Subjects -> MEDICAL SCIENCES (Total: 8803 journals)
    - ALLERGOLOGY AND IMMUNOLOGY (225 journals)
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    - CARDIOVASCULAR DISEASES (350 journals)
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    - COMMUNICABLE DISEASES, EPIDEMIOLOGY (234 journals)
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    - DERMATOLOGY AND VENEREOLOGY (167 journals)
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    - GASTROENTEROLOGY AND HEPATOLOGY (191 journals)
    - GERONTOLOGY AND GERIATRICS (142 journals)
    - HEMATOLOGY (159 journals)
    - HYPNOSIS (4 journals)
    - INTERNAL MEDICINE (178 journals)
    - LABORATORY AND EXPERIMENTAL MEDICINE (98 journals)
    - MEDICAL GENETICS (58 journals)
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    - SPORTS MEDICINE (83 journals)
    - SURGERY (412 journals)
    - UROLOGY, NEPHROLOGY AND ANDROLOGY (159 journals)

INTERNAL MEDICINE (178 journals)                     

Showing 1 - 180 of 180 Journals sorted alphabetically
Abdomen     Open Access  
ACP Hospitalist     Full-text available via subscription   (Followers: 9)
ACP Internist     Full-text available via subscription   (Followers: 10)
ACP Journal Club     Full-text available via subscription   (Followers: 11)
Acta Clinica Belgica     Hybrid Journal   (Followers: 1)
Acute and Critical Care     Open Access   (Followers: 11)
Acute Medicine     Full-text available via subscription   (Followers: 9)
Advances in Hepatology     Open Access   (Followers: 4)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
African Journal of Primary Health Care & Family Medicine     Open Access   (Followers: 6)
African Journal of Thoracic and Critical Care Medicine     Open Access  
American Family Physician     Full-text available via subscription   (Followers: 38)
American Journal of Hypertension     Hybrid Journal   (Followers: 31)
Anales de Medicina Interna     Open Access   (Followers: 1)
Anatomy & Physiology : Current Research     Open Access   (Followers: 9)
Angiology     Hybrid Journal   (Followers: 5)
Annals of Colorectal Research     Open Access   (Followers: 1)
Annals of Internal Medicine     Full-text available via subscription   (Followers: 392)
AORN Journal     Hybrid Journal   (Followers: 27)
Apollo Medicine     Open Access  
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archivos de Medicina Interna     Open Access   (Followers: 1)
Asia Oceania Journal of Nuclear Medicine & Biology     Open Access   (Followers: 4)
Asian Pacific Journal of Tropical Disease     Full-text available via subscription   (Followers: 3)
Australasian Physical & Engineering Sciences in Medicine     Hybrid Journal   (Followers: 1)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access   (Followers: 1)
BMJ Open Diabetes Research & Care     Open Access   (Followers: 35)
BMJ Quality & Safety     Hybrid Journal   (Followers: 69)
Bone & Joint Journal     Hybrid Journal   (Followers: 139)
Brain Communications     Open Access   (Followers: 4)
Brain Science Advances     Open Access  
Canadian Journal of General Internal Medicine     Open Access   (Followers: 2)
Cardiovascular Medicine in General Practice     Full-text available via subscription   (Followers: 7)
Case Reports in Internal Medicine     Open Access   (Followers: 1)
Cell Death & Disease     Open Access   (Followers: 3)
Cellular and Molecular Gastroenterology and Hepatology     Open Access   (Followers: 3)
Cephalalgia     Hybrid Journal   (Followers: 8)
Cephalalgia Reports     Open Access   (Followers: 4)
Chronic Diseases and Injuries in Canada     Free   (Followers: 1)
Clinical Ethics     Hybrid Journal   (Followers: 13)
Clinical Liver Disease     Open Access   (Followers: 5)
Clinical Nutrition     Hybrid Journal   (Followers: 98)
Clinical Thyroidology     Full-text available via subscription   (Followers: 1)
CNE Pflegemanagement     Hybrid Journal  
Communication Law and Policy     Hybrid Journal   (Followers: 5)
Current Diabetes Reports     Hybrid Journal   (Followers: 30)
Current Hepatology Reports     Hybrid Journal  
Current Research: Integrative Medicine     Open Access  
CVIR Endovascular     Open Access   (Followers: 1)
Der Internist     Hybrid Journal   (Followers: 12)
