Postprandial fatty acid-binding protein 4 is associated with muscle insulin resistance.

AIMS/HYPOTHESIS: Fatty acid-binding protein 4 (FABP4) has been reported to act as a hepatic insulin resistance factor. We previously reported that fasting FABP4 was correlated with insulin resistance measurements derived from the glucose clamp, and another study reported that postprandial FABP4 levels were decreased in healthy volunteers but were not reported (or known) in participants with type 2 diabetes. We have limited knowledge about the direct effect of FABP4 on muscle cells. We investigated the postprandial FABP4 levels in participants with type 2 diabetes, and the basic mechanism of muscle insulin resistance and FABP4. METHODS: We performed a meal tolerance test and hyperinsulinaemic-euglycaemic clamp in 22 participants with type 2 diabetes and 26 participants without diabetes. We measured fasting and postprandial serum FABP4. We cultured mouse C2C12 muscle cells, and investigated the effect of FABP4 on glucose uptake. We analysed insulin signalling by western blot and insulin binding assay. RESULTS: The postprandial FABP4 level in participants with type 2 diabetes was higher than that in participants without diabetes. Participants without diabetes had lower postprandial FABP4 than fasting except for one participant, whereas one-third of participants with type 2 diabetes had higher postprandial FABP4 than fasting. Postprandial FABP4 was correlated with the muscle insulin resistance M/I value from a glucose clamp in participants without diabetes (r=-0.42, p<0.05). The increase in FABP4 after a meal correlated with the muscle insulin resistance M/I value (r=-0.44, p<0.05) and the difference between fasting and postprandial glucagon in participants with type 2 diabetes (r=0.36, p<0.05). FABP4 alone appears to increase glucose uptake, and the combination of FABP4 and insulin decreases glucose uptake when compared with insulin alone. FABP4 inhibits insulin signalling of muscle cells through decreases in phosphorylation of insulin receptor substrate 1 and Akt. The physiological concentration of FABP4 did not inhibit insulin binding to muscle cells. CONCLUSIONS/INTERPRETATION: These results suggested that the postprandial FABP4 level is associated with insulin resistance, and FABP4 may suppress insulin signals.

Epstein-Barr virus reactivation in peripheral B lymphocytes induces IgM-type thyrotropin receptor autoantibody production in patients with Graves' disease.

Epstein-Barr virus (EBV) is a human herpes virus that latently infects B lymphocytes. When EBV is reactivated, host B cells differentiate into plasma cells and produce IgM-dominant antibodies as well as many progeny virions. The aims of the present study were to confirm the IgM dominance of thyrotropin-receptor antibodies (TRAbs) produced by EBV reactivation and investigate the roles of TRAb-IgM in Graves' disease. Peripheral blood mononuclear cells (PBMCs) containing TRAb-producing cells were stimulated for EBV reactivation, and TRAb-IgM and TRAb-IgG were measured by ELISA. TRAb-IgM were purified and TSH-binding inhibitory activities were assessed using a radio-receptor assay. Porcine thyroid follicular epithelial cells were cultured with TRAb-IgM and/or complements to measure the intracellular levels of cAMP and the amount of LDH released. TRAb-IgM/TRAb-IgG (the MG ratio) was examined in sequential serum samples of Graves' disease and compared among groups of thyroid function. The results obtained showed that IgM-dominant TRAb production was induced by EBV reactivation. TRAb-IgM did not inhibit TSH binding to TSH receptors and did not transduce hormone-producing signals. However, it destroyed thyroid follicular epithelial cells with complements. The MG ratio was significantly higher in samples of hyperthyroidism or hypothyroidism than in those with normal function or in healthy controls. A close relationship was observed between TRAb-IgM produced by EBV reactivation and the development and exacerbation of Graves' disease. The present results provide novel insights for the development of prophylaxis and therapeutics for Graves' disease.

Low signal intensities of MRI T1 mapping predict refractory diplopia in Graves' ophthalmopathy.

