Adipose tissue complement factor B promotes adipocyte maturation.

OBJECTIVES: It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. METHODS: We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. RESULTS: Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. CONCLUSIONS: CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation.

Insulin Secretory Defect and Insulin Resistance in Isolated Impaired Fasting Glucose and Isolated Impaired Glucose Tolerance.

OBJECTIVE: To investigate the characteristics of isolated impaired glucose tolerance (IGT) and isolated impaired fasting glucose (IFG), we analyzed the factors responsible for elevation of 2-hour postchallenge plasma glucose (2 h PG) and fasting plasma glucose (FPG) levels. METHODS: We investigated the relationship between 2 h PG and FPG levels who underwent 75 g OGTT in 5620 Japanese subjects at initial examination for medical check-up. We compared clinical characteristics between isolated IGT and isolated IFG and analyzed the relationships of 2 h PG and FPG with clinical characteristics, the indices of insulin secretory capacity, and insulin sensitivity. RESULTS: In a comparison between isolated IGT and isolated IFG, insulinogenic index was lower in isolated IGT than that of isolated IFG (0.43 ± 0.34 versus 0.50 ± 0.47, resp.; p < 0.01). ISI composite was lower in isolated IFG than that of isolated IGT (6.87 ± 3.38 versus 7.98 ± 4.03, resp.; p < 0.0001). In isolated IGT group, insulinogenic index showed a significant correlation with 2 h PG (r = -0.245, p < 0.0001) and had the strongest correlation with 2 h PG (ß = -0.290). In isolated IFG group, ISI composite showed a significant correlation with FPG (r = -0.162, p < 0.0001) and had the strongest correlation with FPG (ß = -0.214). CONCLUSIONS: We have elucidated that decreased early-phase insulin secretion is the most important factor responsible for elevation of 2 h PG levels in isolated IGT subjects, and decreased insulin sensitivity is the most important factor responsible for elevation of FPG levels in isolated IFG subjects.

ß cell dysfunction versus insulin resistance in the pathogenesis of type 2 diabetes in East Asians.

Type 2 diabetes (T2DM) is one of the most serious global health problems and is mainly a result of the drastic increase in East Asia, which includes over a fourth of the global diabetes population. Lifestyle factors and ethnicity are two determinants in the etiology of T2DM, and lifestyle changes such as higher fat intake and less physical activity link readily to T2DM in East Asians. It is widely recognized that T2DM in East Asians is characterized primarily by ß cell dysfunction, which is evident immediately after ingestion of glucose or meal, and less adiposity compared to the disease in Caucasians. These pathophysiological differences have an important impact on therapeutic approaches. Here, we revisit the pathogenesis of T2DM in light of ß cell dysfunction versus insulin resistance in East Asians and discuss ethnic differences in the contributions of insulin secretion and insulin resistance, together with incretin secretin and action, to glucose intolerance.

Relationship and factors responsible for regulating fasting and post-challenge plasma glucose levels in the early stage development of type 2 diabetes mellitus.

AIMS/INTRODUCTION: Elevation of 2-h plasma glucose (2-h PG) levels keeps step with fasting plasma glucose (FPG) levels elevation, but some individuals show dominant elevation of 2-h PG and others FPG. We analyzed dependent and independent relationships between 2-h PG and FPG, and investigated the factors regulating 2-h PG and FPG. MATERIALS AND METHODS: In 1,657 Japanese participants who underwent a 75-g oral glucose tolerance test at the initial examination for a medical check-up, we carried out simple linear regression analysis between 2-h PG and FPG levels on the three patterns of independent variables. We divided the participants into two subgroups: the 2-h PG-side group and the FPG-side from the regression line, and examined the relationships between 2-h PG-FPG and factors responsible for elevation of plasma glucose levels. RESULTS: There was a significant positive correlation between 2-h PG and FPG levels. The regression line of both 2-h PG and FPG as independent variables was in accordance with the regression line of 2-h PG as an independent variable and FPG as a dependent variable. In 2-h PG-side group, age was the independent factor affecting 2-h PG in addition to insulinogenic index and insulin sensitivity index (ISI composite). In the FPG-side group, triglyceride was the independent factor affecting FPG in addition to insulinogenic index and ISI composite. CONCLUSIONS: Two-hour PG was an independent predictor of FPG. In addition to the importance of decreased insulin secretion and insulin sensitivity, age was the strong factor to elevate 2-h PG levels in the 2-h PG-side group and triglyceride was the strong factor to elevate FPG levels in the FPG-side group in the early stage of development of type 2 diabetes.