Diabetes     Full-text available via subscription   (Followers: 603)
Diabetes Care     Full-text available via subscription   (Followers: 577)
Diabetes Internacional     Open Access  
Diabetes Spectrum     Full-text available via subscription   (Followers: 17)
Diagnosis     Hybrid Journal   (Followers: 1)
Egyptian Journal of Bronchology     Open Access  
Egyptian Journal of Internal Medicine     Open Access   (Followers: 1)
Egyptian Journal of Neurosurgery     Open Access  
Egyptian Liver Journal     Open Access   (Followers: 2)
Egyptian Spine Journal     Open Access  
EMC - Aparato Locomotor     Hybrid Journal  
Endovascular Neuroradiology / Ендоваскулярна нейрорентгенохірургія     Open Access   (Followers: 1)
eNeuro     Open Access   (Followers: 3)
Ergonomics     Hybrid Journal   (Followers: 24)
European Journal of Inflammation     Open Access   (Followers: 2)
European Journal of Internal Medicine     Full-text available via subscription   (Followers: 10)
European Journal of Translational Myology     Open Access  
European Radiology Experimental     Open Access   (Followers: 2)
Head and Neck Tumors     Open Access   (Followers: 1)
Health Sociology Review     Hybrid Journal   (Followers: 14)
HemaSphere     Open Access   (Followers: 2)
Hepatology Communications     Open Access  
Hepatoma Research     Open Access   (Followers: 3)
Human Physiology     Hybrid Journal   (Followers: 5)
ImmunoHorizons     Open Access  
Immunological Medicine     Open Access  
Infectious Diseases: Research and Treatment     Open Access   (Followers: 5)
Inflammation and Regeneration     Open Access   (Followers: 2)
Inflammatory Intestinal Diseases     Open Access  
Innere Medizin up2date     Hybrid Journal   (Followers: 1)
Internal and Emergency Medicine     Hybrid Journal   (Followers: 5)
Internal Medicine Journal     Hybrid Journal   (Followers: 9)
International Journal of Abdominal Wall and Hernia Surgery     Open Access   (Followers: 1)
International Journal of Anatomy and Research     Open Access   (Followers: 2)
International Journal of Angiology     Hybrid Journal  
International Journal of Artificial Organs     Hybrid Journal   (Followers: 3)
International Journal of Hyperthermia     Open Access  
International Journal of Internal Medicine     Open Access   (Followers: 3)
International Journal of Noncommunicable Diseases     Open Access  
International Journal of Psychiatry in Clinical Practice     Hybrid Journal   (Followers: 6)
Iranian Journal of Neurosurgery     Open Access   (Followers: 1)
Italian Journal of Anatomy and Embryology     Open Access   (Followers: 1)
JAC-Antimicrobial Resistance     Open Access   (Followers: 4)
JAMA Internal Medicine     Full-text available via subscription   (Followers: 363)
JCSM Clinical Reports     Open Access   (Followers: 3)
JHEP Reports     Open Access  
JIMD Reports     Open Access  
JMV - Journal de Médecine Vasculaire     Hybrid Journal   (Followers: 1)
Joint Commission Journal on Quality and Patient Safety     Hybrid Journal   (Followers: 41)
JOP. Journal of the Pancreas     Open Access   (Followers: 2)
Journal of Basic & Clinical Physiology & Pharmacology     Hybrid Journal   (Followers: 1)
Journal of Bone Oncology     Open Access   (Followers: 1)
Journal of Cancer & Allied Specialties     Open Access  
Journal of Clinical and Experimental Hepatology     Full-text available via subscription   (Followers: 3)
Journal of Clinical Movement Disorders     Open Access   (Followers: 3)
Journal of Community Hospital Internal Medicine Perspectives     Open Access  
Journal of Cutaneous Immunology and Allergy     Open Access  
Journal of Developmental Origins of Health and Disease     Hybrid Journal   (Followers: 2)
Journal of Endoluminal Endourology     Open Access  
Journal of Gastroenterology and Hepatology Research     Open Access   (Followers: 4)
Journal of General Internal Medicine     Hybrid Journal   (Followers: 23)
Journal of Hypertension     Hybrid Journal   (Followers: 14)
Journal of Infectious Diseases     Hybrid Journal   (Followers: 48)
Journal of Interdisciplinary Medicine     Open Access  
Journal of Internal Medicine     Hybrid Journal   (Followers: 11)
Journal of Liver : Disease & Transplantation     Hybrid Journal   (Followers: 7)
