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Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 562  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 497 - 498
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db20-ti04
      Issue No: Vol. 69, No. 4 (2020)
       
  • Stress-Induced Translational Regulation Mediated by RNA Binding Proteins:
           Key Links to {beta}-Cell Failure in Diabetes
    • Authors: Good; A. L.; Stoffers, D. A.
      Pages: 499 - 507
      Abstract: In type 2 diabetes, β-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to β-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in β-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in β-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of β-cell failure in type 2 diabetes.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi18-0068
      Issue No: Vol. 69, No. 4 (2020)
       
  • Remnants of the Triglyceride-Rich Lipoproteins, Diabetes, and
           Cardiovascular Disease
    • Authors: Chait; A.; Ginsberg, H. N.; Vaisar, T.; Heinecke, J. W.; Goldberg, I. J.; Bornfeldt, K. E.
      Pages: 508 - 516
      Abstract: Diabetes is now a pandemic disease. Moreover, a large number of people with prediabetes are at risk for developing frank diabetes worldwide. Both type 1 and type 2 diabetes increase the risk of atherosclerotic cardiovascular disease (CVD). Even with statin treatment to lower LDL cholesterol, patients with diabetes have a high residual CVD risk. Factors mediating the residual risk are incompletely characterized. An attractive hypothesis is that remnant lipoprotein particles (RLPs), derived by lipolysis from VLDL and chylomicrons, contribute to this residual risk. RLPs constitute a heterogeneous population of lipoprotein particles, varying markedly in size and composition. Although a universally accepted definition is lacking, for the purpose of this review we define RLPs as postlipolytic partially triglyceride-depleted particles derived from chylomicrons and VLDL that are relatively enriched in cholesteryl esters and apolipoprotein (apo)E. RLPs derived from chylomicrons contain apoB48, while those derived from VLDL contain apoB100. Clarity as to the role of RLPs in CVD risk is hampered by lack of a widely accepted definition and a paucity of adequate methods for their accurate and precise quantification. New specific methods for RLP quantification would greatly improve our understanding of their biology and role in promoting atherosclerosis in diabetes and other disorders.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi19-0007
      Issue No: Vol. 69, No. 4 (2020)
       
  • Exercise Combats Hepatic Steatosis: Potential Mechanisms and Clinical
           Implications
    • Authors: Thyfault; J. P.; Rector, R. S.
      Pages: 517 - 524
      Abstract: Hepatic steatosis, the excess storage of intrahepatic lipids, is a rampant clinical problem associated with the obesity epidemic. Hepatic steatosis is linked to increased risk for insulin resistance, type 2 diabetes, and cardiovascular and advanced liver disease. Accumulating evidence shows that physical activity, exercise, and aerobic capacity have profound effects on regulating intrahepatic lipids and mediating susceptibility for hepatic steatosis. Moreover, exercise can effectively reduce hepatic steatosis independent of changes in body mass. In this perspective, we highlight 1) the relationship between obesity and metabolic pathways putatively driving hepatic steatosis compared with changes induced by exercise; 2) the impact of physical activity, exercise, and aerobic capacity compared with caloric restriction on regulating intrahepatic lipids and steatosis risk; 3) the effects of exercise training (modalities, volume, intensity) for treatment of hepatic steatosis, and 4) evidence for a sustained protection against steatosis induced by exercise. Overall, evidence clearly indicates that exercise powerfully regulates intrahepatic storage of fat and risk for steatosis.
      Keywords: Exercise
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi18-0043
      Issue No: Vol. 69, No. 4 (2020)
       
  • Epigenetic Regulation of Hepatic Lipogenesis: Role in Hepatosteatosis and
           Diabetes
    • Authors: Viscarra; J.; Sul, H. S.
      Pages: 525 - 531
      Abstract: Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi18-0032
      Issue No: Vol. 69, No. 4 (2020)
       
  • Repositioning Glucagon Action in the Physiology and Pharmacology of
           Diabetes
    • Authors: Finan; B.; Capozzi, M. E.; Campbell, J. E.
      Pages: 532 - 541
      Abstract: Glucagon is historically described as the counterregulatory hormone to insulin, induced by fasting/hypoglycemia to raise blood glucose through action mediated in the liver. However, it is becoming clear that the biology of glucagon is much more complex and extends beyond hepatic actions to exert control on glucose metabolism. We discuss the inconsistencies with the canonical view that glucagon is primarily a hyperglycemic agent driven by fasting/hypoglycemia and highlight the recent advances that have reshaped the metabolic role of glucagon. These concepts are placed within the context of both normal physiology and the pathophysiology of disease and then extended to discuss emerging strategies that incorporate glucagon agonism in the pharmacology of treating diabetes.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi19-0004
      Issue No: Vol. 69, No. 4 (2020)
       