Eating disorder examination questionnaire (EDE-Q): norms for undergraduate Japanese women.

The aim of the present study was to provide normative data for the Eating Disorder Examination Questionnaire (EDE-Q) among undergraduate Japanese women and to compare these data to norms obtained from previous studies. Undergraduate Japanese women (n = 289), aged 18-24 years, were administered the EDE-Q. The mean global score in the present study was 1.55 (SD = 1.03). Japanese women reported significantly higher scores of shape concern and weight concern in spite of lower body mass index but a significantly lower score of restraint, compared with women in other normative studies. There were significant differences with respect to the occurrence of some specific eating disorder behaviours between Japanese women and women in the previous studies. Differences in normative data for the EDE-Q between young Japanese women and young women in the previous studies suggest that there may be certain cultural differences in eating disorder psychopathology.

Circulating TNF receptor 2 is closely associated with the kidney function in non-diabetic Japanese subjects.

AIM: Chronic kidney disease (CKD) is associated with cardiovascular events. Tumor necrosis factor (TNF) and/or its receptors have been postulated to be involved in renal pathophysiology. It is unclear whether an increased TNF system activity is present before the development of apparent CKD. METHODS: Four hundred and twenty non-diabetic Japanese subjects with an estimated GFR (eGFR) greater than 60 ml/min/1.73 m(2) were recruited for measurement of the HbA1c, insulin, TNF system activity (TNF-α, soluble TNF receptor 1 (sTNF-R1) and sTNF-R2) levels and various parameters, including the lipid, high-sensitivity C-reactive protein (hsCRP), high-molecular-weight (HMW) adiponectin and leptin levels. The subjects were stratified according to the eGFR: the G1 level (eGFR ≧90 ml/min/1.73 m(2)) and the G2 level (90 ＞eGFR ≧60 ml/min/1.73 m(2)). RESULTS: Whereas no significant differences were observed in gender, body mass index (BMI), blood pressure, insulin, TNF-α, hsCRP, HMW adiponectin or leptin between the two groups, the values for age, HbA1c, triglycerides, sTNF-R1 and sTNF-R2 were significantly higher in the subjects with a G2 level of eGFR than in those with a G1 level. In contrast, the HDL cholesterol levels were significantly lower in the subjects with a G2 level than in those with a G1 level. Linear negative correlations were also observed between eGFR and age, BMI, HbA1c, triglycerides, sTNF-R1 and sTNFR2, respectively. A multiple logistic regression analysis revealed that only sTNF-R2 was associated with the presence of a G2 level of eGFR (Odds ratio 1.092, 95% CI 1.013-1.177, P=0.021). CONCLUSIONS: The circulating sTNF-R2 level is closely associated with the kidney function in non-diabetic Japanese subjects.

Typical and atypical anorexia nervosa in a Japanese sample.

OBJECTIVE: We examined the existence of nonfat-phobic anorexia nervosa (NFP-AN) and fat-phobic AN, with no evidence of distortions related to body shape and weight (AN-NED), in a Japanese sample and studied eating disorder pathology and psychopathology in NFP-AN and AN-NED. METHOD: The study participants were 200 (52.2%) women with typical AN, 86 (22.5%) women with NFP-AN, and 97 (25.3%) women with AN-NED. Diagnosis of the three types of AN was made by structured clinical interviews. The Eating Attitudes Test (EAT) and the Eating Disorder Inventory (EDI) were administered to all the participants. RESULTS: There were significant differences among the three groups in terms of duration of illness, maximum and minimum BMIs and AN subtypes. There was no transition from the NFP-AN and AN-NED groups to the typical AN group during the 2- to 7-year follow-up period. There were significant differences among the three groups in scores of the EAT, the EDI total, and all the subscales of the EDI. DISCUSSION: Besides typical AN, there were two types of atypical AN in terms of fat phobia and body image disturbance in this Japanese sample. The findings of the current study suggest that there may be significant differences among the three groups in terms of eating disorder pathology and psychopathology.

The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD. METHODS: The study was designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach. RESULTS: DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-α stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid. CONCLUSIONS: Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.

Neutralization of leukotriene C4 and D4 activity by monoclonal and single-chain antibodies.