OBJECTIVE: In Graves' ophthalmopathy (GO), fibrosis in extraocular muscles (EOMs) may be related to intravenous glucocorticoid (ivGC)-resistant diplopia. Signal intensity (SI) of magnetic resonance imaging (MRI) T1 mapping can quantify properties of EOM components, including fibrosis. We investigated EOM features of GO patients with diplopia using T1 mapping SI and the predictive value of T1 mapping SI in the response of diplopia to ivGCs. DESIGN: We performed a cross-sectional study that included 13 active GO patients, 34 inactive GO patients with history of diplopia, including 20 with a history of diplopia disappearance, 14 GO patients with refractory diplopia and 35 control subjects. In nine active GO patients, the relationship between T1 mapping SI at pretreatment and at diplopia outcome after ivGC treatment was prospectively investigated. METHODS: T1 mapping SI of left and right inferior rectus and medial rectus muscles was measured in all participants. RESULTS: T1 mapping SI in inactive GO patients with refractory diplopia was significantly lower than that of other groups in all evaluated EOMs. Diagnostic accuracy for refractory diplopia by T1 mapping SI in GO patients with a history of diplopia disappearance was excellent (AUC 0.89) compared with other assessments. Furthermore, among nine active GO patients, pretreatment T1 mapping SI in four patients with ivGC-resistant diplopia tended to be low compared with the other five patients with improved diplopia. CONCLUSIONS: Low intensity T1 mapping in EOMs is likely to be associated with refractory diplopia and may be useful in predicting the response of diplopia to ivGCs.

Evaluation of Outcomes Using a Tablet-Based System to Support Glycemic Management Workflow Operations: A Retrospective Observational Study.

The treatment of hospitalized patients with type 2 diabetes requires glycemic management to maintain the patients' blood glucose levels within a normal range. We developed a blood glucose management system (BGM) system in 2015, which is a tablet-based workflow support system. This system enables medical staff to continually confirm the physicians' instructions by measuring the blood glucose levels while using a tablet terminal.In this study, we examined electronic medical records (EMRs) to evaluate the usage frequency of the BGM system and the time required for the glycemic management workflow in comparison to conventional PC terminals in a large hospital setting. The data includes 197,927 blood glucose level measurements that were taken in the general wards of Tottori University Hospital between January 2016 and June 2017. The usage frequency of the glycemic management workflow while using the BGM system was 145,864 times (approximately 74% of the total blood glucose measurements). The mean time until the completion of the glycemic management workflow in the case of hyperglycemia was 16 min 33 s, which is 26% shorter than using a PC terminal for treatment that involves injection or infusion (1454 times). The BGM system is proactively utilized by medical staff, thereby improving the operating efficiency. The results of this study indicate that the BGM system installed on tablet terminals can improve the efficiency in large-scale medical institutions that treat patients with diabetes.

Implications of FoxP3-positive and -negative CD4(+) CD25(+) T cells in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is a common manifestation of Graves' disease (GD); however, its pathogenesis is not well understood. Recently, the dysregulation of regulatory T cells (Tregs) has been thought to be closely associated with the pathogenesis and clinical symptoms of autoimmune disease. We therefore evaluated whether T cell subsets, including Tregs, are associated with GO pathogenesis and clinical symptoms. In this observational study we evaluated 35 GD patients with overt ophthalmopathy (GOs) and 28 patients without ophthalmopathy (non-GOs). Fifteen healthy euthyroid patients served as healthy controls (HCs). Peripheral blood mononuclear cells from GOs, non-GOs and HCs were analyzed for CD4, CD25, and FoxP3 expression using flow cytometry. We also evaluated their correlation with disease activity according to the clinical activity score (CAS) and magnetic resonance imaging (MRI) findings. Disease severity was evaluated using the NOSPECS score, and clinical progression of GO was followed for 24 weeks. The main outcome measures were the frequencies of FoxP3-positive and -negative CD4(+) CD25(+) T cells at study outset, namely Tregs and effector T cells (Teffs), respectively. GOs had higher frequencies of Teffs (30.8±8.4%) than non-GOs (19.4±7.1%) and HCs (22.7±7.9%). Notably, patients with improved GOs had lower frequencies of Tregs (5.8±1.1%) than patients with stable or deteriorated GOs (7.3±1.2%), although ophthalmic and radiological parameters were not significantly different at the start of the study. In conclusion, an expanded Teff population may be associated with GO pathogenesis. Additionally, decreased Tregs in peripheral blood may predict a good clinical outcome.