Journal of Medical Internet Research     Open Access   (Followers: 24)
Journal of Movement Disorders     Open Access   (Followers: 2)
Journal of Pain and Symptom Management     Hybrid Journal   (Followers: 46)
Journal of Pancreatic Cancer     Open Access  
Journal of Renal and Hepatic Disorders     Open Access  
Journal of Solid Tumors     Open Access   (Followers: 1)
Journal of Sports Medicine and Allied Health Sciences : Official Journal of the Ohio Athletic Trainers Association     Open Access   (Followers: 1)
Journal of the American Board of Family Medicine     Open Access   (Followers: 11)
Journal of the European Mosquito Control Association     Open Access  
Journal of Translational Internal Medicine     Open Access  
Jurnal Vektor Penyakit     Open Access  
La Revue de Medecine Interne     Full-text available via subscription   (Followers: 3)
Lege artis - Das Magazin zur ärztlichen Weiterbildung     Hybrid Journal   (Followers: 1)
Liver Cancer International     Open Access  
Liver Research     Open Access  
Molecular Diagnosis & Therapy     Hybrid Journal   (Followers: 3)
Molecular Therapy - Oncolytics     Open Access  
Multiple Sclerosis and Demyelinating Disorders     Open Access   (Followers: 7)
MYOPAIN. A journal of myofascial pain and fibromyalgia     Hybrid Journal   (Followers: 18)
Neuro-Oncology Advances     Open Access   (Followers: 1)
Neurobiology of Pain     Open Access   (Followers: 2)
Neurointervention     Open Access   (Followers: 6)
Neuromuscular Diseases     Open Access  
Nigerian Journal of Gastroenterology and Hepatology     Full-text available via subscription  
OA Alcohol     Open Access   (Followers: 5)
Oncological Coloproctology     Open Access  
Open Journal of Internal Medicine     Open Access  
Pleura and Peritoneum     Open Access  
Pneumo News     Full-text available via subscription  
Polish Archives of Internal Medicine     Full-text available via subscription   (Followers: 2)
Preventing Chronic Disease     Free   (Followers: 2)
Progress in Transplantation     Hybrid Journal   (Followers: 1)
Prostate International     Open Access   (Followers: 2)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Pulmonary Therapy     Open Access   (Followers: 2)
Quality of Life Research     Hybrid Journal   (Followers: 20)
Research and Practice in Thrombosis and Haemostasis     Open Access  
Revista Chilena de Fonoaudiología     Open Access   (Followers: 1)
Revista de la Sociedad Peruana de Medicina Interna     Open Access   (Followers: 4)
Revista del Instituto de Medicina Tropical     Open Access  
Revista Hispanoamericana de Hernia     Open Access   (Followers: 1)
Revista Médica Internacional sobre el Síndrome de Down     Full-text available via subscription   (Followers: 1)
Revista Virtual de la Sociedad Paraguaya de Medicina Interna     Open Access   (Followers: 1)
Romanian Journal of Diabetes Nutrition and Metabolic Diseases     Open Access   (Followers: 1)
Romanian Journal of Internal Medicine     Open Access  
Russian Journal of Child Neurology     Open Access   (Followers: 1)
Scandinavian Journal of Primary Health Care     Open Access   (Followers: 8)
Schlaf     Hybrid Journal  
Schmerzmedizin     Hybrid Journal  
Scientific Journal of the Foot & Ankle     Open Access   (Followers: 1)
SciMedicine Journal     Open Access   (Followers: 3)
SEMERGEN - Medicina de Familia     Full-text available via subscription   (Followers: 1)
The Journal of Critical Care Medicine     Open Access   (Followers: 9)
Therapeutic Advances in Chronic Disease     Open Access   (Followers: 8)
Therapeutic Advances in Musculoskeletal Disease     Hybrid Journal   (Followers: 6)
Thieme Case Report     Hybrid Journal   (Followers: 1)
Tijdschrift voor Urologie     Hybrid Journal  
Tissue Barriers     Hybrid Journal   (Followers: 1)
Transactions of the Royal Society of Tropical Medicine and Hygiene     Hybrid Journal   (Followers: 3)
Transgender Health     Open Access   (Followers: 3)
Trends in Anaesthesia and Critical Care     Full-text available via subscription   (Followers: 23)
US Cardiology Review     Open Access  
Vascular and Endovascular Review     Open Access   (Followers: 1)
Ожирение и метаболизм     Open Access  