  • A Primary Role for {alpha}-Cells as Amino Acid Sensors
    • Authors: Dean; E. D.
      Pages: 542 - 549
      Abstract: Glucagon and its partner insulin are dually linked in both their secretion from islet cells and their action in the liver. Glucagon signaling increases hepatic glucose output, and hyperglucagonemia is partly responsible for the hyperglycemia in diabetes, making glucagon an attractive target for therapeutic intervention. Interrupting glucagon signaling lowers blood glucose but also results in hyperglucagonemia and α-cell hyperplasia. Investigation of the mechanism for α-cell proliferation led to the description of a conserved liver–α-cell axis where glucagon is a critical regulator of amino acid homeostasis. In return, amino acids regulate α-cell function and proliferation. New evidence suggests that dysfunction of the axis in humans may result in the hyperglucagonemia observed in diabetes. This discussion outlines important but often overlooked roles for glucagon that extend beyond glycemia and supports a new role for α-cells as amino acid sensors.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi19-0021
      Issue No: Vol. 69, No. 4 (2020)
       
  • The Local Paracrine Actions of the Pancreatic {alpha}-Cell
    • Authors: Rodriguez-Diaz; R.; Tamayo, A.; Hara, M.; Caicedo, A.
      Pages: 550 - 558
      Abstract: Secretion of glucagon from the pancreatic α-cells is conventionally seen as the first and most important defense against hypoglycemia. Recent findings, however, show that α-cell signals stimulate insulin secretion from the neighboring β-cell. This article focuses on these seemingly counterintuitive local actions of α-cells and describes how they impact islet biology and glucose metabolism. It is mostly based on studies published in the last decade on the physiology of α-cells in human islets and incorporates results from rodents where appropriate. As this and the accompanying articles show, the emerging picture of α-cell function is one of increased complexity that needs to be considered when developing new therapies aimed at promoting islet function in the context of diabetes.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi19-0002
      Issue No: Vol. 69, No. 4 (2020)
       
  • Energy Regulation Mechanism and Therapeutic Potential of Asprosin
    • Authors: Hoffmann; J. G.; Xie, W.; Chopra, A. R.
      Pages: 559 - 566
      Abstract: Genetic studies of patients with neonatal progeroid syndrome led to the discovery of the novel fasting-induced, glucogenic, and orexigenic hormone named asprosin, the C-terminal cleavage product of profibrillin. Upon secretion, asprosin travels to the liver, where it exerts a glucogenic effect through OR4M1, an olfactory G-protein–coupled receptor. It also crosses the blood-brain barrier to stimulate appetite-modulating neurons in the arcuate nucleus of the hypothalamus, exerting an orexigenic effect via an as yet unidentified receptor. Specifically, it stimulates appetite by activating orexigenic AgRP neurons and inhibiting anorexigenic POMC neurons. Studies have also focused on the therapeutic potential of inhibiting asprosin for treatment of obesity and type 2 diabetes, both of which are characterized by high levels of circulating asprosin. It has been shown that anti-asprosin monoclonal antibodies reduce blood glucose, appetite, and body weight, validating asprosin as a therapeutic target. Current work aims to uncover key features of the asprosin biology such as the identification of its neuronal receptor, identification of the secretion mechanism from adipose tissue, and development of anti-asprosin monoclonal antibodies as diabetes and obesity therapies.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/dbi19-0009
      Issue No: Vol. 69, No. 4 (2020)
       
  • Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid
           Partitioning and Hepatic Insulin Resistance Through Increased
           Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2
           Diabetes
    • Authors: Carreau; A.-M.; Noll, C.; Blondin, D. P.; Frisch, F.; Nadeau, M.; Pelletier, M.; Phoenix, S.; Cunnane, S. C.; Guerin, B.; Turcotte, E. E.; Lebel, S.; Biertho, L.; Tchernof, A.; Carpentier, A. C.
      Pages: 567 - 577
      Abstract: Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0773
      Issue No: Vol. 69, No. 4 (2020)
       
