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Aims/Introduction: The FreeStyle Libre (FSL) intermittently scanned continuous glucose monitoring (isCGM) system continually measures interstitial glucose levels and provides the data to users in numerical and graphical formats that guide users in their daily diabetes self‐management. Although numerous studies have demonstrated the glycemic benefits of FSL in pediatric and adult populations, few studies have characterized FSL use specifically by Japanese adults with type 1 or 2 diabetes. We utilized established CGM metrics to assess glycemic control in a large cohort of Japanese adults with type 1 and 2 diabetes. Materials and Methods: A total of 3,463 anonymized FSL users provided categorization into one of four therapy groups of interest: type 1 diabetes (n = 1,768), type 2 diabetes‐multiple daily injections (MDI) (n = 612), type 2 diabetes‐basal (BOI) (n = 343), and type 2 diabetes‐non‐insulin (NIT) (n = 740). Established CGM metrics were used to assess glycemic control. Results: All study groups showed relatively good glycemic control. Type 1 diabetes users showed the highest glucose variability (SD, 61 mg/dL; and %CV, 40%), above the established target level (%CV ≤ 36%). type 2 diabetes‐MDI and type 2 diabetes‐BOI users had similar levels of glucose variability (both within target). Type 2 diabetes‐NIT users had the highest mean % time in range (TIR) (84.3%) and largest percentage of users that met the target of %TIR > 70% (87.4%). In contrast, type 1 diabetes users had the lowest mean %TIR (62.6%) and the lowest percentage meeting the established %TIR target (30.5%). Conclusions: By utilizing CGM devices in daily diabetes care, both healthcare professionals and patients can monitor glycemic excursions and gain insights into their historical glucose control patterns. [ABSTRACT FROM AUTHOR]

Context Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. Objective We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Methods Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Results Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Conclusion Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs. [ABSTRACT FROM AUTHOR]

Introduction: Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. Methods: The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. Results: By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70–180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. Conclusion: Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. Trial Registration: jRCTs2051190029 and NCT04018365. [ABSTRACT FROM AUTHOR]

Aims: Whereas homeostasis model assessment of insulin resistance (HOMA‐IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes. Methods: This retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic‐euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA‐IR were determined as measures of insulin resistance. The ratio of the peak early‐ to late‐diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively. Results: The ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA‐IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045). Conclusions: Insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF). Methods: We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS < 18% and RV free-wall strain < 20%, respectively. Results: RV free-wall strain in T2DM patients was significantly lower than that in normal controls (19.3% ± 4.8% vs. 24.4% ± 5.1%; P < 0.0001). RV free-wall strain in T2DM patients and LV longitudinal dysfunction was similar compared to that in T2DM patients without (19.0 ± 4.5% vs. 19.6 ± 5.0%, P = 0.40). Furthermore, multivariate logistic regression analyses showed that GLS was independently associated with RV systolic dysfunction as well as mitral inflow E and mitral e′ annular velocities ratio (odds ratio, 1.16; 95% confidence interval: 1.03–1.31; P < 0.05). Sequential logistic models evaluating the association of RV systolic dysfunction in T2DM patients showed an improvement in clinical variables (χ2 = 6.2) with the addition of conventional echocardiographic parameters (χ2 = 13.4, P < 0.001) and a further improvement with the addition of GLS (χ2 = 20.8, P < 0.001). Conclusion: RV subclinical systolic dysfunction was observed in T2DM patients with preserved LVEF and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the cardiorenal benefits of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians. Methods: In this exploratory analysis of the EMPA‐REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all‐cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category. Results: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all‐cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were.6772,.3087 and.6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher. Conclusion: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI. [ABSTRACT FROM AUTHOR]