BACKGROUND: Cysteinyl leukotrienes (LTs) are key mediators in inflammation. To explore the structure of the antigen-recognition site of a monoclonal antibody against LTC4 (mAbLTC), we previously isolated full-length cDNAs for heavy and light chains of the antibody and prepared a single-chain antibody comprising variable regions of these two chains (scFvLTC). METHODS: We examined whether mAbLTC and scFvLTC neutralized the biological activities of LTC4 and LTD4 by competing their binding to their receptors. RESULTS: mAbLTC and scFvLTC inhibited their binding of LTC4 or LTD4 to CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R) overexpressed in Chinese hamster ovary cells. The induction by LTD4 of monocyte chemoattractant protein-1 and interleukin-8 mRNAs in human monocytic leukemia THP-1 cells expressing CysLT1R was dose-dependently suppressed not only by mAbLTC but also by scFvLTC. LTC4- and LTD4-induced aggregation of mouse platelets expressing CysLT2R was dose-dependently suppressed by either mAbLTC or scFvLTC. Administration of mAbLTC reduced pulmonary eosinophil infiltration and goblet cell hyperplasia observed in a murine model of asthma. Furthermore, mAbLTC bound to CysLT2R antagonists but not to CysLT1R antagonists. CONCLUSIONS: These results indicate that mAbLTC and scFvLTC neutralize the biological activities of LTs by competing their binding to CysLT1R and CysLT2R. Furthermore, the binding of cysteinyl LT receptor antagonists to mAbLTC suggests the structural resemblance of the LT-recognition site of the antibody to that of these receptors. GENERAL SIGNIFICANCE: mAbLTC can be used in the treatment of inflammatory diseases such as asthma.

Comparison of DSM-IV diagnostic criteria versus the Broad Categories for the Diagnosis of Eating Disorders scheme in a Japanese sample.

The purposes of this study were to compare DSM-IV diagnostic criteria and the Broad Categories for the Diagnosis of Eating Disorders (BCD-ED) scheme in terms of the number of cases of Eating Disorder Not Otherwise Specified (EDNOS) and to test which diagnostic tool better captures the variance of psychiatric symptoms in a Japanese sample. One thousand and twenty-nine women with an eating disorder (ED) participated in this study. Assessment methods included structured clinical interviews and administration of the Eating Attitudes Test and the Eating Disorder Inventory. The BCD-ED scheme dramatically decreased the proportion of DSM-IV EDNOS from 45.1% to 1.5%. However, the categorization of patients with the BCD-ED scheme was less able to capture the variance in psychopathology scales than the DSM-IV, suggesting that the BCD-ED scheme may differentiate ED groups less effectively than the DSM-IV. These results suggest that the BCD-ED scheme may have the potential to eliminate the use of DSM-IV EDNOS, but it may have problems capturing the variance of psychiatric symptoms.

Circulating TNF receptor 2 is associated with the development of chronic kidney disease in non-obese Japanese patients with type 2 diabetes.

AIMS: Chronic low-grade inflammation and/or obesity are suggested to induce chronic kidney disease (CKD) in patients with type 2 diabetes. This cross-sectional study was performed to investigate the relationship between inflammatory biomarkers and CKD in non-obese patients with type 2 diabetes. METHODS: 106 non-obese Japanese patients with type 2 diabetes were recruited for the measurement of GFR, TNF, HMW adiponectin, leptin, hsCRP and some variables including urinary albumin. BMI, serum creatinine, and urinary albumin levels were 22.2 ± 0.2 kg/m(2) (17.1-24.9 kg/m(2)), 0.76 ± 0.02 mg/dl (0.39-1.38 mg/dl), 40.4 ± 4.3mg/gCr (1.6-195.0mg/gCr), respectively. They were stratified into two groups based on the value of eGFR: low eGFR (eGFR<60 ml/min/1.73 m(2)) and normal eGFR (eGFR>60 ml/min/1.73 m(2)). Logistic regression analysis was used for statistical analysis. RESULTS: Whereas univariate logistic regression analysis showed that gender, diabetes duration, triglyceride, HDL cholesterol, uric acid, urinary albumin, and soluble TNF receptors (sTNF-R1, sTNF-R2) are associated with the development of stage 3 CKD, multivariate logistic regression analysis revealed that sTNF-R2 (Odds ratio 1.003, 95% confidence interval 1.000 to 1.005, P=0.030) showed significant associations with the development of stage 3 CKD. CONCLUSIONS: Circulating TNF receptor 2 is an independent risk factor for CKD in non-obese Japanese patients with type 2 diabetes.

