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ISSN / EISSN : 0012-1797 / 1939-327X
Published by: American Diabetes Association (10.2337)
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Alexis Vivoli, Julien Ghislain, Ali Filali-Mouhim, Zuraya Elisa Angeles, Anne-Laure Castell, Robert Sladek,
Published: 3 October 2022
Journal: Diabetes
Abstract:
The functional mass of insulin-secreting pancreatic beta cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing beta cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the beta-cell compensatory response, but their underlying mechanisms of action remain poorly understood. Herein, we investigated the transcriptional mechanisms of beta-cell proliferation in response to fatty acids. Isolated rat islets were exposed to 16.7 mM glucose with or without 0.5 mM oleate (C18:1) or palmitate (C16:0) for 48 h. The islet transcriptome was assessed by single cell RNA-sequencing. Beta-cell proliferation was measured by flow cytometry. Unsupervised clustering of pooled beta cells identified different subclusters, including proliferating beta cells. Beta-cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved energy metabolism and mitochondrial activity. Comparison of proliferating vs. non-proliferating beta cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, N-acetyl cysteine and the peroxiredoxin inhibitor Conoidin A both blocked oleate-induced beta-cell proliferation. Our study reveals a key role for ROS signaling through peroxiredoxin activation in oleate-induced beta-cell proliferation.
Hwan Hee Lee, Gyu Won Jeong, Byeong Jin Ye, Eun Jin Yoo, Keoung Sun Son, Dong Ki Kim, Hye-Kyung Park, Byoung Heon Kang, Whaseon Lee-Kwon, , et al.
Published: 28 September 2022
Journal: Diabetes
Abstract:
The phenotypic and functional plasticity of adipose tissue macrophages during obesity play a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity, but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced pro-inflammatory phenotype of metabolically activated macrophages; decreased expression of inflammatory factors related to insulin resistance; and enhanced insulin sensitivity. TonEBP expression was elevated in the adipose tissue macrophages of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions, and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.
, Angela C. Olvera, Alex Marti, Shi Fang, Jeffrey R. White, Michael Westphal, Rana Hewezi, Salma T. AshShareef, Luis Miguel Garcia Pena, Jivan Koneru, et al.
Published: 28 September 2022
Journal: Diabetes
Abstract:
Mitochondria play a vital role in white adipose tissue homeostasis including adipogenesis, fatty acid synthesis, and lipolysis. We recently reported that the mitochondrial fusion protein optic atrophy 1 (OPA1) is required for induction of fatty acid oxidation and thermogenic activation in brown adipocytes. The present study investigated the role of OPA1 in white adipose tissue (WAT) function in vivo. We generated mice with constitutive or inducible knockout of OPA1 selectively in adipocytes. Studies were conducted under baseline conditions, at thermoneutrality, following high-fat feeding or during cold exposure. OPA1 deficiency reduced mitochondrial respiratory capacity in white adipocytes, impaired lipolytic signaling, repressed expression of de novo lipogenesis and triglyceride synthesis pathways and promoted adipose tissue senescence and inflammation. Reduced WAT mass was associated with hepatic triglycerides accumulation and glucose intolerance. Moreover, mice deficient for OPA1 in adipocytes had impaired adaptive thermogenesis, reduced cold-induced browning of sub-cutaneous WAT, and were completely resistant to diet-induced obesity. In conclusion, OPA1 expression and function in adipocytes is essential for adipose tissue expansion, lipid biosynthesis and fatty acid mobilization of WAT and brown adipocytes, and for thermogenic activation of brown and beige adipocytes.
Chieh Min Jamie Chu, Honey Modi, Cara Ellis, Nicole A.J. Krentz, Søs Skovsø, Yiwei Bernie Zhao, Haoning Cen, N Noursadeghi, Evgeniy Panzhinskiy, Xiaoke Hu, et al.
Published: 28 September 2022
Journal: Diabetes
Abstract:
Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in β-cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ∼25% of β-cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single β-cells over time. Autocorrelation analysis revealing a subset of cells with oscillating behavior, with oscillation periods of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing determined that Ins2(GFP)HIGH β-cells were enriched for markers of β-cell maturity. Ins2(GFP)HIGH β-cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β-cells, can be accounted for by dynamic states of insulin gene activity.
William P. Miller, Congzhou M. Sha, Siddharth Sunilkumar, Allyson L. Toro, Ashley M. VanCleave, Scot R. Kimball, Nikolay V. Dokholyan,
Published: 28 September 2022
Journal: Diabetes
Abstract:
The stress response protein regulated in development and DNA damage response 1 (REDD1) has been implicated in visual deficits in diabetic patients. The aim here was to investigate the mechanism responsible for the increase in retinal REDD1 protein content that is observed with diabetes. We found that REDD1 protein expression was increased in the retina of streptozotocin-induced diabetic mice in the absence of a change in REDD1 mRNA abundance or ribosome association. Oral antioxidant supplementation reduced retinal oxidative stress and suppressed REDD1 protein expression in the retina of diabetic mice. In human retinal Müller cell cultures, hyperglycemic conditions increased oxidative stress, enhanced REDD1 expression, and inhibited REDD1 degradation independently of the proteasome. Hyperglycemic conditions promoted a redox-sensitive cross-strand disulfide bond in REDD1 at C150/C157 that was required for reduced REDD1 degradation. Discrete molecular dynamics simulations of REDD1 structure revealed allosteric regulation of a degron upon formation of the disulfide bond that disrupted lysosomal proteolysis of REDD1. REDD1 acetylation at K129 was required for REDD1 recognition by the cytosolic chaperone HSC70 and degradation by chaperone-mediated autophagy. Disruption of REDD1 allostery upon C150/C157 disulfide bond formation prevented the suppressive effect of hyperglycemic conditions on REDD1 degradation and reduced oxidative stress in cells exposed to hyperglycemic conditions. The results reveal redox regulation of REDD1 and demonstrate the role of a REDD1 disulfide switch in development of oxidative stress.