Presurgery health influences outcomes following vertical sleeve gastrectomy in adolescents.

OBJECTIVE: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG. METHODS: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG. RESULTS: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m2. Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m2 (35.3%) versus the BAWL group, who lost 8.8 kg/m2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities. CONCLUSIONS: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG.

Aldehyde dehydrogenase 2 polymorphism is an important gene for insulin resistance in Japanese patients with type 2 diabetes.

Background: Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme involved in alcohol metabolism. ALDH2 polymorphism has been reported as a risk factor for type 2 diabetes mellitus (T2DM) and is associated with liver insulin resistance due to alcohol consumption in non-diabetic individuals. Herein, we investigated the association between ALDH2 polymorphisms and insulin resistance in patients with T2DM. Methods: We performed a meal tolerance test and the hyperinsulinemic-euglycemic clamp on 71 Japanese participants: 34 patients with T2DM, and 37 non-diabetic participants. We analyzed the ALDH2 polymorphism (ALDH2 rs67); GG type was defined as the T2DM high-risk group, compared with the low-risk AG and AA groups. Results: Glucose levels were similar in the high- and low-risk T2DM groups. The high-risk group for T2DM showed a significantly higher BMI (p < 0.005), insulin resistance in HOMA-IR (p < 0.05), and Insulin sensitivity index (p < 0.05); however, there were no significant differences in insulin resistance in the clamp test (p = 0.10). Alcohol consumption did not differ significantly between groups (p = 0.66). Non-diabetic participants also showed higher HOMA-IR insulin resistance in the high-risk group (p < 0.05), but insulin resistance levels in the glucose clamp tests (p = 0.56) and insulin secretion were not significant. Conclusion: The results suggest that ALDH2 is an important gene associated with insulin resistance and obesity in Japanese patients with type 2 diabetes.

Fasting hepatic insulin clearance reflects postprandial hepatic insulin clearance: a brief report.

BACKGROUND: Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. HIC is originally calculated by post-load insulin and C-peptide from the oral glucose tolerance test (OGTT). However, OGTT or meal tolerance tests are a burden for patients, and OGTT is not suitable for overt diabetes due to the risk of hyperglycemia. If we can calculate the HIC from the fasting state, it is preferable. We hypothesized that fasting HIC correlates with postprandial HIC in both participants with T2DM and without diabetes. We investigated whether fasting HIC correlates with postprandial HIC in overt T2DM and nondiabetes subjects (non-DM) evaluated by using glucose clamp and meal load. METHODS: We performed a meal tolerance test and hyperinsulinemic-euglycemic clamp in 70 subjects, 31 patients with T2DM and 39 non-DM subjects. We calculated the postprandial C-peptide AUC-to-insulin AUC ratio as the postprandial HIC and the fasting C-peptide-to-insulin ratio as the fasting HIC. We also calculated whole-body insulin clearance from the glucose clamp test. RESULTS: The fasting HIC significantly correlated with postprandial HIC in T2DM (r_S = 0.82, P < 0.001). Nondiabetes subjects also showed a significant correlation between fasting and postprandial HIC (r_S = 0.71, P < 0.001). Fasting HIC in T2DM was correlated with BMI, HbA1c, gamma-glutamyl transpeptidase, HOMA-IR, HOMA-beta, M/I, and whole-body insulin clearance. Fasting HIC in nondiabetes subjects was correlated with HOMA-IR and HOMA-beta. CONCLUSIONS: These results suggest that fasting HIC is strongly correlated with postprandial HIC in both overt T2DM and non-DM patients, as evaluated by the meal test and glucose clamp method. Fasting HIC could be a convenient marker of HIC.

Hyperthyroidism in Graves Disease Causes Sleep Disorders Related to Sympathetic Hypertonia.

