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Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes
Maria Bettini? and Matthew L. Bettini?
doi : 10.2337/dbi18-0058
Diabetes 2021 Jun; 70(6): 1211-1219.
Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.
The Role of TCF7L2 in Type 2 Diabetes
Laura del Bosque-Plata1?, Eduardo Martínez-Martínez2, Miguel Ángel Espinoza-Camacho1 and Claudia Gragnoli3,4,5,6
doi : 10.2337/db20-0573
Diabetes 2021 Jun; 70(6): 1220-1228.
TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies. TCF7L2 is a transcription factor that forms a basic part of the Wnt signaling pathway. This gene has highly conserved sequence regions that correspond to functional domains. The association of TCF7L2 with T2D is one of the most powerful genetically discovered in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins. The mechanisms over which TCF7L2 exerts its effect on T2D are still not well understood. In this article, we describe the main molecular mechanisms of how TCF7L2 is related to T2D. TCF7L2 variants associated with T2D risk exert an influence on the initial therapeutic success of the hypoglycemic oral agent sulfonylurea. Thus, it is important to know whether there are other TCF7L2 variants associated with T2D that can influence treatment with oral hypoglycemic agents. Resequencing of the TCF7L2 gene in diverse ethnic groups is required to reveal common and rare variations and their role in different pathologies and in adverse reactions to drugs. Identification of TCF7L2-susceptibility disease variants will permit, at a given moment, offering of therapies to patients according to their genotype.
A Selective Look at Autophagy in Pancreatic ?-Cells
Gemma L. Pearson1, Morgan A. Gingerich1, Emily M. Walker1, Trevor J. Biden2 and Scott A. Soleimanpour1,3?
doi : 10.2337/dbi20-0014
Diabetes 2021 Jun; 70(6): 1229-1241.
Insulin-producing pancreatic ?-cells are central to glucose homeostasis, and their failure is a principal driver of diabetes development. To preserve optimal health ?-cells must withstand both intrinsic and extrinsic stressors, ranging from inflammation to increased peripheral insulin demand, in addition to maintaining insulin biosynthesis and secretory machinery. Autophagy is increasingly being appreciated as a critical ?-cell quality control system vital for glycemic control. Here we focus on the underappreciated, yet crucial, roles for selective and organelle-specific forms of autophagy as mediators of ?-cell health. We examine the unique molecular players underlying each distinct form of autophagy in ?-cells, including selective autophagy of mitochondria, insulin granules, lipid, intracellular amyloid aggregates, endoplasmic reticulum, and peroxisomes. We also describe how defects in selective autophagy pathways contribute to the development of diabetes. As all forms of autophagy are not the same, a refined view of ?-cell selective autophagy may inform new approaches to defend against the various insults leading to ?-cell failure in diabetes.
Sexual Dimorphic Effects of Exercise Training on Subcutaneous White Adipose Tissue of Mice
Gregory D. Cartee?
doi : 10.2337/dbi21-0014
Diabetes 2021 Jun; 70(6): 1242-1243.
Is Bariatric Surgery Brain Surgery?
Leticia E. Sewaybricker and Ellen A. Schur?
doi : 10.2337/dbi21-0022
Diabetes 2021 Jun; 70(6): 1244-1246.
The SAgA of Antigen-Specific Immunotherapy for Type 1 Diabetes
Roberto Mallone1,2? and Sylvaine You1
doi : 10.2337/dbi21-0011
Diabetes 2021 Jun; 70(6): 1247-1249.
Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue
Pasquale Nigro1, Roeland J.W. Middelbeek1,2, Christiano R.R. Alves1, Susana Rovira-Llopis1, Krithika Ramachandran1, Leslie A. Rowland1, Andreas B. Møller1, Hirokazu Takahashi1, Ana B. Alves-Wagner1, Maria Vamvini1,2, Nathan S. Makarewicz1, Brent G. Albertson1, Michael F. Hirshman1 and Laurie J. Goodyear1,3?
doi : 10.2337/db20-0790
Diabetes 2021 Jun; 70(6): 1250-1264.
Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 (Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.
Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
Kristina E. Almby1, Martin H. Lundqvist1, Niclas Abrahamsson1, Sofia Kvernby2, Markus Fahlström2, Maria J. Pereira1, Malin Gingnell3, F. Anders Karlsson1, Giovanni Fanni1, Magnus Sundbom2, Urban Wiklund4, Sven Haller2,5, Mark Lubberink2, Johan Wikström2 and Jan W. Eriksson1?
doi : 10.2337/db20-1172
Diabetes 2021 Jun; 70(6): 1265-1277.
While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by 18F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.
PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPAR? Target Gene
Ye Yin, Yangyang Wu, Xu Zhang, Yeting Zhu, Yue Sun, Jiani Yu, Yufei Gong, Peng Sun, Haiyan Lin? and Xiao Han?
doi : 10.2337/db20-0622
Diabetes 2021 Jun; 70(6): 1278-1291.
Downregulation of mitochondrial function in adipose tissue is considered as one important driver for the development of obesity-associated metabolic disorders. Inorganic pyrophosphatase 1 (PPA1) is an enzyme that catalyzes the hydrolysis of inorganic pyrophosphate to inorganic phosphate and is required for anabolism to take place in cells. Although alteration of PPA1 has been related to some diseases, the importance of PPA1 in metabolic syndromes has never been discussed. In this study, we found that global PPA1 knockout mice (PPA1+/–) showed impaired glucose tolerance and severe insulin resistance under high-fat-diet feeding. In addition, impaired adipose tissue development and ectopic lipid accumulation were observed. Conversely, overexpression of PPA1 in adipose tissue by adeno-associated virus injection can partly reverse the metabolic disorders in PPA1+/– mice, suggesting that impaired adipose tissue function is responsible for the metabolic disorders observed in PPA1+/– mice. Mechanistic studies revealed that PPA1 acted as a PPAR? target gene to maintain mitochondrial function in adipocytes. Furthermore, specific knockdown of PPA1 in fat body of Drosophila led to impaired mitochondria morphology, decreased lipid storage, and made Drosophila more sensitive to starvation. In conclusion, for the first time, our findings demonstrate the importance of PPA1 in maintaining adipose tissue function and whole-body metabolic homeostasis.
The Importance of the Mechanisms by Which Insulin Regulates Meal-Associated Liver Glucose Uptake in the Dog
Guillaume Kraft, Katie C. Coate, Marta Smith, Ben Farmer, Melanie Scott, Alan D. Cherrington and Dale S. Edgerton?
doi : 10.2337/db20-1271
Diabetes 2021 Jun; 70(6): 1292-1302.
Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels fivefold in healthy dogs. In one group (n = 7), the physiologic response was allowed to fully occur, while in another (n = 7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothalamic insulin signaling for 4 h. In contrast to the indirect hepatic effects of insulin, which were previously shown capable of independently generating a half-maximal stimulation of HGU, direct hepatic insulin action was by itself able to fully stimulate HGU. This suggests that under hyperinsulinemic/hyperglycemic conditions insulin’s indirect effects are redundant to direct engagement of hepatocyte insulin receptors.
Adiponectin Alleviates Diet-Induced Inflammation in the Liver by Suppressing MCP-1 Expression and Macrophage Infiltration
Jiyoon Ryu1, Jason T. Hadley1, Zhi Li1, Feng Dong2, Huan Xu1, Xiaoban Xin1, Ye Zhang1, Cang Chen2, Senlin Li2,3, Xiaoning Guo1, Jared L. Zhao1, Robin J. Leach1, Muhammad A. Abdul-Ghani2, Ralph A. DeFronzo2, Amrita Kamat2,4, Feng Liu3 and Lily Q. Dong1?
doi : 10.2337/db20-1073
Diabetes 2021 Jun; 70(6): 1303-1316.
Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet–induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte–specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-?–stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2–mTORC1–MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.
DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation
Lin Shuai1, Bo-Han Li1,2, Hao-Wen Jiang1, Lin Yang1,2, Jia Li1,2,3? and Jing-Ya Li1,2,3?
doi : 10.2337/db20-1110
Diabetes 2021 Jun; 70(6): 1317-1333.
Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes
Rebuma Firdessa-Fite1, Stephanie N. Johnson2, Martin A. Leon3, Mohsen Khosravi-Maharlooei1, Rocky L. Baker4, Joshua O. Sestak5, Cory Berkland2,6,7 and Remi J. Creusot1?
doi : 10.2337/db20-0845
Diabetes 2021 Jun; 70(6): 1334-1346.
Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address the limited clinical efficacy of ASIT. Soluble antigen arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using either hydrolysable linkers (hSAgAs) or stable click chemistry linkers (cSAgAs). They were evaluated for the ability to block spontaneous development of disease in a nonobese diabetic mouse model of type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgAs) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers, such as CD73, interleukin-10, programmed death-1, and KLRG-1. Anaphylaxis caused by free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely nonoverlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to free peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.
Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects
Jonatan I. Bagger1,2?, Magnus F.G. Grøndahl1, Asger Lund1,3, Jens J. Holst2,4, Tina Vilsbøll1,3,5 and Filip K. Knop1,3,4,5?
doi : 10.2337/db20-0998
Diabetes 2021 Jun; 70(6): 1347-1356.
Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide–negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.
Nanopore 16S Amplicon Sequencing Enhances the Understanding of Pathogens in Medically Intractable Diabetic Foot Infections
Jangsup Moon1,2, Narae Kim1, Han Sang Lee1, Soon-Tae Lee1, Keun-Hwa Jung1, Kyung-Il Park3, Sang Kun Lee1, Dong-Oh Lee4, Dong Yeon Lee4? and Kon Chu1?
doi : 10.2337/db20-0907
Diabetes 2021 Jun; 70(6): 1357-1371.
Diabetic foot infections (DFIs) cause substantial morbidity and mortality. The mainstay of the treatment is empiric antibiotics and surgical debridement in severe cases. In this study, we performed nanopore 16S rDNA sequencing from the debridement specimens of DFIs. Fifty-four surgical debridement specimens obtained from 45 patients with medically intractable DFI were included. The 16S rDNA PCR was performed on each specimen, and Nanopore sequencing was performed for up to 3 h. The reads were aligned to the BLAST database, and the results were compared with conventional culture studies. The 16S sequencing results revealed that the majority of the DFIs (44 of 54, 81.5%) were polymicrobial infections. All bacteria isolated by conventional culture studies were detected by 16S sequencing. Several anaerobes (Prevotella, Finegoldia, Anaerococcus, Bacteroides) were commonly identified by 16S sequencing but were frequently missed by culture studies. In many cases, certain bacteria only revealed by the 16S sequencing were more abundant than the bacteria isolated by the culture studies. In conclusion, nanopore 16S sequencing was capable of pathogen identification in DFIs and has many advantages over conventional culture studies. Nanopore 16S sequencing enables a comprehensive understanding of the bacteria involved in DFIs.
Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease
Hua Qu, Xiaoli Gong, Xiufei Liu, Rui Zhang, Yuren Wang, Bangliang Huang, Linlin Zhang, Hongting Zheng? and Yi Zheng?
doi : 10.2337/db20-1157
Diabetes 2021 Jun; 70(6): 1372-1387.
Mitochondrial function is essential for bioenergetics, metabolism, and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity, and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. In this study, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury, and glomerular pathology. RNA sequencing revealed that mGPDH regulated the receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.
Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium–Glucose Cotransporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice
Shuiling Zhao1, Chao-Sheng Lo1, Kana N. Miyata1, Anindya Ghosh1, Xin-Ping Zhao1, Isabelle Chenier1, Jean-Francois Cailhier1, Jean Ethier1, Jean-Baptiste Lattouf1, Janos G. Filep2, Julie R. Ingelfinger3, Shao-Ling Zhang1? and John S.D. Chan1?
doi : 10.2337/db20-1126
Diabetes 2021 Jun; 70(6): 1388-1403.
We investigated the impact of nuclear factor erythroid 2–related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury, and sodium–glucose cotransporter 2 (Sglt2) expression in diabetic Akita Nrf2?/?/Nrf2RPTC transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the SGLT2 promoter and human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-to-creatinine ratio, tubulointerstitial fibrosis, and Sglt2 expression in Akita Nrf2?/?/Nrf2RPTC Tg mice compared with their Akita Nrf2?/? littermates. In vitro, oltipraz or transfection of NRF2 cDNA stimulated SGLT2 expression and SGLT2 promoter activity in HK2, and these effects were inhibited by trigonelline or NRF2 siRNA. The deletion of the NRF2-responsive element (NRF2-RE) in the SGLT2 promoter abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 binding to the NRF2-RE of the SGLT2 promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.