Xuanming Hong, Zhiyu Wu, Weihua Cao, Jun Lv, Canqing Yu, Tao Huang, Dianjianyi Sun, Chunxiao Liao, Yuanjie Pang, Zengchang Pang, et al.
Published: 28 September 2022
Journal: Diabetes
Abstract:
Previous cross-sectional Epigenome-Wide Association Studies (EWASs) in adults have reported hundreds of 5′-cytosine-phosphate-guanine-3′ (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWASs have been inconsistent, and longitudinal observations of these associations are scarce. Twin studies provide a valuable tool for epigenetic studies, as they are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and EMBASE for EWASs, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17 and 16 CpG sites from previous studies were validated for T2DM, HbA1c and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 on 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none was from the other cross-lagged direction, indicating CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed, and the potential role of DNAm of cg19693031, cg00574958 and cg04816311 in mediating the effect of glycemic traits on T2DM was detected.
Bastian Ramms, Dennis P. Pollow, Han Zhu, Chelsea Nora, Austin R. Harrington, Ibrahim Omar, Philip L.S.M. Gordts, ,
Published: 28 September 2022
Journal: Diabetes
Abstract:
The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.
Kate M. Root, Brian Akhaphong, Melissa A. Cedars, Alexa M. Molin, Margaretta E. Huchthausen, Connor F. Laule, Ronald R. Regal, Emilyn U. Alejandro, Jean F. Regal
Published: 20 September 2022
Journal: Diabetes
Abstract:
Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring including increased susceptibility to type 2 diabetes (T2D) in adulthood. In rat Reduced Uteroplacental Perfusion Pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimics aspects of preeclampsia and resulted in female embryonic day (e)19 offspring with reduced β-cell area and increased β-cell apoptosis compared to offspring of Sham pregnancies. Decreased pancreatic β-cell area persists to Postnatal Day (PD)13 in females and could influence whether T2D develops in adulthood. Macrophage changes also occur in islets in T2D. Therefore, we hypothesized that macrophages are crucial to reduction in pancreatic β-cell area in female offspring following chronic placental ischemia. The macrophage marker CD68 mRNA expression was significantly elevated in e19 and PD13 islets isolated from female RUPP offspring compared to Sham. Postnatal injections of clodronate liposomes into female RUPP and Sham offspring on PD2 and PD9 significantly depleted macrophages compared to animals injected with control liposomes. Depletion of macrophages rescued reduced β-cell area and increased β-cell proliferation and size in RUPP offspring. Our studies suggest that the presence of macrophages is important for reduced β-cell area in female RUPP offspring and changes in macrophages could contribute to development of T2D in adulthood.
Yang Zurong, Li Yuandong, Tan Xiankui, , Liu Tang, Zhan Junkun
Published: 20 September 2022
Journal: Diabetes
Abstract:
The aim of this study was to explore changes in morphological and mechanical properties of lower limb skeletal muscles in diabetic patients with and without diabetic peripheral neuropathy (DPN) and seek to find a potential image indicator for monitoring the progress of DPN in patients with type 2 diabetes mellitus (T2DM). A total of 203 patients with type 2 diabetes mellitus (T2DM), with and without DPN, were included in this study. Ultrasonography and ultrasound shear wave imaging (USWI) of the abductor hallux (AbH), tibialis anterior (TA), and peroneal longus (PER) muscles were performed for each subject, and the shear wave velocity (SWV) and cross-sectional area (CSA) of each AbH, TA, and PER were measured. The clinical factors influencing AbH_CSA and AbH_SWV were analyzed, and the risk factors for DPN complications were investigated. AbH_CSA and AbH_SWV in the T2DM group with DPN decreased significantly (p < 0.05), but no significant differences were found in the SWV and CSA of the TA and PER between the two groups. TCSS score and glycosylated haemoglobin were independent predictors of AbH_CSA and AbH_SWV. As AbH_SWV and AbH_CSA decreased, the TCSS score and glycosylated haemoglobin increased, and the incidence of DPN increased significantly. In conclusion, the AbH muscle of T2DM patients with DPN became smaller and softer, while its morphological and mechanical properties were associated with the clinical indicators related to the progression of DPN. Thus, they could be potential imaging indicators for monitoring the progress of DPN in T2DM patients.
, M.D. Peter Achenbach, Vibha Anand, M.D. Brigitte I. Frohnert, M.D. William Hagopian, Jianying Hu, M.Phil. Eileen Koski, Åke Lernmark, Olivia Lou, Frank Martin, et al.
Published: 16 September 2022
Journal: Diabetes
Abstract:
Our previous data-driven analysis of evolving patterns of islet autoantibodies (IAbs) against insulin (IAA), glutamic acid decarboxylase (GADA) and islet antigen 2 (IA-2A) discovered three trajectories characterized by either multiple IAbs (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n=643) to those remaining undiagnosed (n=1,502). Using thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlayed onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (p<0.001), but for IAA dwell times differed only within TR2 (p<0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has been long appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb positive children who progressed to type 1 diabetes from those who did not.
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