           

Similar Journals
Journal Cover
Diabetes
Journal Prestige (SJR): 4.435
Citation Impact (citeScore): 6
Number of Followers: 603  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
Published by American Diabetes Association Homepage  [4 journals]
  • A Special Thanks to the Reviewers of Diabetes
    • Pages: 821 - 822
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db21-en04
      Issue No: Vol. 70, No. 4 (2021)
       
  • Pregnancies in Diabetes and Obesity: The Capacity-Load Model of Placental
           Adaptation
    • Authors: Desoye; G.; Wells, J. C. K.
      Pages: 823 - 830
      Abstract: Excess nutritional supply to the growing fetus, resulting from maternal diabetes and obesity, is associated with increased risks of fetal maldevelopment and adverse metabolic conditions in postnatal life. The placenta, interposed between mother and fetus, serves as the gateway between the two circulations and is usually considered to mediate maternal exposures to the fetus through a direct supply line. In this Perspective, however, we argue that the placenta is not an innocent bystander and mounts responses to fetal "signals of distress" to sustain its own adequate function and protect the fetus. We describe several types of protection that the placenta can offer the fetus against maternal metabolic perturbations and offer a theoretical model of how the placenta responds to the intrauterine environment in maternal diabetes and obesity to stabilize the fetal environment. Our approach supports growing calls for early screening and control of pregnancy metabolism to minimize harmful fetal outcomes.
      Keywords: Pregnancy-Basic Science/Translational
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-1111
      Issue No: Vol. 70, No. 4 (2021)
       
  • Uncovering Pathways to Personalized Therapies in Type 1 Diabetes
    • Authors: Linsley; P. S.; Greenbaum, C. J.; Nepom, G. T.
      Pages: 831 - 841
      Abstract: The goal of personalized medicine is to match the right drugs to the right patients at the right time. Personalized medicine has been most successful in cases where there is a clear genetic linkage between a disease and a therapy. This is not the case with type 1 diabetes (T1D), a genetically complex immune-mediated disease of β-cell destruction. Researchers over decades have traced the natural history of disease sufficiently to use autoantibodies as predictive biomarkers for disease risk and to conduct successful clinical trials of disease-modifying therapy. Recent studies, however, have highlighted heterogeneity associated with progression, with nonuniform rate of insulin loss and distinct features of the peri-diagnostic period. Likewise, there is heterogeneity in immune profiles and outcomes in response to therapy. Unexpectedly, from these studies demonstrating perplexing complexity in progression and response to therapy, new biomarker-based principles are emerging for how to achieve personalized therapies for T1D. These include therapy timed to periods of disease activity, use of patient stratification biomarkers to align therapeutic target with disease endotype, pharmacodynamic biomarkers to achieve personalized dosing and appropriate combination therapies, and efficacy biomarkers for "treat-to-target" strategies. These principles provide a template for application of personalized medicine to complex diseases.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-1185
      Issue No: Vol. 70, No. 4 (2021)
       
  • Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic
           Polypeptide Receptor by Positron Emission Tomography
    • Authors: Eriksson; O.; Velikyan, I.; Haack, T.; Bossart, M.; Evers, A.; Lorenz, K.; Laitinen, I.; Larsen, P. J.; Plettenburg, O.; Johansson, L.; Pierrou, S.; Wagner, M.
      Pages: 842 - 853
      Abstract: Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with 68Ga. The resulting PET tracer [68Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68Ga]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68Ga]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-1096
      Issue No: Vol. 70, No. 4 (2021)
       
  • Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood
           DNA Methylation, Which Associates With Body Composition in the Offspring
    • Authors: Jönsson; J.; Renault, K. M.; Garcia-Calzon, S.; Perfilyev, A.; Estampador, A. C.; Norgaard, K.; Lind, M. V.; Vaag, A.; Hjort, L.; Michaelsen, K. F.; Carlsen, E. M.; Franks, P. W.; Ling, C.
      Pages: 854 - 866
      Abstract: Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR]
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0487
      Issue No: Vol. 70, No. 4 (2021)
       
  • Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight
           Regain by Potentiating Energy Expenditure
    • Authors: Presby; D. M.; Rudolph, M. C.; Sherk, V. D.; Jackman, M. R.; Foright, R. M.; Jones, K. L.; Houck, J. A.; Johnson, G. C.; Higgins, J. A.; Neufer, P. D.; Eckel, R. H.; MacLean, P. S.
      Pages: 867 - 877
      Abstract: Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0763
      Issue No: Vol. 70, No. 4 (2021)
       
  • Dynamic Uni- and Multicellular Patterns Encode Biphasic Activity in
           Pancreatic Islets
    • Authors: Jaffredo; M.; Bertin, E.; Pirog, A.; Puginier, E.; Gaitan, J.; Oucherif, S.; Lebreton, F.; Bosco, D.; Catargi, B.; Cattaert, D.; Renaud, S.; Lang, J.; Raoux, M.
      Pages: 878 - 888
      Abstract: Biphasic secretion is an autonomous feature of many endocrine micro-organs to fulfill physiological demands. The biphasic activity of islet β-cells maintains glucose homeostasis and is altered in type 2 diabetes. Nevertheless, underlying cellular or multicellular functional organizations are only partially understood. High-resolution noninvasive multielectrode array recordings permit simultaneous analysis of recruitment, of single-cell, and of coupling activity within entire islets in long-time experiments. Using this unbiased approach, we addressed the organizational modes of both first and second phase in mouse and human islets under physiological and pathophysiological conditions. Our data provide a new uni- and multicellular model of islet β-cell activation: during the first phase, small but highly active β-cell clusters are dominant, whereas during the second phase, electrical coupling generates large functional clusters via multicellular slow potentials to favor an economic sustained activity. Postprandial levels of glucagon-like peptide 1 favor coupling only in the second phase, whereas aging and glucotoxicity alter coupled activity in both phases. In summary, biphasic activity is encoded upstream of vesicle pools at the micro-organ level by multicellular electrical signals and their dynamic synchronization between β-cells. The profound alteration of the electrical organization of islets in pathophysiological conditions may contribute to functional deficits in type 2 diabetes.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0214
      Issue No: Vol. 70, No. 4 (2021)
       