Background: Left ventricular (LV) longitudinal myocardial dysfunction is considered a marker of preclinical LV dysfunction in patients with type 2 diabetes mellitus (T2DM). High heart rate (HR) is associated with cardiovascular outcomes, but the effect of HR on LV longitudinal myocardial function in T2DM patients is uncertain. Methods: We studied 192 T2DM patients with preserved LV ejection fraction (LVEF), and 81 age-, sex-, and LVEF-matched healthy volunteers. HR was measured as the average HR during echocardiography, and high HR was defined as resting HR ≥ 70 beats/minute. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The predefined cutoff for subclinical LV dysfunction was set at GLS < 18%. Results: GLS in T2DM patients with high HR was significantly lower than that in T2DM patients with low HR (16.3% ± 4.2% vs. 17.8% ± 2.8%; P = 0.03), whereas GLS in normal subjects with high and low HR was similar (20.3 ± 1.7% vs. 20.3 ± 2.0%; P = 0.99). Multivariable logistic regression analysis showed that high HR (odds ratio: 1.04; 95% confidence interval: 1.01–1.07; P = 0.01) was independently associated with GLS < 18% in T2DM patients as well as HbA1c, T2DM duration, LVEF, body mass index, and mitral inflow E and mitral e' annular velocity ratio. One sequential logistic model evaluating the associations between GLS < 18% and clinical variables in T2DM patients showed an improvement with the addition of LVEF and E/e' (P < 0.001) and a further improvement with the addition of high HR (P < 0.001). Conclusion: Compared with normal subjects, resting HR was associated with LV longitudinal myocardial function in asymptomatic T2DM patients with preserved LVEF. Our findings provide new insights on the management of T2DM patients. [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationships between various clinical variables and the metformin‐induced accumulation of fluorodeoxyglucose (FDG) in the intestine, with distinction between the intestinal wall and lumen, in individuals with type 2 diabetes who were receiving metformin treatment and underwent 18F‐labelled FDG ([18F]FDG) positron emission tomography (PET)‐MRI. Materials and Methods: We evaluated intestinal accumulation of [18F]FDG with both subjective (a five‐point visual scale determined by two experienced radiologists) and objective analyses (measurement of the maximum standardized uptake value [SUVmax]) in 26 individuals with type 2 diabetes who were receiving metformin and underwent [18F]FDG PET‐MRI. [18F]FDG accumulation within the intestinal wall was discriminated from that in the lumen on the basis of SUVmax. Results: SUVmax for the large intestine was correlated with blood glucose level (BG) and metformin dose, but not with age, body mass index, HbA1c level or estimated glomerular filtration rate (eGFR). SUVmax for the small intestine was not correlated with any of these variables. Visual scale analysis yielded essentially similar results. Metformin dose and eGFR were correlated with SUVmax for the wall and lumen of the large intestine, whereas BG was correlated with that for the wall. Multivariable analysis identified metformin dose as an explanatory factor for SUVmax in the wall and lumen of the large intestine after adjustment for potential confounders including BG and eGFR. Conclusions: Metformin dose is an independent determinant of [18F]FDG accumulation in the wall and lumen of the large intestine in individuals treated with this drug. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We investigated the effect of FreeStyle LibreTM on glycemic control in Japanese type 2 diabetes patients treated with basal–bolus insulin therapy. Materials and Methods: This prospective, 90‐day single‐arm study enrolled 94 adults with type 2 diabetes treated with insulin. A 14‐day masked baseline phase was followed by an 11‐week treatment phase during which participants used the device to monitor glucose levels. The primary end‐point was time spent in hypoglycemia (<70 mg/dL) for baseline versus study end (days 76–90). Secondary end‐points included other measures of glycemic control, along with patient satisfaction using the Japanese Diabetes Treatment and Satisfaction Questionnaire. Results: Time spent in hypoglycemia was low at baseline (0.51 ± 0.93 h/day) and did not significantly decrease at study end (0.47 ± 0.63 h/day, P = 0.6354). Time in range, time in hyperglycemia and estimated A1c all improved versus baseline (by +1.7 ± 3.0 h/day, −1.6 ±.4 h/day and −0.4 ± 0.8%, respectively, P < 0.0001 in each). Finger stick tests fell from 2.9 ± 1.3 to 1.9 ± 1.4/day, and mean scanning frequency during the intervention phase was 11.3/day. The mean treatment satisfaction score increased by 11.8 ± 5.3 (P < 0.0001). Two severe hypoglycemia‐related adverse events were reported; one of which was possibly related to the device. Three participants reported mild device‐related skin trauma, site discomfort or subcutaneous bleeding. Conclusions: Use of FreeStyle Libre by Japanese type 2 patients diabetes treated with basal–bolus insulin therapy showed a low baseline of hypoglycemia, and enabled improved glycemic control and treatment satisfaction. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Metformin therapy has been associated with vitamin B12 (VB12) deficiency, but information regarding this adverse effect in Asian populations is limited. We have now examined the relationship between metformin use and VB12 status in individuals with type 2 diabetes mellitus in Japan. Materials and Methods: This cross‐sectional study was carried out with type 2 diabetes mellitus patients treated (Met group, n = 122) or not treated (control group, n = 63) with metformin. The primary end‐point was the difference in the serum concentration of homocysteine, a marker of VB12 activity, between the two groups. The serum concentrations of VB12, blood hemoglobin level and mean corpuscular volume were also compared between the groups. Subset analysis was carried out with individuals aged ≥70 years. The potential correlation between the daily dose or duration of metformin treatment and the other measured parameters was also examined. Results: The level of homocysteine, as well as the VB12 level, hemoglobin concentration and mean corpuscular volume, did not differ significantly between the control and treated with metformin groups. The level of homocysteine was positively and that of VB12 negatively correlated with the daily dose of metformin. Among elderly individuals, the hemoglobin level was significantly lower in the treated with metformin group than in the control group, although the mean corpuscular volume was similar in the two groups. Conclusions: The risk of VB12 deficiency during metformin treatment appears to be low in Japanese type 2 diabetes mellitus patients. However, high doses of metformin might result in a moderate decrease in the circulating VB12 level, as well as in anemia in elderly individuals. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Sulfonylurea‐related hypoglycemia increases the risk of cardiovascular sequela, such as cardiac arrhythmia. This study aimed to clarify the relationship between the level of glycated hemoglobin (HbA1c) and the duration of hypoglycemia in type 2 diabetes patients treated with sulfonylureas. Materials and Methods: Glucose levels in the enrolled patients (n = 300) were investigated with a professional continuous glucose monitoring device in the outpatient setting at six diabetes centers in Japan. Results: A total of 269 participants completed the study. The duration of hypoglycemia with glucose values of <54 mg/dL was significantly longer in patients with an HbA1c level of ≤6.4% than in those with an HbA1c level of ≥8.0%, and that of hypoglycemia with glucose values of <70 mg/dL was significantly longer in patients with an HbA1c level of ≤6.4%, 6.5–6.9% or 7.0–7.4% than in those with an HbA1c level of ≥8.0%. Patients with an HbA1c level of ≤6.4% were exposed to glucose values of <70 mg/dL for >10% of the time in daily life (6.8 ± 5.6 min/h). The duration of hypoglycemia with glucose values of <70 mg/dL was longer at night than during the daytime, and the nadir of glucose values occurred between 03.00 and 05.00 hours irrespective of HbA1c level. The duration of hypoglycemia was associated with the duration of diabetes and sulfonylurea dose. Conclusions: The duration of hypoglycemia was inversely correlated with HbA1c level and was longer during the night‐time than daytime in type 2 diabetes patients treated with sulfonylureas. [ABSTRACT FROM AUTHOR]