Comparison of DSM-IV versus proposed DSM-5 diagnostic criteria for eating disorders in a Japanese sample.

OBJECTIVE: The purpose of this study was to compare the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) and the proposed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria in terms of the number of cases of eating disorder not otherwise specified (EDNOS) and to see which diagnostic system can effectively capture variance in psychiatric symptoms in a Japanese sample. METHOD: One thousand and twenty-nine women with an eating disorder (ED) participated in this study. Assessment methods included structured clinical interviews and administration of the Eating Attitudes Test and the Eating Disorder Inventory. RESULTS: Relaxing the diagnostic criteria for anorexia nervosa and bulimia nervosa and recognizing binge ED decreased the proportion of EDNOS (from 45.1% to 26.1%). The DSM-5 categorization of patients was better able to capture variance in psychopathology scales. CONCLUSIONS: The proposed revisions to EDs in the DSM-5 partially reduced reliance on EDNOS. The DSM-5 may differentiate ED groups more effectively than the DSM-IV.

Smoking and adipose tissue inflammation suppress leptin expression in Japanese obese males: potential mechanism of resistance to weight loss among Japanese obese smokers.

BACKGROUND: The effect of smoking on leptin regulation is controversial. Smoking may induce low-grade inflammation. Recent series of studies indicated the critical role of macrophage migration in the establishment of adipose tissue inflammation. In this study, we aimed to see the effects of smoking and inflammation on leptin regulation both at cellular and epidemiological levels. METHODS: We compared the concentration of inflammatory markers and serum leptin levels among Japanese male subjects. Additionally, leptin and intercellular adhesion molecule (ICAM) -1 gene expression was assessed in adipocytes co-cultured with or without macrophages in the presence or absence of nicotine and/or lipopolysaccharide (LPS). RESULTS: In subjects with BMI below 25 kg/m2, both WBC counts and soluble-ICAM-1 levels are significantly higher in smokers than in non-smokers. However, leptin concentration did not differ according to smoking status. However, in subjects with BMI over 25 kg/m2, smokers exhibited significantly lower serum leptin level as well as higher WBC counts and s-ICAM-1 concentration as compared with non-smokers. Leptin gene expression was markedly suppressed in adipocytes co-cultured with macrophages than in adipocyte culture alone. Furthermore, nicotine further suppressed leptin gene expression. ICAM-1 gene expression was markedly up-regulated in adipocytes co-cultured with macrophages when stimulated with LPS. CONCLUSIONS: Adipose tissue inflammation appears to down-regulate leptin expression in adipose tissues. Nicotine further suppresses leptin expression. Thus, both smoking and inflammation may diminish leptin effect in obese subjects. Therefore, obese, but not normal weight, smokers might be more resistant to weight loss than non-smokers.

Insulin secretion and computed tomography values of the pancreas in the early stage of the development of diabetes.

UNLABELLED: Aims/Introduction: The computed tomography (CT) value of the pancreas was examined across the range of glucose tolerance, and the relationships between pancreatic CT values and factors responsible for glucose intolerance were analyzed. MATERIALS AND METHODS: A total of 167 health-check examinees were classified into normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) according to 75 g oral glucose tolerance test (OGTT). Pancreatic and hepatic CT values were estimated at decreasing stages of glucose tolerance. The association of CT values of the pancreas and the indices of glucose tolerance were analyzed. RESULTS: Insulinogenic index (II) was decreased from NGT through IGT to DM. Mean pancreatic CT value was decreased significantly from NGT through IGT to DM. Mean area under the curves of glucose (AUC-G) was significantly associated with II and insulin sensitivity index (ISI) composite in univariate analysis. In multiple regression analysis, II was most strongly inversely correlated with mean AUC-G, suggesting that II is the strongest determinant of glucose tolerance in Japanese. In addition, II was significantly associated with mean pancreatic CT value in univariate analysis. In multiple regression analysis, mean pancreatic CT value was strongly correlated with II. CONCLUSIONS: Pancreatic CT values were significantly decreased from NGT through IGT to DM. II was the strongest determinant of glucose tolerance, and was significantly influenced by pancreatic CT values. Thus, pancreatic fat deposition might impair insulin secretion in the early stage of development of type 2 diabetes, before overt deterioration of glucose tolerance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00212.x, 2012).

