دسترسی یکساله به بیش از ۵۰۰ ژورنال روز جهان موجود در سامانه
-
http://medilib.ir
- ﻣﺪﺕ ﺯﻣﺎﻥ : 365 ﺭﻭﺯ
قیمت : 3,800,000 تومان- قیمت ویژه : 1,900,000تومان
Regulation of Hepatic Metabolism and Cell Growth by the ATF/CREB Family of Transcription Factors
Aoyuan Cui, Dong Ding and Yu Li
doi : 10.2337/dbi20-0006
Diabetes 2021 Mar; 70 (3): 653-664
The liver is a major metabolic organ that regulates the whole-body metabolic homeostasis and controls hepatocyte proliferation and growth. The ATF/CREB family of transcription factors integrates nutritional and growth signals to the regulation of metabolism and cell growth in the liver, and deregulated ATF/CREB family signaling is implicated in the progression of type 2 diabetes, nonalcoholic fatty liver disease, and cancer. This article focuses on the roles of the ATF/CREB family in the regulation of glucose and lipid metabolism and cell growth and its importance in liver physiology. We also highlight how the disrupted ATF/CREB network contributes to human diseases and discuss the perspectives of therapeutically targeting ATF/CREB members in the clinic.
Ncor2/PPAR?-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function
Federico Cividini, Brian T. Scott, Jorge Suarez, Darren E. Casteel, Sven Heinz, Anzhi Dai, Tanja Diemer, Jorge A. Suarez, Christopher W. Benner, Majid Ghassemian and Wolfgang H. Dillmann
doi : 10.2337/db20-0779
Diabetes 2021 Mar; 70 (3): 665-679
The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. In this study, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9-based gene promoter pulldown approach coupled with mass spectrometry, we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor corepressor 2 repression, and chromatin immunoprecipitation assays identified peroxisome proliferator–activated receptor ? as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca2+ uptake and impairs mitochondrial energy production via glucose oxidation by depressing pyruvate dehydrogenase complex activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUbW246R/V251E) in vivo rescued T2D cardiomyocytes from metabolic inflexibility and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban phosphorylation via protein kinase A. We conclude that MCUb represents one newly discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically stressed diabetic heart.
Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
Regine Å. Jersin, Divya Sri Priyanka Tallapragada, André Madsen, Linn Skartveit, Even Fjære, Adrian McCann, Laurence Dyer, Aron Willems, Jan-Inge Bjune, Mona S. Bjune, Villy Våge, Hans Jørgen Nielsen, Håvard Luong Thorsen, Bjørn Gunnar Nedrebø, Christian Busch, Vidar M. Steen, Matthias Blüher, Peter Jacobson, Per-Arne Svensson, Johan Fernø, Mikael Rydén, Peter Arner, Ottar Nygård, Melina Claussnitzer, Ståle Ellingsen, Lise Madsen, Jørn V. Sagen, Gunnar Mellgren and Simon N. Dankel
doi : 10.2337/db20-0096
Diabetes 2021 Mar; 70 (3): 680-695
Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
Heme Oxygenase-1 Regulates Ferrous Iron and Foxo1 in Control of Hepatic Gluconeogenesis
Wang Liao, Wanbao Yang, Zheng Shen, Weiqi Ai, Quan Pan, Yuxiang Sun and Shaodong Guo
doi : 10.2337/db20-0954
Diabetes 2021 Mar; 70 (3): 696-709
The liver is a key player for maintaining glucose homeostasis. Excessive hepatic glucose production is considered to be a key for the onset of type 2 diabetes. The primary function of heme oxygenase-1 (HO1) is to catalyze the degradation of heme into biliverdin, ferrous iron, and carbon monoxide. Previous studies have demonstrated that the degradation of heme by HO1 in the liver results in mitochondrial dysfunction and drives insulin resistance. In this study, by overexpressing HO1 in hepatocytes and mice, we showed that HO1 promotes gluconeogenesis in a Foxo1-dependent manner. Importantly, HO1 overexpression increased the generation of ferrous iron in the liver, which further activates nuclear factor-?B and phosphorylates Foxo1 at Ser273 to enhance gluconeogenesis. We further assessed the role of HO1 in insulin-resistant liver-specific knockout of IRS1 and IRS2 genes (L-DKO) mice, which exhibit upregulation of HO1 in the liver and hepatic ferrous iron overload. HO1 knockdown by shRNA or treatment of iron chelator rescued the aberrant gluconeogenesis in L-DKO mice. In addition, we found that systemic iron overload promotes gluconeogenesis by activating the hepatic protein kinase A?Foxo1 axis. Thus, our results demonstrate the role of HO1 in regulating hepatic iron status and Foxo1 to control gluconeogenesis and blood glucose.
Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance
Hao Wang, Yongyan Song, Yuxin Wu, Virender Kumar, Ram I. Mahato and Qiaozhu Su
doi : 10.2337/db20-0181
Diabetes 2021 Mar; 70 (3): 710-719
MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here, we report that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine tumor necrosis factor-?. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated, which, in turn, targeted the 3?-untranslated region of PPAR? mRNA, impaired mitochondrial fatty acid ?-oxidation, and induced mitochondrial and endoplasmic reticulum stress. More importantly, the upregulated miR-378a can directly bind to and activate the double-strand RNA (dsRNA)–dependent protein kinase R (PKR) to sustain the metabolic stress. In vivo, genetic depletion of miR-378a prevented PKR activation and ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPAR? activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in fructose-fed mice. Our study delineated a novel mechanism of miR-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPAR?) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding proteins (e.g., PKR) is biologically significant because it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.
Deficiency of Stat1 in CD11c+ Cells Alters Adipose Tissue Inflammation and Improves Metabolic Dysfunctions in Mice Fed a High-Fat Diet
Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R. Cox, Pradip Saha, Lothar Hennighausen, Sean M. Hartig, Christie M. Ballantyne and Huaizhu Wu
doi : 10.2337/db20-0634
Diabetes 2021 Mar; 70 (3): 720-732
CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 weeks) had reductions in MDC (mainly CD11c+ macrophage) M1-like polarization and interferon-?–expressing T-helper type 1 (Th1) cells but increases in interleukin 5–expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrate that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.
Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver
Sunmi Seok, Hao Sun, Young-Chae Kim, Byron Kemper and Jongsook Kim Kemper
doi : 10.2337/db20-0856
Diabetes 2021 Mar; 70 (3): 733-744
Aberrantly elevated expression in obesity of microRNAs (miRNAs), including the miRNA miR-802, contributes to obesity-associated metabolic complications, but the mechanisms underlying the elevated expression are unclear. Farnesoid X receptor (FXR), a key regulator of hepatic energy metabolism, has potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced small heterodimer partner (SHP) regulates expression of miR-802 to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of miR-802 by aromatic hydrocarbon receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In patients with nonalcoholic fatty liver disease (NAFLD) and in obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the miR-802 promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance, and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.
Placental Insulin/IGF-1 Signaling, PGC-1?, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4–6 Years of Age: The ECHO Healthy Start Cohort
Madeline Rose Keleher, Kathryn Erickson, Harry A. Smith, Katerina J. Kechris, Ivana V. Yang, Dana Dabelea, Jacob E. Friedman, Kristen E. Boyle and Thomas Jansson
doi : 10.2337/db20-0902
Diabetes 2021 Mar; 70 (3): 745-751
An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4–6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4–6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3? phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator–activated receptor ? coactivator (PGC)-1? abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1?, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.
One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent-Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24
Teresa Rodriguez-Calvo, Lars Krogvold, Natalie Amirian, Knut Dahl-Jørgensen and Matthias von Herrath
doi : 10.2337/db20-0908
Diabetes 2021 Mar; 70 (3): 752-758
In type 1 diabetes (T1D), a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against ?-cell antigens have been detected in peripheral blood and in the pancreas of patients with short- or long-term disease. In the Diabetes Virus Detection (DiViD) study, researchers collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset T1D. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T-cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We also show the heterogeneity of islet distribution and CD8+ T-cell infiltration. Our findings contribute to the current limited existing knowledge of T-cell reactivity in the pancreas of donors with recent-onset T1D and indicate that antigen-specific therapies directed toward preproinsulin could have high clinical impact.
Lung and Kidney ACE2 and TMPRSS2 in Renin-Angiotensin System Blocker–Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19
Sri Nagarjun Batchu, Harmandeep Kaur, Veera Ganesh Yerra, Suzanne L. Advani, M. Golam Kabir, Youan Liu, Thomas Klein and Andrew Advani
doi : 10.2337/db20-0765
Diabetes 2021 Mar; 70 (3): 759-771
The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography–tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.
Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis
Arpeeta Sharma, Judy S.Y. Choi, Nada Stefanovic, Annas Al-Sharea, Daniel S. Simpson, Nigora Mukhamedova, Karin Jandeleit-Dahm, Andrew J. Murphy, Dmitri Sviridov, James E. Vince, Rebecca H. Ritchie and Judy B. de Haan
doi : 10.2337/db20-0357
Diabetes 2021 Mar; 70 (3): 772-787
Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1? (IL-1?). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte–macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1?, tumor necrosis factor-?, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow–derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate–differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1? and/or caspase-1 secretion and attenuated leukocyte–smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.