CONTEXT: It is well known that Graves disease (GD) causes sleep disorders (SDs). However, the characteristics and associated factors of SD and its clinical course post hyperthyroidism normalization remain unclear. OBJECTIVE: To clarify the characteristics and associated factors of subjective SD and its clinical course after GD treatment. METHODS: From November 2017 to October 2020, we enrolled 72 participants (22 newly diagnosed with GD with untreated hyperthyroidism, 20 previously diagnosed with GD with normal thyroid function, and 30 normal controls) with no other underlying SD-related diseases. We compared the groups at enrollment and conducted prospective observations after 12 months of treatment on participants with newly diagnosed GD. Main outcome measures were differences and changes in the Pittsburgh Sleep Quality Index (PSQI) global and component sleep quality scores. RESULTS: PSQI global sleep quality scores (P = .036) and sleep disturbance scores (P = .011) were significantly different among the 3 groups, and were highest in the untreated hyperthyroidism group. Multiple regression analysis demonstrated that free thyroxine level, which was positively correlated with sympathetic tone (ST) as evaluated by pulse rate, and urinary total metanephrines was associated with poorer PSQI global sleep quality scores independently of other factors (P = .006). Prospective observation showed that PSQI global sleep quality scores (P = .018) and sleep disturbance scores (P = .011) significantly improved with thyroid function normalization and ST attenuation. CONCLUSION: Hyperthyroidism caused by GD augmented ST and exacerbated subjective SD. Normalization of hyperthyroidism caused by GD improved subjective SD.

Dipeptidyl peptidase 4 inhibitor improves insulin resistance in Japanese patients with type 2 diabetes: a single-arm study, a brief report.

BACKGROUND: Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). METHODS: We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. RESULTS: HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. CONCLUSIONS: Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion.

The sodium-glucose cotransporter 2 inhibitor ipragliflozin improves liver function and insulin resistance in Japanese patients with type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is a therapeutic approach for type 2 diabetes mellitus (T2DM). Some reports have shown that SGLT2i treatment improves insulin resistance; however, few studies have evaluated insulin resistance by the glucose clamp method. Hepatic insulin clearance (HIC) is a new pathophysiological mechanism of T2DM. The effect of SGLT2i treatment on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i treatment on insulin resistance, insulin secretion, incretin levels, body composition, and hepatic insulin clearance. We conducted a meal tolerance test (MTT) and a hyperinsulinemic-euglycemic clamp test in 9 T2DM patients. Ipragliflozin (50 mg/day) was administered, and the MTT and clamp test were performed after 4 months. We calculated HIC as the postprandial C-peptide AUC-to-insulin AUC ratio. We also measured GLP-1, GIP, and glucagon levels during the MTT. Body weight and HbA1c were decreased, although not significantly, after 4 months of treatment. Postprandial glucose, fasting insulin and postprandial insulin were significantly decreased. Insulin resistance with the glucose clamp was not changed, but the HOMA-IR and insulin sensitivity indices were significantly improved. Incretin and glucagon levels were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. The FIB-4 index and fatty liver index were significantly reduced. The HOMA-beta and insulinogenic indices were not changed, but the C-peptide index was significantly increased. Although the number of patients was small, these results suggested that SGLT2i treatment improved liver function, decreased hepatic insulin resistance, and increased hepatic insulin clearance, despite the small weight reduction.

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes.

INTRODUCTION: Pancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion in a genome-wide association study of intravenous glucose tolerance test. It was not associated with type 2 diabetes risk and insulin secretion in a genome-wide oral glucose tolerance test study. However, there have been no reports of overt type 2 diabetes and insulin resistance evaluation using a glucose clamp. We investigated PDX-1 polymorphism, insulin secretion, and insulin resistance in overt type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a meal tolerance test (MTT) and hyperinsulinemic-euglycemic clamping on 63 Japanese subjects, 30 with type 2 diabetes and 33 non-diabetic. We analyzed the rs1124607 PDX-1 gene polymorphism and defined A/C and C/C as the high-risk group and A/A as the low-risk group. RESULTS: HOMA-beta (homeostatic model assessment beta-cell function) was significantly lower in the high-risk group than in the low-risk group for all subjects (72.9±54.2% vs 107.0±63.5%, p<0.05). Glucose levels and glucose area under the curve (AUC) were not significantly different between both the risk groups. The insulin levels at 60 and 120 min and the insulin AUC after MTT were remarkably lower in the high-risk group than those in the low-risk group for all subjects (AUC 75.7±36.7 vs 112.7±59.5, p<0.05). High-risk subjects with type 2 diabetes had significantly lower insulin levels at 30 and 60 min and insulin AUC than low-risk subjects. Non-diabetic high-risk subjects depicted significantly lower insulin levels at 120 and 180 min. There were negligible differences in insulin resistance between the risk groups. CONCLUSIONS: These results suggest that the PDX-1 genetic polymorphism is crucial for insulin secretion in Japanese patients with type 2 diabetes.