Highlights from the article: For type 1 diabetes patients with inadequate glycemic control, one treatment option is to increase the insulin dose (scenario 1), which should not give rise to a "metabolic imbalance". Although the results of clinical trials for ipragliflozin in type 1 diabetes are not yet publicly available, those for other SGLT2 inhibitors have shown that the drugs reduce glycated hemoglobin levels, body mass and the required insulin dose in patients with type 1 diabetes. Information regarding the reduction in insulin dose at the time of the events was not available, but the reduction in insulin dose at the end of the 18-week trial was greater in patients who took a high dose of the drug (300 mg) and developed DKA than in those who did not develop DKA. The serum level of ketone bodies was found to be greater in type 1 diabetes patients who reduced their insulin dose by >20% after the initiation of SGLT2 inhibitors than in those who reduced it by <=20%, suggesting that caution is warranted in patients who reduce their insulin dose by the larger amount[13].

Aims/Introduction: The preservation of pancreatic β‐cell mass is an essential factor in the onset and development of type 2 diabetes mellitus. Recently, sodium–glucose cotransporter 2 inhibitors have been launched as antihyperglycemic agents, and their organ‐protective effects are attracting attention. They are also reported to have favorable effects on the preservation of pancreatic β‐cell mass, but the appropriate timing for the administration of sodium–glucose cotransporter 2 inhibitors is obscure. Materials and Methods: In the present study, we administered a sodium–glucose cotransporter 2 inhibitor, dapagliflozin, to an animal model of type 2 diabetes mellitus, db/db mice, and investigated the adequate timing and duration for its administration. We also carried out microarray analysis using pancreatic islets from db/db mice. Results: We found that dapagliflozin preserved pancreatic β‐cell mass depending on the duration of administration and markedly improved blood glucose levels. If the duration was the same, the earlier administration of dapagliflozin was more effective in preserving pancreatic β‐cell mass, increasing serum insulin levels and improving blood glucose levels. From microarray analysis, we discovered that the expression of Agr2, Tff2 and Gkn3 was significantly upregulated after the early administration of dapagliflozin. This upregulated gene expression might provide a legacy effect for the preservation of pancreatic β‐cell mass. Conclusions: We expect that the early administration of dapagliflozin would provide a long‐lasting effect in preserving pancreatic β‐cell mass. [ABSTRACT FROM AUTHOR]