  • Syntaxin 4 Mediates NF-{kappa}B Signaling and Chemokine Ligand Expression
           via Specific Interaction With I{kappa}B{beta}
    • Authors: Veluthakal; R.; Oh, E.; Ahn, M.; Chatterjee Bhowmick, D.; Thurmond, D. C.
      Pages: 889 - 902
      Abstract: Enrichment of human islets with syntaxin 4 (STX4) improves functional β-cell mass through a nuclear factor-B (NF-B)–dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. For determination of the signaling events linking STX4 enrichment and downregulation of NF-B activity, STX4 was overexpressed in human islets, EndoC-βH1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interferon- individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of IBβ but not IBα. Inhibition of IKKβ prevented IBβ degradation, suggesting that IKKβ phosphorylates IBβ. Moreover, the IKKβ inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKKβ in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected IBβ from proteasomal degradation, and like wild-type STX4, stabilized STX4 coimmunoprecipitated with IBβ and the p50-NF-B. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-B signaling in β-cells via associating with and preventing IBβ degradation, suppressing chemokine expression, and protecting islet β-cells from cytokine-mediated dysfunction and demise.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0868
      Issue No: Vol. 70, No. 4 (2021)
       
  • Cell Cycle Regulation of the Pdx1 Transcription Factor in Developing
           Pancreas and Insulin-Producing {beta}-Cells
    • Authors: Zhu; X.; Oguh, A.; Gingerich, M. A.; Soleimanpour, S. A.; Stoffers, D. A.; Gannon, M.
      Pages: 903 - 916
      Abstract: Current evidence indicates that proliferating β-cells express lower levels of some functional cell identity genes, suggesting that proliferating cells are not optimally functional. Pdx1 is important for β-cell specification, function, and proliferation and is mutated in monogenic forms of diabetes. However, its regulation during the cell cycle is unknown. Here we examined Pdx1 protein expression in immortalized β-cells, maternal mouse islets during pregnancy, and mouse embryonic pancreas. We demonstrate that Pdx1 localization and protein levels are highly dynamic. In nonmitotic cells, Pdx1 is not observed in constitutive heterochromatin, nucleoli, or most areas containing repressive epigenetic marks. At prophase, Pdx1 is enriched around the chromosomes before Ki67 coating of the chromosome surface. Pdx1 uniformly localizes in the cytoplasm at prometaphase and becomes enriched around the chromosomes again at the end of cell division, before nuclear envelope formation. Cells in S phase have lower Pdx1 levels than cells at earlier cell cycle stages, and overexpression of Pdx1 in INS-1 cells prevents progression toward G2, suggesting that cell cycle–dependent regulation of Pdx1 is required for completion of mitosis. Together, we find that Pdx1 localization and protein levels are tightly regulated throughout the cell cycle. This dynamic regulation has implications for the dichotomous role of Pdx1 in β-cell function and proliferation.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0599
      Issue No: Vol. 70, No. 4 (2021)
       
  • Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by
           Increasing {beta}-Cell Mass in db/db Mice
    • Authors: Omori; K.; Nakamura, A.; Miyoshi, H.; Yamauchi, Y.; Kawata, S.; Takahashi, K.; Kitao, N.; Nomoto, H.; Kameda, H.; Cho, K. Y.; Terauchi, Y.; Atsumi, T.
      Pages: 917 - 931
      Abstract: Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in β-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
      Keywords: Integrated Physiology-Insulin Secretion In Vivo
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0881
      Issue No: Vol. 70, No. 4 (2021)
       