Pemafibrate Ameliorates Liver Dysfunction and Fatty Liver in Patients with Non-Alcoholic Fatty Liver Disease with Hypertriglyceridemia: A Retrospective Study with the Outcome after a Mid-Term Follow-Up.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome. No standard pharmacological treatment has yet been established. We retrospectively evaluated the efficacy of pemafibrate in 16 NAFLD patients (11 men and 5 women; median age, 59 years; range, 27-81 years) who had taken pemafibrate for at least one year. They were all diagnosed with fatty liver according to imaging and clinical criteria. They were administered pemafibrate from October 2018 to October 2021 (median, 94 weeks; range, 56-157 weeks). Serum triglyceride was significantly decreased by -41.9% (342.3 ± 54.0 to 198.9 ± 20.4 mg/dL, p < 0.001). Aspartate aminotransferase (AST), alanine aminotransferase, and gamma-glutamyl transferase levels significantly decreased by -42.1% (49.6 ± 7.0 to 28.7 ± 3.4 U/L, p < 0.001), -57.1% (65.1 ± 10.8 to 27.9 ± 3.7 U/L, p < 0.001), and -43.2% (68.9 ± 10.9 to 39.1 ± 5.3 U/L, p < 0.05), respectively. The AST to platelet ratio (APRI) (0.8 ± 0.1 to 0.4 ± 0.1, p < 0.001) and fibrosis based on four factors (FIB-4) index (1.8 ± 0.3 to 1.4 ± 0.2, p < 0.05) also significantly decreased. Liver attenuation (39.1 ± 1.2 to 57.8 ± 2.7 HU, p = 0.028) and liver/spleen ratio (0.76 ± 0.04 to 1.18 ± 0.02, p = 0.012) significantly improved in three patients, as assessed by computed tomography. In conclusion, pemafibrate significantly improves serum triglyceride levels, liver function, FIB-4 index, APRI, and fatty liver in NAFLD patients with hypertriglyceridemia.

Free advanced glycation end product distribution in blood components and the effect of genetic polymorphisms.

One hypothesis regarding the cause of diabetic complications is that advanced glycation end products (AGEs) bind to the AGE receptor and induce changes in gene expression. However, what AGEs exist in vivo and how individual AGEs are produced and impact body metabolic process to cause diabetes complications are not understood. We developed a new precise method to measure AGEs using LC-MS/MS with a new column and measured 7 free AGEs, including N(6)-carboxymethyllysine (CML), N(6)-(1-carboxyethyl)-l-lysine (CEL) and N5-(5-hydro-5-methyl-4-imidazolon-2-yl)L-ornithine (MG-H1), in human blood components. Blood was obtained from 9 people, and free AGEs were measured in individual blood components with LC-MS/MS before and after a meal. Free CML and CEL were abundant in erythrocytes, with 92% of free CML and 85% of free CEL localized in erythrocytes. In contrast, 60% of free MG-H1 was distributed in the serum. After the meal, free serum MG-H1 increased, but CML and CEL did not. CML and CEL are mainly distributed in erythrocytes and were not affected by the meal, indicating that they are produced in vivo. However, the main source of MG-H1 is the meal. The effect of genetic polymorphisms on AGEs was also investigated. Low activity type aldehyde dehydrogenase 2 (ALDH2) increased the CML concentration in the blood. This is the first observation that shows that the metabolic process of CML and CEL is different from that of MG-H1 and the effect of ALDH2 SNPs on CML.

Effects of a Self-efficacy Theory-Based Training Program for Peers of Patients with Type 2 Diabetes.