Objective Although serum insulin like growth factor type 1 (IGF-I) levels are negatively correlated with hemoglobin A1c (HbA1c) in patients with type 1 diabetes, this correlation is controversial in patients with type 2 diabetes mellitus (T2DM) because of the influence of multiple factors including insulin secretion and obesity. The aim of this study was to evaluate the influence of T2DM on serum growth hormone (GH) and IGF-I levels in Japanese patients, who exhibited relatively low BMI compared with white patients in the previous studies. Design We retrospectively analysed 315 consecutive Japanese hospitalized patients with T2DM. We analysed factors correlated with changes in serum IGF-I levels and those related to diabetes. Results The median HbA1c was 8.7% (7.4–10.2) and the median body mass index (BMI) was 26.2 kg/m 2 (23.1–29.7), which was relatively low compared with the previous studies. Overall, no correlations was found between serum GH or IGF-I levels and fasting plasma glucose (FPG) or HbA1c; however, when stratified by FPG and HbA1c levels, serum IGF-I levels were significantly lower in patients with FPG ≥ 200 mg/dL than in those with FPG < 200 mg/dL ( p = 0.039). In addition, serum IGF-I levels were significantly lower in patients with HbA1c ≥ 12% than in those with HbA1c < 12% ( p = 0.046). Multiple linear regression analysis revealed a positive correlation between fasting C-peptide levels and serum IGF-I levels ( p = 0.040), whereas no correlations was found for BMI, duration of T2DM, FPG levels, or HbA1c. Moreover, patients with improved HbA1c levels during the follow up period showed a significant increase in serum IGF-I levels. Conclusions Serum IGF-I levels were significantly decreased in Japanese patients with uncontrolled T2DM, and impaired insulin secretion may be a mechanism underlying this effect. When diagnosing acromegaly in patients with uncontrolled diabetes, these factors should be taken into account. [ABSTRACT FROM AUTHOR]

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein β (C/EBPβ) expression levels. The effect of C/EBPβ phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBPβ transgenic mice to investigate the relationship between C/EBPβ expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBPβ lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBPβ expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBPβ transgenic mice decreased C/EBPβ expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBPβ expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure. [ABSTRACT FROM AUTHOR]

OBJECTIVE--An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis. RESEARCH DESIGN AND METHODS--We investigated whether the transcription factor KLF15 has a role in the regulation of gluconeogenesis and whether KLF15 participates in the antidiabetes effect of metformin. RESULTS--Here we show that KLF15 regulates the expression of genes for gluconeogenic or amino acid-degrading enzymes in coordination with the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α. Liver-specific ablation of KLF15 in diabetic mice resulted in downregulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes and in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and downregulation of its mRNA. Metformin suppressed the expression of genes for gluconeogenic or amino acid-degrading enzymes in cultured hepatocytes, and these effects of metformin were attenuated by restoration of KLF15 expression. Administration of metformin to mice inhibited both the expression of KLF15 and glucose production in the liver, the latter effect also being attenuated by restoration of hepatic KLF15 expression. CONCLUSIONS--KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes. Diabetes 59:1608-1615, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The aim of this study was to assess the reliability and validity of an evaluation scale for self-management behavior related to physical activity of type 2 diabetic patients (ES-SMBPA-2D). RESEARCH DESIGN AND METHODS -- Outpatients with type 2 diabetes (n = 146) completed a self-administered questionnaire supported by a semistructured interview based on a literature review. The content, factor, and concurrent validity and internal consistency and reproducibility of the scale were analyzed. Pearson's correlation coefficients for the ES-SMBPA-2D and International Physical Activity Questionnaire (IPAQ) subscale scores were calculated to evaluate the concurrent validity. RESULTS -- The ES-SMBPA-2D was divided into two parts, the first dealing with self-management behavior to enhance physical activity in daily life and the second with behavior to maintain the level of physical activity. Factor analysis showed that the first part comprised four factors and the second five. The ES-SMBPA-2D correlated with the IPAQ subscales. Cronbach's α coefficient was between 0.56 and 0.90, and the intraclass test-retest correlation coefficient of the subscales was between 0.60 and 0.88. CONCLUSIONS -- The ES-SMBPA-2D is reasonably reliable and valid and is expected to prove useful for the assessment of patients' self-management behavior and for individualized instruction. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a major cause of heart failure (HF) with preserved ejection fraction (HFpEF), usually presenting as left ventricular (LV) diastolic dysfunction. Thus, LV diastolic function should be considered a crucial marker of a preclinical form of DM-related cardiac dysfunction. However, the impact of glycemic variability (GV) on LV diastolic function in such patients remains unclear. Methods: We studied 100 asymptomatic T2DM patients with preserved LV ejection fraction (LVEF) without coronary artery disease (age: 60 ± 14 years, female: 45%). GV was evaluated as standard deviation of blood glucose level using continuous glucose monitoring system for at least 72 consecutive hours. LV diastolic function was defined as mitral inflow E and mitral e' annular velocities (E/e'), and > 14 was determined as abnormal. Results: E/e' in patients with high GV (≥ 35.9 mg/dL) was significantly higher than that in patients with low GV (11.3 ± 3.9 vs. 9.8 ± 2.8, p = 0.03) despite similar age, gender-distribution, and hemoglobin A1c (HbA1c). Multivariate logistic regression analysis showed that GV ≥ 35.9 mg/dL (odds ratio: 3.67; 95% confidence interval: 1.02–13.22; p < 0.05) was an independently associated factor, as was age, of E/e' > 14. In sequential logistic models for the associations of LV diastolic dysfunction, one model based on clinical variables including age, gender and hypertension was not improved by addition of HbA1c (p = 0.67) but was improved by addition of high GV (p = 0.04). Conclusion: Since HFpEF is a syndrome caused by diverse agents, reducing GV may represent a potential new therapeutic strategy for the prevention of the development of HFpEF in T2DM patients. [ABSTRACT FROM AUTHOR]