  • Genetic Composition and Autoantibody Titers Model the Probability of
           Detecting C-Peptide Following Type 1 Diabetes Diagnosis
    • Authors: Williams; M. D.; Bacher, R.; Perry, D. J.; Grace, C. R.; McGrail, K. M.; Posgai, A. L.; Muir, A.; Chamala, S.; Haller, M. J.; Schatz, D. A.; Brusko, T. M.; Atkinson, M. A.; Wasserfall, C. H.
      Pages: 932 - 943
      Abstract: We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA–2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0–60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA–2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous β-cell function.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0937
      Issue No: Vol. 70, No. 4 (2021)
       
  • Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1
           Diabetes Staging and Pancreas Size
    • Authors: Ross; J. J.; Wasserfall, C. H.; Bacher, R.; Perry, D. J.; McGrail, K.; Posgai, A. L.; Dong, X.; Muir, A.; Li, X.; Campbell-Thompson, M.; Brusko, T. M.; Schatz, D. A.; Haller, M. J.; Atkinson, M. A.
      Pages: 944 - 954
      Abstract: Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and before disease onset. We hypothesized that three pancreas enzymes (amylase, lipase, and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody–positive (1AAb+) and multiple-AAb+ (≥2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb-negative (AAb–) first-degree relatives, and AAb– control subjects. Lipase and trypsinogen were significantly reduced in ≥2AAb+, recent-onset, and established type 1 diabetes subjects versus control subjects and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (area under the receiver operating characteristic curve [AUROC] = 81.4%) performed equivalently to all three enzymes (AUROC = 81.4%) in categorizing ≥2AAb+ versus 1AAb+ subjects. For cohort 2 (n = 246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPVBMI, P < 0.001), previously measured by MRI. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPVBMI and may improve disease staging in pretype 1 diabetes.
      Keywords: Immunology
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0995
      Issue No: Vol. 70, No. 4 (2021)
       
  • Natural Protection From Type 1 Diabetes in NOD Mice Is Characterized by a
           Unique Pancreatic Islet Phenotype
    • Authors: Boldison; J.; Thayer, T. C.; Davies, J.; Wong, F. S.
      Pages: 955 - 965
      Abstract: The NOD mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally protected from developing diabetes, and currently, studies characterizing this cohort are very limited. Here, using both immunofluorescence and multiparameter flow cytometry, we focus on the pancreatic islet morphology and immune infiltrate observed in naturally protected NOD mice. We show that naturally protected NOD mice are characterized by an increased frequency of insulin-containing, smaller-sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed toward a regulatory phenotype in both T- and B-cell compartments. Pancreatic islets have an increased frequency of IL-10–producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift toward reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0945
      Issue No: Vol. 70, No. 4 (2021)
       
  • Longitudinal Assessment of 11C-5-Hydroxytryptophan Uptake in Pancreas
           After Debut of Type 1 Diabetes
    • Authors: Espes; D.; Carlsson, P.-O.; Selvaraju, R. K.; Rosestedt, M.; Cheung, P.; Ahlström, H.; Korsgren, O.; Eriksson, O.
      Pages: 966 - 975
      Abstract: The longitudinal alterations of the pancreatic β-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by 11C-5-hydroxytryptophan (11C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of β-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of 11C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of 11C-5-HTP correlated with the long-term metabolic control as estimated by HbA1c (P < 0.05). Our findings argue against a major destruction of β-cell or islet mass in the 2-year period after diagnosis of T1D.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0776
      Issue No: Vol. 70, No. 4 (2021)
       
  • Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates
           Diabetes in NOD Mice
    • Authors: Mhanna; V.; Fourcade, G.; Barennes, P.; Quiniou, V.; Pham, H. P.; Ritvo, P.-G.; Brimaud, F.; Gouritin, B.; Churlaud, G.; Six, A.; Mariotti-Ferrandiz, E.; Klatzmann, D.
      Pages: 976 - 985
      Abstract: Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic β-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2–expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.
      Keywords: Immunology
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0896
      Issue No: Vol. 70, No. 4 (2021)
       