  • A Single Bout of One-Legged Exercise to Local Exhaustion Decreases Insulin
           Action in Nonexercised Muscle Leading to Decreased Whole-Body Insulin
           Action
    • Authors: Steenberg; D. E.; Hingst, J. R.; Birk, J. B.; Thorup, A.; Kristensen, J. M.; Sjoberg, K. A.; Kiens, B.; Richter, E. A.; Wojtaszewski, J. F. P.
      Pages: 578 - 590
      Abstract: A single bout of exercise enhances insulin action in the exercised muscle. However, not all human studies find that this translates into increased whole-body insulin action, suggesting that insulin action in rested muscle or other organs may be decreased by exercise. To investigate this, eight healthy men underwent a euglycemic-hyperinsulinemic clamp on 2 separate days: one day with prior one-legged knee-extensor exercise to local exhaustion (~2.5 h) and another day without exercise. Whole-body glucose disposal was ~18% lower on the exercise day as compared with the resting day due to decreased (~37%) insulin-stimulated glucose uptake in the nonexercised muscle. Insulin signaling at the level of Akt2 was impaired in the nonexercised muscle on the exercise day, suggesting that decreased insulin action in nonexercised muscle may reduce GLUT4 translocation in response to insulin. Thus, the effect of a single bout of exercise on whole-body insulin action depends on the balance between local effects increasing and systemic effects decreasing insulin action. Physiologically, this mechanism may serve to direct glucose into the muscles in need of glycogen replenishment. For insulin-treated patients, this complex relationship may explain the difficulties in predicting the adequate insulin dose for maintaining glucose homeostasis following physical activity.
      Keywords: Exercise
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-1010
      Issue No: Vol. 69, No. 4 (2020)
       
  • Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity
           by Regulating L-Type Pyruvate Kinase
    • Authors: Shi; J.-H.; Lu, J.-Y.; Chen, H.-Y.; Wei, C.-C.; Xu, X.; Li, H.; Bai, Q.; Xia, F.-Z.; Lam, S. M.; Zhang, H.; Shi, Y.-N.; Cao, D.; Chen, L.; Shui, G.; Yang, X.; Lu, Y.; Chen, Y.-X.; Zhang, W. J.
      Pages: 591 - 602
      Abstract: Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK.
      Keywords: Integrated Physiology-Macronutrient Metabolism and Food Intake
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0388
      Issue No: Vol. 69, No. 4 (2020)
       
  • Perivascular Adipose Tissue Controls Insulin-Stimulated Perfusion,
           Mitochondrial Protein Expression, and Glucose Uptake in Muscle Through
           Adipomuscular Arterioles
    • Authors: Turaihi; A. H.; Serne, E. H.; Molthoff, C. F. M.; Koning, J. J.; Knol, J.; Niessen, H. W.; Goumans, M. J. T. H.; van Poelgeest, E. M.; Yudkin, J. S.; Smulders, Y. M.; Jimenez, C. R.; van Hinsbergh, V. W. M.; Eringa, E. C.
      Pages: 603 - 613
      Abstract: Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and diabetes.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db18-1066
      Issue No: Vol. 69, No. 4 (2020)
       
  • L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and
           Paracrine GLP-1 and Serotonin Signaling
    • Authors: Lund; M. L.; Sorrentino, G.; Egerod, K. L.; Kroone, C.; Mortensen, B.; Knop, F. K.; Reimann, F.; Gribble, F. M.; Drucker, D. J.; de Koning, E. J. P.; Schoonjans, K.; Bäckhed, F.; Schwartz, T. W.; Petersen, N.
      Pages: 614 - 623
      Abstract: Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein–coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1–dependent and serotonin-mediated mechanism.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0764
      Issue No: Vol. 69, No. 4 (2020)
       
  • Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in
           Patients and in a LADA Rat Model Compared With Type 1 Diabetes
    • Authors: Jörns; A.; Wedekind, D.; Jähne, J.; Lenzen, S.
      Pages: 624 - 633
      Abstract: Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.
      Keywords: Islet Biology-Apoptosis
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0865
      Issue No: Vol. 69, No. 4 (2020)
       
  • Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting
           Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic
           Endocrine Progenitor Cells After Implantation in Mice
    • Authors: Mochida; T.; Ueno, H.; Tsubooka-Yamazoe, N.; Hiyoshi, H.; Ito, R.; Matsumoto, H.; Toyoda, T.
      Pages: 634 - 646
      Abstract: The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0728
      Issue No: Vol. 69, No. 4 (2020)
       
  • Lamin C Counteracts Glucose Intolerance in Aging, Obesity, and Diabetes
           Through {beta}-Cell Adaptation
    • Authors: de Toledo; M.; Lopez-Mejia, I. C.; Cavelier, P.; Pratlong, M.; Barrachina, C.; Gromada, X.; Annicotte, J.-S.; Tazi, J.; Chavey, C.
      Pages: 647 - 660
      Abstract: Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C only–expressing mice (LmnaLCS/LCS) become obese but remain glucose tolerant due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that LmnaLCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in LmnaLCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a β-cell–adaptive transcriptional program during metabolic stresses, highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0377
      Issue No: Vol. 69, No. 4 (2020)
       
  • Maternal Type 1 Diabetes Reduces Autoantigen-Responsive CD4+ T Cells in
           Offspring
    • Authors: Knoop; J.; Eugster, A.; Gavrisan, A.; Lickert, R.; Sedlmeier, E.-M.; Dietz, S.; Lindner, A.; Warncke, K.; Hummel, N.; Ziegler, A.-G.; Bonifacio, E.
      Pages: 661 - 669
      Abstract: Autoimmunity against pancreatic β-cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4+ T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4+ T cells, and improved regulation of CD4+ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0751
      Issue No: Vol. 69, No. 4 (2020)
       
  • {beta}-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal
           Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum
           Aminopeptidase 1
    • Authors: Thomaidou; S.; Kracht, M. J. L.; van der Slik, A.; Laban, S.; de Koning, E. J.; Carlotti, F.; Hoeben, R. C.; Roep, B. O.; Zaldumbide, A.
      Pages: 670 - 680
      Abstract: The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0984
      Issue No: Vol. 69, No. 4 (2020)
       
  • Evidence Against an Important Role of Plasma Insulin and Glucagon
           Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors
    • Authors: Alatrach; M.; Laichuthai, N.; Martinez, R.; Agyin, C.; Ali, A. M.; Al-Jobori, H.; Lavynenko, O.; Adams, J.; Triplitt, C.; DeFronzo, R.; Cersosimo, E.; Abdul-Ghani, M.
      Pages: 681 - 688
      Abstract: Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.
      Keywords: Clinical Therapeutics/New Technology-Oral Agents
      PubDate: 2020-03-20T11:50:28-07:00
      DOI: 10.2337/db19-0770
      Issue No: Vol. 69, No. 4 (2020)
       
  • Retinopathy in a Diet-Induced Type 2 Diabetic Rat Model and Role of
           Epigenetic Modifications
    • Authors: Kowluru; R. A.
      Pages: 689 - 698
      Abstract: Type 2 diabetes accounts for 90% of the population with diabetes, and these patients are generally obese and hyperlipidemic. In addition to hyperglycemia, hyperlipidemia is also closely related with diabetic retinopathy. The aim was to investigate retinopathy in a model closely mimicking the normal progression and metabolic features of the population with type 2 diabetes and elucidate the molecular mechanism. Retinopathy was evaluated in rats fed a 45% kcal as fat diet for 8 weeks before administering streptozotocin, 30 mg/kg body weight (T2D), and compared with age- and duration-matched type 1 diabetic rats (T1D) (60 mg/kg streptozotocin). The role of epigenetic modifications in mitochondrial damage was evaluated in retinal microvasculature. T2D rats were obese and severely hyperlipidemic, with impaired glucose and insulin tolerance compared with age-matched T1D rats. While at 4 months of diabetes, T1D rats had no detectable retinopathy, T2D rats had significant retinopathy, their mitochondrial copy numbers were lower, and mtDNA and Rac1 promoter DNA methylation was exacerbated. At 6 months, retinopathy was comparable in T2D and T1D rats, suggesting that obesity exaggerates hyperglycemia-induced epigenetic modifications, accelerating mitochondrial damage and diabetic retinopathy. Thus, maintenance of good lifestyle and BMI could be beneficial in regulating epigenetic modifications and preventing/retarding retinopathy in patients with diabetes.
      Keywords: Complications-Retinopathy
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-1009
      Issue No: Vol. 69, No. 4 (2020)
       
