Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation.

Aims/hypothesis: Glucagon-expressing pancreatic alpha cells have attracted much attention for their plasticity to transdifferentiate into insulin-producing beta cells; however, it remains unclear precisely when, and from where, alpha cells emerge and what regulates alpha cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha cell differentiation using a novel time-resolved reporter system.

Methods: We established the mouse model, 'Gcg-Timer', in which newly generated alpha cells can be distinguished from more-differentiated cells by their fluorescence.

Postprandial Plasma Glucagon Kinetics in Type 2 Diabetes Mellitus: Comparison of Immunoassay and Mass Spectrometry.

Context: Accurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes.

Objective: To evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus.

Design And Participants: Twenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks.

Enhanced Expression of the Key Mitosis Regulator Cyclin B1 Is Mediated by PDZ-Binding Kinase in Islets of Pregnant Mice.

The proliferation of pancreatic cells is enhanced to enable an increase in -cell mass and to compensate for insulin resistance during pregnancy. To elucidate the mechanisms involved, we previously investigated islets from pregnant and nonpregnant mice by gene expression profiling and found that the expression of postsynaptic density-95/Discs large/zonula occludens-1 (PDZ)-binding kinase (Pbk), a member of the mitogen-activated protein kinase kinase family, is increased in pregnant mouse islets compared with control mouse islets. Among the pregnancy hormones, treatment with estradiol upregulated expression.

One year follow-up after a randomized controlled trial of a 130 g/day low-carbohydrate diet in patients with type 2 diabetes mellitus and poor glycemic control.

Background & Aims: Recently, we conducted a prospective randomized controlled trial (RCT) showing that a 6-month 130g/day low-carbohydrate diet (LCD) reduced HbA1c and BMI more than a calorie restricted diet (CRD). [1] To assess whether the benefits of the LCD persisted after the intensive intervention, we compared HbA1c and BMI between the LCD and CRD groups at 1 year after the end of the 6-month RCT.

Methods: Following the end of the 6-month RCT, patients were allowed to manage their own diets with periodic outpatient visits.

Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin.

Background: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day).

Research Design And Methods: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks.

Normal pancreatic β-cell function in mice with RIP-Cre-mediated inactivation of p62/SQSTM1.

Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic β-cell homeostasis is regulated by various types of signaling molecules and stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) is a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, and autophagy.

Relationships between lifestyle patterns and cardio-renal-metabolic parameters in patients with type 2 diabetes mellitus: A cross-sectional study.

Introduction: While individuals tend to show accumulation of certain lifestyle patterns, the effect of such patterns in real daily life on cardio-renal-metabolic parameters remains largely unknown. This study aimed to assess clustering of lifestyle patterns and investigate the relationships between such patterns and cardio-renal-metabolic parameters.

Participants And Methods: The study participants were 726 Japanese type 2 diabetes mellitus (T2DM) outpatients free of history of cardiovascular diseases.

Efficacy and Safety of Vildagliptin as an Add-On Therapy in Inadequately Controlled Type 2 Diabetes Patients Treated With Basal Insulin.

Background: The aim of this study was to investigate the efficacy and safety of vildagliptin as an add-on therapy for patients with type 2 diabetes mellitus inadequately controlled with basal insulin.

Methods: Twenty-four patients treated with basal insulin and oral anti-diabetes drugs were randomly allocated into two groups: the control group (did not receive any add-on drugs) and vildagliptin group (received vildagliptin 100 mg/day for 6 months). The primary outcome was changes in hemoglobin A1c (HbA1c) from baseline to end of study.

A randomized controlled trial of 130 g/day low-carbohydrate diet in type 2 diabetes with poor glycemic control.

Background & Aims: The usefulness of low-carbohydrate diet (LCD) for Japanese patients with type 2 diabetes mellitus (T2DM) has not been fully investigated. Therefore, we compared the effectiveness and safety of LCD with calorie restricted diet (CRD).

Methods: This prospective, randomized, open-label, comparative study included 66 T2DM patients with HbA1c >7.

Effect of treatment guidance using a retrospective continuous glucose monitoring system on glycaemic control in outpatients with type 2 diabetes mellitus: A randomized controlled trial.

