Regulation of Pancreatic β Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein β Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity

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

Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells

Patch-seq shows the heterogeneity of pancreatic islet cells

In 2016, Patch-seq was established to analyze electrophysiology, gene expression and morphology in neuronal cells. Recently, Camunas-Soler et al. used Patch-seq to analyze the functions and gene expression profiles of individual cells in pancreatic islets. I believe this analysis is expected to contribute to the complete characterization of pancreatic islets in diabetes patients

En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina

ObjectiveTo evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data.Research design and methodsWe retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image. Values from en face OCT images were used for statistical analyses. To obtain insight into the pathogenesis of diabetic retinal neurodegeneration, we used the InsPr-Cre;Pdk1flox/flox diabetic mouse model.ResultsBoth OCT grade and relative red color area ratio significantly increased with the advancing stage of diabetic retinopathy (p=0.018 and 0.006, respectively). After a mean follow-up period of 4.6 years, the trend was unchanged in the analyses of 42 untreated eyes (p<0.001 and 0.001, respectively). Visual acuity showed a weak but significant negative correlation with the red color ratio on en face slab OCT images, but central retinal thickness did not exhibit a clinically meaningful correlation with values obtained from en face slab OCT images. Immunohistochemical analyses of InsPr-Cre;Pdk1flox/flox diabetic mice demonstrated the loss of ganglion axon bundles and thinning of laminin without apparent retinal vascular change at the age of 20 weeks.ConclusionsEn face slab OCT imaging would be a novel useful modality for the assessment of diabetic retinal neurodegeneration as it could detect subtle optical changes occurring in the innermost retina in diabetic eyes. Our animal experimental data suggest that dark areas observed on en face slab OCT images might be the impairment of the extracellular matrix as well as neurons

Improving interpretability of individual Diabetes Symptom Checklist-Revised (DSC-R) scores: the role of patient characteristics

IntroductionThe Diabetes Symptom Checklist-Revised (DSC-R) is a well-validated patient-reported outcome designed to assess symptom burden in persons with type 2 diabetes mellitus (T2DM) across eight domains. The DSC-R has so far primarily been used in research settings. With the aim to make the DSC-R applicable in clinical practice by improving its interpretability, we sought to identify patient characteristics associated with DSC-R (domain) scores as a first initiative toward reference values.Research design and methodsWe used baseline data from two large observational studies to select patient characteristics significantly associated with DSC-R domain and total scores. Multivariable Tobit analyses with the backward procedure per (domain) score were performed.ResultsData from 1531 participants with T2DM were included. On a 0–100 scale, the median DSC-R total score was 15.88 (7.06–29.41), with domain scores ranging from 5.00 (0.00–22.50) (pain) to 35.00 (10.00–60.00) (fatigue). Low well-being status was most profoundly associated with higher scores across all domains. Persons with one or more complication, as well as one or more symptomatic hypoglycemic episode during the past 3 months, scored higher on (almost) all domains and the total scale.ConclusionsComplications, symptomatic hypoglycemia, and low well-being are important characteristics to take into account when using the DSC-R in individual patients. Further validation of our findings is warranted in diverse patient populations

Sex difference in the association of obesity with personal or social background among urban residents in Japan

The development of obesity is influenced by genetic and environmental factors and is associated with a variety of health problems. To gain insight into environmental factors that contribute to obesity, we analyzed the relation of personal or social background to obesity in men and women separately with the use of data from a community-based questionnaire survey of 5425 residents aged 20 to 64 years of Kobe, a representative large city in Japan. Obesity and normal weight were defined as a body mass index (BMI) of ≥25 and of ≥ 18.5 and < 25 kg/m(2), respectively, according to the diagnostic criteria of the Japan Society for the Study of Obesity. The personal or social background factors examined included marital status, family structure, employment, household income, residence type, welfare enrollment, economic conditions of current life, educational level, extracurricular activity in school, living conditions at 15 years of age, and childhood adversity. We found that the prevalence of obesity was 27.2% and 10.6% in men and women, respectively. Among women, unmarried status, a low household income, welfare enrollment, difficult current economic conditions, a low educational level, and childhood adversity were associated with obesity, whereas none of the personal or social background factors examined were associated with obesity in men. Our results suggest that the development of obesity in women is strongly influenced by personal or social background, and such factors should be taken into consideration in the management of this condition in women

Roles of mTOR in the Regulation of Pancreatic β-Cell Mass and Insulin Secretion

Pancreatic β-cells are the only type of cells that can control glycemic levels via insulin secretion. Thus, to explore the mechanisms underlying pancreatic β-cell failure, many reports have clarified the roles of important molecules, such as the mechanistic target of rapamycin (mTOR), which is a central regulator of metabolic and nutrient cues. Studies have uncovered the roles of mTOR in the function of β-cells and the progression of diabetes, and they suggest that mTOR has both positive and negative effects on pancreatic β-cells in the development of diabetes