  • Novel Linkage Peaks Discovered for Diabetic Nephropathy in Individuals
           With Type 1 Diabetes
    • Authors: Haukka; J.; Sandholm, N.; Valo, E.; Forsblom, C.; Harjutsalo, V.; Cole, J. B.; McGurnaghan, S. J.; Colhoun, H. M.; Groop, P.-H.; on behalf of the FinnDiane Study Group
      Pages: 986 - 995
      Abstract: Genome-wide association studies (GWAS) and linkage studies have had limited success in identifying genome-wide significantly linked regions or risk loci for diabetic nephropathy (DN) in individuals with type 1 diabetes (T1D). As GWAS cohorts have grown, they have also included more documented and undocumented familial relationships. Here we computationally inferred and manually curated pedigrees in a study cohort of>6,000 individuals with T1D and their relatives without diabetes. We performed a linkage study for 177 pedigrees consisting of 452 individuals with T1D and their relatives using a genome-wide genotyping array with>300,000 single nucleotide polymorphisms and PSEUDOMARKER software. Analysis resulted in genome-wide significant linkage peaks on eight chromosomal regions from five chromosomes (logarithm of odds score>3.3). The highest peak was localized at the HLA region on chromosome 6p, but whether the peak originated from T1D or DN remained ambiguous. Of other significant peaks, the chromosome 4p22 region was localized on top of ARHGAP24, a gene associated with focal segmental glomerulosclerosis, suggesting this gene may play a role in DN as well. Furthermore, rare variants have been associated with DN and chronic kidney disease near the 4q25 peak, localized on top of CCSER1.
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0158
      Issue No: Vol. 70, No. 4 (2021)
       
  • The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The
           Progress in Diabetes Genetics in Youth (ProDiGY) Consortium
    • Authors: Srinivasan; S.; Chen, L.; Todd, J.; Divers, J.; Gidding, S.; Chernausek, S.; Gubitosi-Klug, R. A.; Kelsey, M. M.; Shah, R.; Black, M. H.; Wagenknecht, L. E.; Manning, A.; Flannick, J.; Imperatore, G.; Mercader, J. M.; Dabelea, D.; Florez, J. C.; on behalf of the ProDiGY Consortium
      Pages: 996 - 1005
      Abstract: The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ~10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 x 10–8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 x 10–20; OR 1.58), rs72982988 near MC4R (P = 4.4 x 10–14; OR 1.53), rs200893788 in CDC123 (P = 1.1 x 10–12; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 x 10–11; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 x 10–9; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 x 10–8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 x 10–8; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-0443
      Issue No: Vol. 70, No. 4 (2021)
       
  • Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased
           Endoplasmic Reticulum Stress
    • Authors: Montaser; H.; Patel, K. A.; Balboa, D.; Ibrahim, H.; Lithovius, V.; Näätänen, A.; Chandra, V.; Demir, K.; Acar, S.; Ben-Omran, T.; Colclough, K.; Locke, J. M.; Wakeling, M.; Lindahl, M.; Hattersley, A. T.; Saarimäki-Vire, J.; Otonkoski, T.
      Pages: 1006 - 1018
      Abstract: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)–resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse β-cells, its precise role in human β-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired β-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human β-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of β-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human β-cell function and demonstrate the crucial role of MANF in this process.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db20-1174
      Issue No: Vol. 70, No. 4 (2021)
       
  • Erratum. Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts
           Future Weight Gain in Healthy Adults. Diabetes 2020;69:181-192
    • Authors: Begaye; B.; Vinales, K. L.; Hollstein, T.; Ando, T.; Walter, M.; Bogardus, C.; Krakoff, J.; Piaggi, P.
      Pages: 1019 - 1019
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db21-er04a
      Issue No: Vol. 70, No. 4 (2021)
       
  • Issues and Events
    • Pages: 1020 - 1020
      PubDate: 2021-03-19T12:25:25-07:00
      DOI: 10.2337/db21-ie04
      Issue No: Vol. 70, No. 4 (2021)
       
 
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