DNA Methylation GrimAge and Incident Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Kyeezu Kim1,2,3, Brian T. Joyce1,2, Yinan Zheng1,2, Pamela J. Schreiner4, David R. Jacobs Jr.4, Janet M. Catov5, James M. Shikany6, Mercedes R. Carnethon2, Philip Greenland2, Linda V. Van Horn2, Norrina B. Allen2, Donald M. Lloyd-Jones2, Erica P. Gunderson7 and Lifang Hou1,2?
doi : 10.2337/db20-1167
Diabetes 2021 Jun; 70(6): 1404-1413.
DNA methylation (DNAm)-based biological age (epigenetic age) has been suggested as a useful biomarker of age-related conditions including type 2 diabetes (T2D), and its newest iterations (GrimAge measurements) have shown early promise. In this study, we explored the association between epigenetic age and incident T2D in the context of their relationships with obesity. A total of 1,057 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were included in the current analyses. We stratified the participants into three groups: normal weight, overweight, and obese. A 1-year increase of GrimAge was associated with higher 10-year (study years 15–25) incidence of T2D (odds ratio [OR] 1.06, 95% CI 1.01–1.11). GrimAge acceleration, which represents the deviation of GrimAge from chronological age, was derived from the residuals of a model of GrimAge and chronological age, and any GrimAge acceleration (positive GrimAA: having GrimAge older than chronological age) was associated with significantly higher odds of 10-year incidence of T2D in obese participants (OR 2.57, 95% CI 1.61–4.11). Cumulative obesity was estimated by years since obesity onset, and GrimAge partially mediated the statistical association between cumulative obesity and incident diabetes or prediabetes (proportion mediated = 8.0%). In conclusion, both older and accelerated GrimAge were associated with higher risk of T2D, particularly among obese participants. GrimAge also statistically mediated the associations between cumulative obesity and T2D. Our findings suggest that epigenetic age measurements with DNAm can potentially be used as a risk factor or biomarker associated with T2D development.
Erratum. Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr+ Treg Cells. Diabetes 2020;69:965–980
Luigi Cari, Pia Montanucci, Giuseppe Basta, Maria G. Petrillo, Erika Ricci, Teresa Pescara, Alessia Greco, Sabrina Cipriani, Jun Shimizu, Graziella Migliorati, Giuseppe Nocentini, Riccardo Calafiore and Carlo Riccardi
doi : 10.2337/db21-er06a
Diabetes 2021 Jun; 70(6): 1414-1414.
Erratum. Exercise-Induced Increases in Insulin Sensitivity After Bariatric Surgery Are Mediated By Muscle Extracellular Matrix Remodeling. Diabetes 2020;69:1675–1691
Wagner S. Dantas, Hamilton Roschel, Igor H. Murai, Saulo Gil, Gangarao Davuluri, Christopher L. Axelrod, Sujoy Ghosh, Susan S. Newman, Hui Zhang, Samuel K. Shinjo, Willian das Neves, Carlos Merege-Filho, Walcy R. Teodoro, Vera L. Capelozzi, Rosa Maria Pereira, Fabiana B. Benatti, Ana L. de Sá-Pinto, Roberto de Cleva, Marco A. Santo, John P. Kirwan and Bruno Gualano
doi : 10.2337/db21-er06b
Diabetes 2021 Jun; 70(6): 1415-1415.
Erratum. Inhibition of TNF-? Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes. Diabetes 2012;61:2134–2145
Zongwei Wang, Zhiyong Cheng, Vivian Cristofaro, Jijun Li, Xingyuan Xiao, Pablo Gomez, Rongbin Ge, Edward Gong, Klemen Strle, Maryrose P. Sullivan, Rosalyn M. Adam, Morris F. White and Aria F. Olumi
doi : 10.2337/db21-er06c
Diabetes 2021 Jun; 70(6): 1416-1416.