Objectives: To assess the effect of treatment guidance based on data from a continuous glucose monitoring (CGM) device on glycaemic control, and patient satisfaction, in patients with type 2 diabetes mellitus (T2DM).

Methods: Patients with poorly-controlled T2DM treated with insulin were randomly assigned to the intervention or nonintervention group. Continuous blood-glucose levels were recorded for 4-5 days using a CGM device on three separate occasions during the 8-month study period.

Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study.

The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction.

Expression mechanism of tryptophan hydroxylase 1 in mouse islets during pregnancy.

Serotonin signaling plays key roles in augmentation of pancreatic β-cell function during pregnancy. Increased expression of tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme for serotonin synthesis by lactogenic hormones, is involved in this phenomenon. To investigate its mechanisms, we here performed 5'-RACE and identified β-cell-specific transcription initiation sites for Tph1.

SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell.

SET7/9 is an enzyme that methylates histone 3 at lysine 4 (H3K4) to maintain euchromatin architecture. Although SET7/9 is enriched in islets and contributes to the transactivation of β cell-specific genes, including Ins1 and Slc2a, SET7/9 has also been reported to bind the p65 subunit of nuclear factor κB in non-β cells and modify its transcriptional activity. Given that inflammation is a central component of β cell dysfunction in Type 1 and Type 2 diabetes, the aim of this study was to elucidate the role of SET7/9 in proinflammatory cytokine signaling in β cells.

Increased expression of ERp57/GRP58 is protective against pancreatic beta cell death caused by autophagic failure.

Autophagy is a tightly regulated self-digestion system. As in other cell types, autophagy plays an essential role in the homeostasis of pancreatic beta cells. However, the mechanisms involved in the deterioration of beta cell function caused by autophagic failure have not yet been fully elucidated.

Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy.

Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP.

Identification and comparison of insulin pharmacokinetics injected with a new 4-mm needle vs 6- and 8-mm needles accounting for endogenous insulin and C-peptide secretion kinetics in non-diabetic adult males.

Aims/introduction: Many patients with diabetes now use 5-, 6- or 8-mm needles for insulin injection. However, it is unclear whether needle length, particularly for shorter needles, affects the pharmacokinetic properties of insulin.

Materials And Methods: This was a three-way, randomized, cross-over, single-center study involving 12 healthy Japanese adult males (age 27.

Gut dysbiosis and detection of "live gut bacteria" in blood of Japanese patients with type 2 diabetes.

Objective: Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and "live gut bacteria" in the systemic circulation of Japanese patients with type 2 diabetes.

Research Design And Methods: Using a sensitive reverse transcription-quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers.

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle.

Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle.

Exendin-4 improves β-cell function in autophagy-deficient β-cells.

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus.

Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes primarily by increasing plasma active glucagon-like peptide-1 (GLP-1) levels. While various combination therapies based on DPP-4 inhibitors have been proposed for treatment of type 2 diabetes, the effects of combination therapy of DPP-4 inhibitors and alpha-glucosidase inhibitors on β-cell function are less characterized. We evaluated the effects of long-term treatment with vildagliptin, a DPP-4 inhibitor, on metabolic parameters and β-cell function, in combination with miglitol, an alpha-glucosidase inhibitor, in diet-controlled db/db mice.

The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.

Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive.

PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress.

The maintenance of intracellular Ca(2+) homeostasis in the pancreatic β-cell is closely regulated by activity of the sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) pump. Our data demonstrate a loss of β-cell SERCA2b expression in several models of type 2 diabetes including islets from db/db mice and cadaveric diabetic human islets. Treatment of 832/13 rat INS-1-derived cells with 25 mm glucose and the proinflammatory cytokine IL-1β led to a similar loss of SERCA2b expression, which was prevented by treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone.

Expression and function of Set7/9 in pancreatic islets.

Histone tail acetylation and methylation are known to enhance accessibility of islet genes to transcription factors and the basal transcriptional machinery.  In this brief report, we follow up on a recent study in which we identified the islet enriched factor Set7/9 as a potentially important histone methyltransferase in β-cells (Deering, et al. Diabetes 2009; 58:185-93).