Interphotoreceptor Retinol-Binding Protein Ameliorates Diabetes-Induced Retinal Dysfunction and Neurodegeneration Through Rhodopsin
Jianglei Chen, Yan Shao, Temmy Sasore, Gennadiy Moiseyev, Kelu Zhou, Xiang Ma, Yanhong Du and Jian-xing Ma
doi : 10.2337/db20-0609
Diabetes 2021 Mar; 70 (3): 788-799
Patients with diabetes often experience visual defects before any retinal pathologies are detected. The molecular mechanism for the visual defects in early diabetes has not been elucidated. Our previous study reported that in early diabetic retinopathy (DR), rhodopsin levels were reduced due to impaired 11-cis-retinal regeneration. Interphotoreceptor retinol-binding protein (IRBP) is a visual cycle protein and important for 11-cis-retinal generation. IRBP levels are decreased in the vitreous and retina of DR patients and animal models. To determine the role of IRBP downregulation in the visual defects in early DR, we induced diabetes in transgenic mice overexpressing IRBP in the retina. IRBP overexpression prevented diabetes-induced decline of retinal function. Furthermore, IRBP overexpression also prevented decreases of rhodopsin levels and 11-cis-retinal generation in diabetic mice. Diabetic IRBP transgenic mice also showed ameliorated retinal oxidative stress, inflammation, apoptosis, and retinal degeneration compared with diabetic wild-type mice. These findings suggest that diabetes-induced IRBP downregulation impairs the regeneration of 11-cis-retinal and rhodopsin, leading to retinal dysfunction in early DR. Furthermore, increased 11-cis-retinal–free opsin constitutively activates the phototransduction pathway, leading to increased oxidative stress and retinal neurodegeneration. Therefore, restored IRBP expression in the diabetic retina may confer a protective effect against retinal degeneration in DR.
SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, but Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Crossover Trial
Katrine M. Lauritsen, Bent R.R. Nielsen, Lars P. Tolbod, Mogens Johannsen, Jakob Hansen, Troels K. Hansen, Henrik Wiggers, Niels Møller, Lars C. Gormsen and Esben Søndergaard
doi : 10.2337/db20-0921
Diabetes 2021 Mar; 70 (3): 800-808
Sodium–glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation, and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. Thirteen individuals with type 2 diabetes were studied after 4 weeks’ treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with 11C-palmitate and 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT). Oxygen consumption and myocardial external efficiency (MEE) were measured with 11C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using 15O-H2O PET/CT. Empagliflozin did not affect myocardial free fatty acids (FFAs) uptake but reduced myocardial glucose uptake by 57% (P < 0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (P < 0.01), but did not significantly affect stress MBF or MFR. In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose toward other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.
Low-Frequency Genetic Variant in the Hepatic Glucokinase Gene Is Associated With Type 2 Diabetes and Insulin Resistance in Chinese Population
Yumin Ma, Yingying Luo, Siqian Gong, Xianghai Zhou, Yufeng Li, Wei Liu, Simin Zhang, Xiaoling Cai, Qian Ren, Lingli Zhou, Xiuying Zhang, Yanai Wang, Xiuting Huang, Xueying Gao, Mengdie Hu, Xueyao Han and Linong Ji
doi : 10.2337/db20-0564
Diabetes 2021 Mar; 70 (3): 809-816
Glucokinase (GCK) regulates insulin secretion and hepatic glucose metabolism, and its inactivating variants could cause diabetes. We aimed to evaluate the association of a low-frequency variant of GCK (rs13306393) with type 2 diabetes (T2D), prediabetes, or both (impaired glucose regulation [IGR]) in a Chinese population. An association study was first conducted in a random cluster sampling population (sample 1: 537 T2D, 768 prediabetes, and 1,912 control), and then another independent population (sample 2: 3,896 T2D, 2,301 prediabetes, and 868 control) was used to confirm the findings in sample 1. The A allele of rs13306393 was associated with T2D (odds ratio 3.08 [95% CI 1.77–5.36], P = 0.00007) in sample 1; rs13306393 was also associated with prediabetes (1.67 [1.05–2.65], P = 0.03) in sample 2. In a pooled analysis of the two samples, the A allele increased the risk of T2D (1.57 [1.15–2.15], P = 0.005), prediabetes (1.83 [1.33–2.54], P = 0.0003) or IGR (1.68 [1.26–2.25], P = 0.0004), insulin resistance estimated by HOMA (? = 0.043, P = 0.001), HbA1c (? = 0.029, P = 0.029), and urinary albumin excretion (? = 0.033, P = 0.025), irrespective of age, sex, and BMI. Thus, the Chinese-specific low-frequency variant increased the risk of T2D through reducing insulin sensitivity rather than islet ?-cell function, which should be considered in the clinical use of GCK activators in the future.
Erratum. The Hypothalamic Arcuate Nucleus–Median Eminence Is a Target for Sustained Diabetes Remission Induced by Fibroblast Growth Factor 1. Diabetes 2019;68:1054–1061
Jenny M. Brown, Jarrad M. Scarlett, Miles E. Matsen, Hong T. Nguyen, Anna Secher, Rasmus Jorgensen, Gregory J. Morton and Michael W. Schwartz
doi : 10.2337/db21-er03a
Diabetes 2021 Mar; 70 (3): 817
Erratum. Adipocyte Pseudohypoxia Suppresses Lipolysis and Facilitates Benign Adipose Tissue Expansion. Diabetes 2015;64:733–745
Zoi Michailidou, Nicholas M. Morton, José Maria Moreno Navarrete, Christopher C. West, Kenneth J. Stewart, José Manuel Fernández-Real, Christopher J. Schofield, Jonathan R. Seckl and Peter J. Ratcliffe
doi : 10.2337/db21-er03b
Diabetes 2021 Mar; 70 (3): 818