BACKGROUND: Training peer leaders to deliver patient education is expected to be a low-cost approach to providing healthcare in urban-poor areas affected by a shortage of healthcare professionals. The purpose of this study was to examine the effects of a training program on the self-efficacy and knowledge of peer leaders with type 2 diabetes. METHODS: A single-group longitudinal survey with baseline, intervention, and follow-up periods was conducted at a diabetes clinic in a small municipality in Metro Manila, Philippines. The intervention, a self-efficacy theory-based training program for peer-leaders of diabetic patients conducted in August 2017, comprised hands-on learning, demonstrations, quizzes, role-playing, group sharing, physical exercise, and a buffet lunch. The primary outcome was participants' self-efficacy for management of their diabetes. Secondary outcomes were participants' knowledge of diabetes and levels of emotional distress, motivation, and confidence for guiding their peers, satisfaction with the training program, hemoglobin A1c, and quality of life. RESULTS: At 12 and 18 months after the intervention, participants' knowledge of diabetes was significantly increased compared with baseline (both P < 0.05). At earlier time points, an increasing, but not significant, trend was observed. The change in knowledge of diabetes from baseline to 18 months after intervention tended to be positively correlated with the change in self-efficacy (r = 0.594, P = 0.054). No significant differences were observed for any of the other outcomes, although the descriptive statistics showed an increasing trend for all of the outcomes except motivation. CONCLUSION: The training program significantly improved participants' knowledge of diabetes at 12 and 18 months after the training programs compared with baseline. A positive correlation between the changes in the levels of knowledge and self-efficacy suggested that the observed improvement of self-efficacy was facilitated by the improvement of knowledge of diabetes.

Hepatic insulin clearance is increased in patients with high HbA1c type 2 diabetes: a preliminary report.

INTRODUCTION: Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins. RESEARCH DESIGN AND METHODS: We performed a meal tolerance test and the hyperinsulinemic-euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism. RESULTS: The HIC significantly correlated with glycated hemoglobin (HbA1c) (r_S=0.58, p<0.01). In patients with high HIC above the median of 6.5, the mean HbA1c was significantly higher compared with low HIC below the median. Homeostatic model assessment (HOMA)-beta (r_S=-0.77, p<0.01) and HOMA-IR (r_S=-0.66, p<0.005) were correlated with HIC. The M/I value in the clamp study was correlated with HIC. GLP-1-AUC and GIP-AUC were not correlated with HIC. Glucagon-AUC was negatively correlated with HIC, but there were no significant differences between the high and low HIC groups. Adiponectin was positively correlated with HIC. The ZnT8 gene polymorphism did not affect HIC. CONCLUSIONS: These results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.

A Randomized Placebo-controlled Trial of an Oral Preparation of High Molecular Weight Fucoidan in Patients with Type 2 Diabetes with Evaluation of Taste Sensitivity.

BACKGROUND: Fucoidan is derived from seaweed widely used in Japanese cuisine, but little is known about its influence on glucose metabolism. To obtain information about the physiological effects of fucoidan on glucose metabolism, the digestive system, and the gustatory system controlling taste sensation in patients with type 2 diabetes, we conducted a randomized, double-blind, placebo-controlled study. METHODS: Thirty patients with type 2 diabetes on diet therapy were recruited from an outpatient clinic (22 men and 8 women aged 59.10 ± 13.24 years, body mass index: 25.18 ± 3.88, hemoglobin A1c: 7.04 ± 1.24%). They were divided into 2 groups and underwent 2 interventions with a 4-week interval. One group received fucoidan for 12 weeks (a daily 60 mL test beverage containing 1,620 mg of fucoidan) and then placebo (60 mL) for the subsequent 12-week period, while the order was reversed in the other group. Evaluation was performed just before and after each intervention. Taste sensitivity was measured for 5 basic tastes by the filter paper disk method and food intake was evaluated with a validated diet questionnaire. RESULTS: No adverse events occurred during the study period. Despite no change of the diet, stool frequency increased during fucoidan intake (from 7.78 ± 4.64/week in Week 1 to 9.15 ± 5.03/week in Week 5, P < 0.001), and it increased more in lean subjects. In 11 subjects whose stool frequency exceeded the mean value, the thresholds for sweet, salty, bitter and umami tastes were significantly reduced (enhancement of sensitivity) after fucoidan intake. In 14 subjects with normal HOMA-IR (homeostatic model assessment of insulin resistance, < 2.5), hemoglobin A1c decreased after fucoidan intake (from 6.73 ± 1.00 to 6.59 ± 1.00%, P < 0.05), as did the fasting plasma level of GLP-1 (glucagon-like peptide-1, from 6.42 ± 3.52 to 4.93 ± 1.88 pmol/L, P < 0.05). CONCLUSION: Sustained fucoidan intake led to alterations of gastrointestinal function, including increased stool frequency and enhanced taste sensitivity, which could contribute to better control of diabetes.