Insulin secretory capacity and insulin sensitivity in impaired fasting glucose in Japanese.

UNLABELLED: Aims/Introduction: Impaired fasting glucose (IFG) increases the risk of developing diabetes mellitus (DM). This study was carried out to characterize Japanese patients who have fasting glucose levels (FPG) between 100 and 109 mg/dL (IFG100-109). MATERIALS AND METHODS: A total of 1383 Japanese participants were examined by oral glucose tolerance test. We compared insulin secretory capacity (insulinogenic index) and insulin sensitivity (ISI composite) of IFG100-109/normal glucose tolerance (NGT; 100 ≤ FPG < 110 mg/dL and 2-h postchallenge glucose level (2-hPG) < 140 mg/dL) with NGT (100 mg/dL < FPG and 2-hPG < 140 mg/dL) and IFG110-125/NGT (110 ≤ FPG < 126 mg/dL and 2-hPG < 140 mg/dL). In addition, IFG100-109 patients were analyzed in three subgroups according to glucose intolerance by 2-hPG. RESULTS: Of the three categories of IFG100-109, IFG100-109/DM had the lowest insulinogenic index despite an ISI composite showing only a small decline from IFG100-109/NGT through IFG100-109/IGT (100 ≤ FPG < 110 mg/dL and 140 ≤ 2-hPG < 200 mg/dL) to IFG100-109/DM (100 ≤ FPG < 110 mg/dL and 200 mg/dL < 2-hPG). By multiple regression analysis, the insulinogenic index showed a significant relationship with 2-h PG levels. Both insulinogenic index and ISI composite were decreased significantly from NGT through IFG100-109/NGT to IFG110-125/NGT. CONCLUSIONS: Although impaired early-phase insulin secretion plays the more important role in the elevation of postchallenge glucose in IFG100-109 patients, both impaired early-phase insulin secretion and decreased insulin sensitivity are involved in the deterioration of FPG in Japanese. In addition, insulin secretory defect and decreased insulin sensitivity already have begun in patients with IFG100-109. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00201.x, 2012).

Smoking, white blood cell counts, and TNF system activity in Japanese male subjects with normal glucose tolerance.

BACKGROUND: Cigarette smokers have increased white blood cell (WBC) counts and the activation of tumor necrosis factor (TNF). The effect of smoking on WBC counts and TNF system activity, however, has not been separately investigated yet. SUBJECTS AND METHODS: One hundred and forty-two Japanese male subjects with normal glucose tolerance were recruited. They were stratified into two groups based on the questionnaire for smoking: one with current smokers (n = 48) and the other with current non-smokers (n = 94). Whereas no significant differences were observed in age, BMI, high molecular weight (HMW) adiponectin, and TNF-α between the two groups, current smokers had significantly higher soluble TNF receptor 1 (sTNF-R1) (1203 ± 30 vs. 1116 ± 21 pg/ml, p = 0.010) and increased WBC counts (7165 ± 242 vs. 5590 ± 163/µl, p < 0.001) and lower HDL cholesterol (55 ± 2 vs. 60 ± 1 mg/dl, p = 0.031) as compared to current non-smokers. Next, we classified 48 current smokers into two subpopulations: one with heavy smoking (Brinkman index ≥ 600) and the other with light smoking (Brinkman index < 600). RESULTS: Whereas no significant difference was observed in age, BMI, HMW adiponectin, WBC counts and TNF-α, sTNF-R1 and sTNF-R2 were significantly higher in heavy smoking group (1307 ± 44 vs. 1099 ± 30 pg/ml, p < 0.001; 2166 ± 86 vs. 827 ± 62 pg/ml, p = 0.005) than in light smoking group, whose sTNF-R1 and sTNF-R2 were similar to non-smokers (sTNF-R1: 1116 ± 15 pg/ml, p = 0.718, sTNF-R2; 1901 ± 32 pg/ml, p = 0.437). In contrast, WBC counts were significantly increased in heavy (7500 ± 324/µl, p < 0.001) or light (6829 ± 352/µl, p = 0.001) smoking group as compared to non-smokers (5590 ± 178/µl). There was no significant difference in WBC counts between heavy and light smoking group (p = 0.158). CONCLUSION: We can hypothesize that light smoking is associated with an increase in WBC counts, while heavy smoking is responsible for TNF activation in Japanese male subjects with normal glucose tolerance.