Insulin plays a central role in glucose homeostasis, and impairment of insulin action causes glucose intolerance and leads to type 2 diabetes mellitus (T2DM). A decrease in the transient peak and sustained increase of circulating insulin following an infusion of glucose accompany T2DM pathogenesis. However, the mechanism underlying this abnormal temporal pattern of circulating insulin concentration remains unknown. Here we show that changes in opposite direction of hepatic and peripheral insulin clearance characterize this abnormal temporal pattern of circulating insulin concentration observed in T2DM. We developed a mathematical model using a hyperglycemic and hyperinsulinemic-euglycemic clamp in 111 subjects, including healthy normoglycemic and diabetic subjects. The hepatic and peripheral insulin clearance significantly increase and decrease, respectively, from healthy to borderline type and T2DM. The increased hepatic insulin clearance reduces the amplitude of circulating insulin concentration, whereas the decreased peripheral insulin clearance changes the temporal patterns of circulating insulin concentration from transient to sustained. These results provide further insight into the pathogenesis of T2DM, and thus may contribute to develop better treatment of this condition. Glucose homeostasis: roles of insulin clearance Type 2 diabetes mellitus (T2DM) is one of the fastest growing public health problems, characterized by chronic hyperglycemia with the failure of glucose homeostasis. Evaluating alteration in biological functions regulating circulating glucose concentration is complicated due to the mutual relation between circulating glucose and insulin. A team led by Wataru Ogawa at Kobe University designed clinical experiments for breaking such feedback relations, and a team led by Shinya Kuroda at University of Tokyo developed mathematical models for specifically quantifying the functions from the clinical data. The estimated model parameters revealed the significant increase in hepatic and decrease in peripheral insulin clearance, which occur before and after insulin delivery into systemic circulation, respectively, from healthy to T2DM subjects. Model analysis suggested these insulin clearances centrally regulate the dynamics of circulating insulin concentration in the glucose-insulin regulatory system. [ABSTRACT FROM AUTHOR]