Correction: Serum fatty acid-binding protein 4 (FABP4) concentration is associated with insulin resistance in peripheral tissues, A clinical study.

[This corrects the article DOI: 10.1371/journal.pone.0179737.].

Coenzyme Q10 suppresses apoptosis of mouse pancreatic ß-cell line MIN6.

BACKGROUND: In mitochondrial diabetes, apoptosis of ß-cells caused by mitochondrial stress plays an important role in impaired insulin secretion. Several studies have reported that coenzyme Q10 (CoQ10) has therapeutic effects on mitochondrial diabetes, but no reports have examined the fundamental effectiveness or mechanism of CoQ10 in mitochondrial diabetes. We previously reported in a Japanese article that CoQ10 has protective effects on pancreatic ß-cells against mitochondrial stress using mouse pancreatic ß-cell line MIN6 and staurosporine (STS). Here, we report that CoQ10 protects MIN6 cells against apoptosis caused by STS and describe the more detailed apoptotic cascade. METHODS: Apoptosis of MIN6 cells was induced by 0.5 µM STS treatment for specific periods with or without 30 µM CoQ10. The apoptosis cascade in MIN6 cells was then investigated using WST-8 assays, annexin-V staining, western blotting, and DNA degradation analysis. RESULTS: Sixteen hours of 0.5 µM STS treatment led to 47% cell viability, but pretreatment with 30 µM CoQ10 resulted in significantly higher viability of 76% (P < 0.01). CoQ10 also prevented translocation of phosphatidylserine from the inner leaflet to the outer leaflet of the cell membrane. CoQ10 prevented cytochrome c release from mitochondria and activation of caspase-3. CONCLUSION: We concluded that CoQ10 protects pancreatic ß-cells through anti-apoptotic effects against STS treatment.

Normal meal tolerance test is preferable to the glucagon stimulation test in patients with type 2 diabetes that are not in a hyperglycemic state: Comparison with the change of C-peptide immunoreactivity.

AIMS/INTRODUCTION: The aim of the present study was to evaluate the properties of the glucagon stimulation test (GST) and the normal meal tolerance test (NMTT) in patients with type 2 diabetes. MATERIALS AND METHODS: We enrolled 142 patients with type 2 diabetes, and carried out a GST and a NMTT. We carried out the NMTT using a calorie-controlled meal based on an intake of 30 kcal/kg ideal bodyweight/day. We calculated the change in C-peptide immunoreactivity (ΔCPR) by subtracting fasting CPR from the CPR 6 min after the 1-mg glucagon injection (GST) or 120 min after the meal (NMTT). RESULTS: Mean ΔCPR for the GST was 2.0 ng/mL, and for the NMTT was 3.1 ng/mL. A total of 104 patients had greater ΔCPR in the NMTT than the GST, and the mean ΔCPR was significantly greater in the NMTT than the GST (P < 0.05). To exclude any influence of antidiabetic drugs, we examined 42 individuals not taking antidiabetic agents, and found the mean ΔCPR was significantly greater in the NMTT than the GST (GST 2.4 ng/mL, NMTT 4.3 ng/mL; P < 0.05). To consider the influence of glucose toxicity, we carried out receiver operating characteristic analyses with fasting plasma glucose and glycated hemoglobin. The optimal cut-off levels predicting GST ΔCPR to be larger than NMTT ΔCPR were fasting plasma glucose 147 mg/dL and glycated hemoglobin 9.0% (fasting plasma glucose: sensitivity 0.64, specificity 0.76, area under the curve 0.73; glycated hemoglobin: sensitivity 0.56, specificity 0.71, area under the curve 0.66). CONCLUSIONS: The NMTT is a reliable insulin secretion test in patients with type 2 diabetes, except for those in a hyperglycemic state.