GIP and GLP-1, the two incretin hormones: Similarities and differences.

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic ß cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic ß cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP-1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP-1 together promote ß cell proliferation and inhibit apoptosis, thereby expanding pancreatic ß cell mass, while GIP enhances postprandial glucagon response and GLP-1 suppresses it. In adipose tissues, GIP but not GLP-1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP-1 inhibits bone absorption. In the brain, both GIP and GLP-1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP-1 and their insulinotropic effects on ß cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic ß cells, and their non-insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00022.x, 2010).

Factors responsible for elevation of 1-h postchallenge plasma glucose levels in Japanese men.

The 1-h postchallenge plasma glucose (1-h PG) level is considered to be a good index of the development of glucose intolerance and type 2 diabetes as well as of diabetic complications. In some cases, in Japanese, 1-h PG is elevated despite normal fasting glucose during oral glucose tolerance test (OGTT), but the factors responsible remain unclear. In the present study, subjects with normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), and isolated impaired glucose tolerance (IGT) were divided into subgroups at 1-h PG of 10.0mM, and the four indices of insulin secretion and insulin sensitivity were compared. In all three categories, the insulinogenic index in subjects with elevated 1-h PG was remarkably lower than in those without elevated 1-h PG. In addition, the insulinogenic index was the strongest factor in elevated 1-h PG according to the multiple regression analysis. Interestingly, one third of the NGT subjects enrolled in this study had elevated 1-h PG. These subjects showed significantly elevated area under the curve of glucose (G-AUC) compared to NGT subjects without 1-h PG elevation. Thus, elevated 1-h PG in Japanese subjects indicates mildly impaired glucose tolerance due to decreased early-phase insulin secretion.

Short-term intensive glycemic control improves vibratory sensation in type 2 diabetes.

Strict long-term glycemic control has been reported to prevent or improve diabetic peripheral neuropathy, but the effects of short-term glycemic control have not been clarified in patients with type 2 diabetes. To investigate reversibility of impaired vibratory sensation by short-term glycemic control, we used the TM31 liminometer and C64 tuning fork methods to measure peripheral neuropathy. Thirty-one type 2 diabetes patients with poor glycemic control (HbA1c: 10.8+/-0.4%, mean+/-S.E.M., range from 7.9% to 16.2%) were administered strict glycemic control. Vibratory sensation before and after short-term glycemic control was evaluated, and the metabolic profile including plasma glucose, HbA1c, total cholesterol, HDL cholesterol, triglyceride, and free fatty acid (FFA) was measured. After 20.0+/-2.1 days of strict glycemic control, vibratory sensation improved significantly in both upper and lower extremities, assessed by TM31 liminometer and C64 tuning fork. Along with the improved glycemic control, lipid metabolism (total cholesterol, triglyceride and FFA) was significantly improved. Thus, short-term intensive glycemic control can improve vibratory sensation, metabolic changes in glucose and lipid metabolism being the factors responsible for improved of peripheral nerve function.

Effect of corosolic acid on gluconeogenesis in rat liver.

Corosolic acid (CRA), an active component of Banaba leaves (Lagerstroemia speciosa L.), decreases blood glucose in diabetic animals and humans. In this study, we investigated the mechanism of action of CRA on gluconeogenesis in rat liver. CRA (20-100 microM) dose-dependently decreased gluconeogenesis in perfused liver and in isolated hepatocytes. Fructose-2,6-bisphosphate (F-2,6-BP), a gluconeogenic intermediate, plays a critical role in hepatic glucose output by regulating gluconeogenesis and glycolysis in the liver. CRA increased the production of F-2,6-BP along with a decrease in intracellular levels of cAMP both in the presence and in the absence of forskolin in isolated hepatocytes. While a cAMP-dependent protein kinase (PKA) inhibitor inhibited hepatic gluconeogenesis, the drug did not intensify the inhibitory effect of CRA on hepatic gluconeogenesis in isolated hepatocytes. These results indicate that CRA inhibits gluconeogenesis by increasing the production of F-2,6-BP by lowering the cAMP level and inhibiting PKA activity in isolated hepatocytes. Furthermore, CRA increased glucokinase activity in isolated hepatocytes without affecting glucose-6-phosphatase activity, suggesting the promotion of glycolysis. These effects on hepatic glucose metabolism may underlie the various anti-diabetic actions of CRA.