  • Major Improvement in Wound Healing Through Pharmacologic Mobilization of
           Stem Cells in Severely Diabetic Rats
    • Authors: Qi; L.; Ahmadi, A. R.; Huang, J.; Chen, M.; Pan, B.; Kuwabara, H.; Iwasaki, K.; Wang, W.; Wesson, R.; Cameron, A. M.; Cui, S.; Burdick, J.; Sun, Z.
      Pages: 699 - 712
      Abstract: Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow–derived CD133+ and CD34+ endothelial progenitor cells and Ym1/2+ M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0907
      Issue No: Vol. 69, No. 4 (2020)
       
  • Troponin T Parallels Structural Nerve Damage in Type 2 Diabetes: A
           Cross-sectional Study Using Magnetic Resonance Neurography
    • Authors: Jende; J. M. E.; Groener, J. B.; Kender, Z.; Hahn, A.; Morgenstern, J.; Heiland, S.; Nawroth, P. P.; Bendszus, M.; Kopf, S.; Kurz, F. T.
      Pages: 713 - 723
      Abstract: Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve’s fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve’s FA (r = –0.52, P < 0.001), with a closer correlation in DN patients (r = –0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = –0.65, P < 0.001) and tibial NCVs (r = –0.44, P = 0.002) and amplitudes (r = –0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-1094
      Issue No: Vol. 69, No. 4 (2020)
       
  • n-3 Fatty Acid and Its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell
           Dysfunction by Enhancing Mùˆller BDNF in Diabetic Retinopathy
    • Authors: Suzumura; A.; Kaneko, H.; Funahashi, Y.; Takayama, K.; Nagaya, M.; Ito, S.; Okuno, T.; Hirakata, T.; Nonobe, N.; Kataoka, K.; Shimizu, H.; Namba, R.; Yamada, K.; Ye, F.; Ozawa, Y.; Yokomizo, T.; Terasaki, H.
      Pages: 724 - 735
      Abstract: Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage, but how BDNF is upregulated in DR remains unclear. We found an increase in hydrogen peroxide (H2O2) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H2O2 by high glucose, and H2O2 reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller glia cell. Oral intake of eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed an increase in several EPA metabolites in the eyes of EPA-E–fed rats. In particular, an EPA metabolite, 18-hydroxyeicosapentaenoic acid (18-HEPE), induced BDNF upregulation in Müller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Müller glia cells by increasing 18-HEPE in the early stages of DR.
      Keywords: Complications-Retinopathy
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0550
      Issue No: Vol. 69, No. 4 (2020)
       
  • PI3K{delta} as a Novel Therapeutic Target in Pathological Angiogenesis
    • Authors: Wu; W.; Zhou, G.; Han, H.; Huang, X.; Jiang, H.; Mukai, S.; Kazlauskas, A.; Cui, J.; Matsubara, J. A.; Vanhaesebroeck, B.; Xia, X.; Wang, J.; Lei, H.
      Pages: 736 - 748
      Abstract: Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.
      Keywords: Complications-Retinopathy
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0713
      Issue No: Vol. 69, No. 4 (2020)
       
  • Exosomes Derived From Schwann Cells Ameliorate Peripheral Neuropathy in
           Type 2 Diabetic Mice
    • Authors: Wang; L.; Chopp, M.; Szalad, A.; Lu, X.; Zhang, Y.; Wang, X.; Cepparulo, P.; Lu, M.; Li, C.; Zhang, Z. G.
      Pages: 749 - 759
      Abstract: Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.
      Keywords: Complications-Neuropathy
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0432
      Issue No: Vol. 69, No. 4 (2020)
       
  • Comprehensive Glycomic Analysis Reveals That Human Serum Albumin Glycation
           Specifically Affects the Pharmacokinetics and Efficacy of Different
           Anticoagulant Drugs in Diabetes
    • Authors: Qiu; H.; Jin, L.; Chen, J.; Shi, M.; Shi, F.; Wang, M.; Li, D.; Xu, X.; Su, X.; Yin, X.; Li, W.; Zhou, X.; Linhardt, R. J.; Wang, Z.; Chi, L.; Zhang, Q.
      Pages: 760 - 770
      Abstract: Long-term hyperglycemia in patients with diabetes leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in patients with diabetes. In this study, a novel mass spectrometry approach was developed to reveal the differences in the profiles of HSA glycation sites between patients with diabetes and healthy subjects. K199 was the glycation site most significantly changed in patients with diabetes, contributing to different interactions of glycated HSA and normal HSA with two types of anticoagulant drugs, heparin and warfarin. An in vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between patients with diabetes and patients without diabetes who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when they are administered anticoagulant drugs or drugs for treating other chronic diseases.
      Keywords: Epidemiology-Cardiovascular Disease
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0738
      Issue No: Vol. 69, No. 4 (2020)
       
  • PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in
           Type 2 Diabetes: Findings From ACCORD-Lipid
    • Authors: Morieri; M. L.; Shah, H. S.; Sjaarda, J.; Lenzini, P. A.; Campbell, H.; Motsinger-Reif, A. A.; Gao, H.; Lovato, L.; Prudente, S.; Pandolfi, A.; Pezzolesi, M. G.; Sigal, R. J.; Pare, G.; Marcovina, S. M.; Rotroff, D. M.; Patorno, E.; Mercuri, L.; Trischitta, V.; Chew, E. Y.; Kraft, P.; Buse, J. B.; Wagner, M. J.; Cresci, S.; Gerstein, H. C.; Ginsberg, H. N.; Mychaleckyj, J. C.; Doria, A.
      Pages: 771 - 783
      Abstract: The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction = 3.7 x 10–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0973
      Issue No: Vol. 69, No. 4 (2020)
       
  • Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes
    • Authors: Forgetta; V.; Manousaki, D.; Istomine, R.; Ross, S.; Tessier, M.-C.; Marchand, L.; Li, M.; Qu, H.-Q.; Bradfield, J. P.; Grant, S. F. A.; Hakonarson, H.; the DCCT/EDIC Research Group; Paterson, A. D.; Piccirillo, C.; Polychronakos, C.; Richards, J. B.
      Pages: 784 - 795
      Abstract: Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF]>5%). We aimed to identify novel rare or low-frequency (MAF
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db19-0831
      Issue No: Vol. 69, No. 4 (2020)
       
  • Erratum. miRNA Regulation of the Hyperproliferative Phenotype of Vascular
           Smooth Muscle Cells in Diabetes. Diabetes 2018;67:2554-2568
    • Authors: Torella; D.; Iaconetti, C.; Tarallo, R.; Marino, F.; Giurato, G.; Veneziano, C.; Aquila, I.; Scalise, M.; Mancuso, T.; Cianflone, E.; Valeriano, C.; Marotta, P.; Tamme, L.; Vicinanza, C.; Sasso, F. C.; Cozzolino, D.; Torella, M.; Weisz, A.; Indolfi, C.
      Pages: 796 - 796
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db20-er04a
      Issue No: Vol. 69, No. 4 (2020)
       
  • Erratum. Comparison of Kidney Transcriptomic Profiles of Early and
           Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease
           Progression. Diabetes 2019;68:2301-2314
    • Authors: Fan; Y.; Yi, Z.; DAgati, V. D.; Sun, Z.; Zhong, F.; Zhang, W.; Wen, J.; Zhou, T.; Li, Z.; He, L.; Zhang, Q.; Lee, K.; He, J. C.; Wang, N.
      Pages: 797 - 797
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db20-er04b
      Issue No: Vol. 69, No. 4 (2020)
       
  • Erratum. Evaluation of the Genetic Association Between Adult Obesity and
           Neuropsychiatric Disease. Diabetes 2019;68:2235-2246
    • Authors: Stahel; P.; Nahmias, A.; Sud, S. K.; Lee, S. J.; Pucci, A.; Yousseif, A.; Youseff, A.; Jackson, T.; Urbach, D. R.; Okrainec, A.; Allard, J. P.; Sockalingam, S.; Yao, T.; Barua, M.; Jiao, H.; Magi, R.; Bassett, A. S.; Paterson, A. D.; Dahlman, I.; Batterham, R. L.; Dash, S.
      Pages: 798 - 798
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db20-er04c
      Issue No: Vol. 69, No. 4 (2020)
       
  • Issues and Events
    • Pages: 799 - 799
      PubDate: 2020-03-20T11:50:29-07:00
      DOI: 10.2337/db20-ie04
      Issue No: Vol. 69, No. 4 (2020)
       
 
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