we examined effects of these polymorphisms on clinical markers of insulin resistance and fatty liver (a liver/spleen CT ratio < 0.9). These polymorphisms were determined in 342 Japanese subjects with type 2 diabetes. The liver/spleen CT ratio was lower in the subjects with the adiponectin +276G/G genotype than that in the subjects with the +276T allele (P < 0.05), indicating that fat accumulation in the liver is associated with the +276G/G genotype. Multiple comparisons among the 4 combinations of each polymorphism of the TNF-α and adiponectin genes revealed a significant difference in the liver/spleen CT ratio (P < 0.05) among the 4 groups, indicating that the gene combinations influence the degree of fat accumulation in the liver. The subjects carrying the TNF-α -857T allele (C/T or T/T genotype) and the adiponectin +276G/G genotype had greater risks for fatty liver and insulin resistance that was evaluated by higher levels of fasting insulin and homeostasis model assessment of insulin resistance, as compared with the other groups. Therefore, Japanese subjects with the TNF-α -857T allele and the adiponectin +276G/G genotype may be more susceptible to insulin resistance and fatty liver. The present study provides the evidence for the interaction between TNF-α and adiponectin genes in the insulin resistance and fatty liver in Japanese subjects with type 2 diabetes.

Serum CXCL1 concentrations are elevated in type 1 diabetes mellitus, possibly reflecting activity of anti-islet autoimmune activity.

BACKGROUND: Identification of unique inflammatory markers may facilitate prediction of type 1 diabetes mellitus (T1DM). We previously compared transcript profiles of bone marrow-derived dendritic cells from non-obese diabetic mice with those from non-obese non-diabetic mice and found that bone marrow-derived dendritic cells' expressions of inflammatory mediators, including chemokine (C-X-C motif) ligand 1 (CXCL1), were three to five times higher in 4-week-old female non-obese diabetic mice than in non-obese non-diabetic mice. In humans, microarray analysis results have suggested this chemokine be a biomarker representing active anti-islet autoimmunity. We investigated whether serum CXCL1 levels, reflecting active autoimmune processes, might serve as biomarkers for T1DM. METHODS: The study groups consisted of 26 subjects with acute-onset T1DM, 20 with slowly progressive T1DM, and 20 with type 2 diabetes mellitus as disease controls. All subjects were Japanese. CXCL1 in sera were quantified by solid phase enzyme-linked immunosorbent assays. RESULTS: Serum CXCL1 levels were significantly higher in subjects with acute-onset [median 113.2 ng/mL (41.75-457.2)] or slowly progressive [median 100.8 ng/mL (32.87-225.0)] T1DM than in those with type 2 diabetes mellitus [median 71.58 ng/mL (32.45-152.6), p=0.01 and 0.03, respectively, Mann-Whitney U-test]. Decreases in fasting C-peptide levels per year correlated significantly with CXCL1 levels (n=11, r2=0.524, p=0.012) in a subpopulation of slowly progressive T1DM subjects displaying preserved beta-cell function. CONCLUSIONS: To our knowledge, this is the first study to show elevated serum CXCL1 in T1DM subjects, regardless of diabetes subtype, as compared to control type 2 diabetes mellitus subjects. We propose serum CXCL1 elevation to be a good T1DM marker, possibly indicating a predisposition to autoimmune disease development.

Higher serum free triiodothyronine levels within the normal range are associated with metabolic syndrome components in type 2 diabetic subjects with euthyroidism.

Associations of thyroid hormones with visceral obesity and insulin resistance in obese subjects with euthyroidism have been reported. However, there are no such reports in subjects with type 2 diabetes. The purpose of our study is to observe a relationship between thyroid hormones and components of metabolic syndrome (MetS) in type 2 diabetic subjects with euthyroidism defined by normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels. Subjects were 301 Japanese patients with type 2 diabetes. Serum TSH, FT4, free triiodothyronine (FT3), and variables related to MetS were measured. MetS was defined by the Japanese criteria and the criteria of the National Cholesterol Education Program modified for Asians. We found that serum FT3 levels were significantly and positively associated with BMI, visceral fat area, systolic and diastolic blood pressure, estimated glomerular filtration rate, serum triglyceride, and urine C peptide as a marker of insulin production, whereas negatively with age and HbA1c. In contrast, fewer numbers of variables were associated with serum TSH and FT4 levels. By a multiple regression analysis, FT3 level was independently associated with components of MetS such as visceral fat area, systolic blood pressure, and fasting blood glucose levels. On the other hand, the presence of these MetS components was independently associated with FT3 levels and urine C peptide. In conclusion, these results suggest a significant relationship between serum FT3 levels and components of MetS in type 2 diabetic subjects with euthyroidism, and imply a role of FT3 in MetS in type 2 diabetes.