Eif2ak4 , a susceptibility gene for type 2 diabetes, encodes GCN2, a molecule activated by amino acid deficiency. Mutations or deletions in GCN2 in pancreatic β-cells increase mTORC1 activity by decreasing Sestrin2 expression in a TSC2-independent manner. In this study, we searched for molecules downstream of GCN2 that suppress mTORC1 activity in a TSC2-dependent manner. To do so, we used a pull-down assay to identify molecules that competitively inhibit the binding of the T1462 phosphorylation site of TSC2 to 14-3-3. l -asparaginase was identified. Although l -asparaginase is frequently used as an anticancer drug for acute lymphoblastic leukemia, little is known about endogenous l -asparaginase. l -Asparaginase, which is expressed downstream of GCN2, was found to bind 14-3-3 and thereby to inhibit its binding to the T1462 phosphorylation site of TSC2 and contribute to TSC2 activation and mTORC1 inactivation upon TSC2 dephosphorylation. Further investigation of the regulation of mTORC1 activity in pancreatic β-cells by l -asparaginase should help to elucidate the mechanism of diabetes and insulin secretion failure during anticancer drug use. • GCN2, an amino acid deficiency sensor, is a type 2 diabetes susceptibility gene. • Loss of GCN2 in pancreatic beta cells induces mTORC1 activation via TSC2 phosphorylation. • TSC2 binding to 14-3-3 maintains inactivation by phosphorylation and induces increased mTORC1 activity. • Proteomic analysis revealed that l -asparaginase expression is induced by GCN2 under amino acid deficiency, which binds to 14-3-3. • Knockdown of l -asparaginase expression enhances mTORC1 activity in pancreatic beta cells. [ABSTRACT FROM AUTHOR]

Decreased pancreatic β-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic β-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic β-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic β-cell protection. • Dapagliflozin significantly reduced blood glucose in model mice with diabetes. • DNA methylation analysis was performed on islets from dapagliflozin-treated mice. • Integrated analysis of gene expression and DNA methylation identified Cdh24 and Cftr. • Cdh24 was increased in the pancreatic beta cells of dapagliflozin-treated mice. • Cftr was significantly increased in insulin/glucagon-negative endocrine cells. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes often exhibit impairments in both glucose-induced insulin secretion (GIIS) and incretin-induced insulin secretion (IIIS). These phenotypes are associated with altered glucose metabolism in pancreatic β-cells, although the molecular mechanisms remain unclear. Here, we used MIN6-K8 pancreatic β-cell lines as a model to examine the effect of O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation), a glucose-induced protein posttranslational modification, on insulin secretion. O-GlcNAcylation was enhanced in high-glucose-treated MIN6-K8 cells, and high levels of O-GlcNAcylation attenuated PKA-dependent phosphorylation, suggesting that the two protein modifications may compete with each other. Immunoprecipitation proteomic analysis identified six candidate proteins that were O-GlcNAcylated by high-glucose treatment, whereas the O-GlcNAcylations were removed by treatment with an incretin mimetic, exendin-4. Among these proteins, knockdown of myocyte enhancer factor 2D (Mef2d) enhanced insulin secretion, and high-glucose treatment increased the level of O-GlcNAcylation of Mef2d in MIN6-K8 cells. Furthermore, knockout of Mef2d promoted GIIS in MIN6-K8 cells, whereas adenovirus-mediated rescue of Mef2d decreased GIIS in the knockout cells. These results suggest that Mef2d negatively regulates insulin secretion through O-GlcNAcylation. • O-GlcNAcylation is enhanced in enlarged islets of the obese diabetic ZFDM rats. • O-GlcNAcylation and PKA-dependent phosphorylation complete in MIN6-K8 cells. • Immunoprecipitation proteomics identified six candidate proteins in MIN6-K8 cells. • High-glucose treatment enhanced O-GlcNAcylation of Mef2d in MIN6-K8 cells. • Knockdown and knockout of Mef2d enhanced glucose-induced insulin secretion. [ABSTRACT FROM AUTHOR]

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic β cell failure. CCAAT/enhancer-binding protein (C/EBP) β is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic β cells, and its accumulation reduces pancreatic β cell mass. We investigated the phosphorylation state of C/EBPβ under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPβ in MIN6 cells. It phosphorylated S222 of C/EBPβ, a previously unidentified phosphorylation site. We found that C/EBPβ is phosphorylated by CK2 under AMPK suppression and ER stress, which are important from the viewpoint of the worsening pathological condition of type 2 diabetes, such as decreased insulin secretion and apoptosis of pancreatic β cells. [ABSTRACT FROM AUTHOR]

Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the &lamda; isoform of PKC in pancreatic β cells (βPKC&lamda;-/- mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from βPKC&lamda;-/- mice. Neither the β cell mass nor the islet insulin content of βPKC&lamda;-/- mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3β was reduced in islets of βPKC&lamda;-/- mice, and the expression of genes regulated by HNF3β was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3β expression by infection of islets from βPKC&lamda;-/- mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKC&lamda; plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for β cell function. [ABSTRACT FROM AUTHOR]