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Principal Investigator: William C Knowler
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2021
Award: $140,115
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project.
In the past year, we published a study in collaboration with the University of Minnesota in which we demonstrated that adolescents with type 1 diabetes exhibit relative kidney hypoxia compared with controls and this relative hypoxia was associated with elevated albuminuria and with increased renal plasma flow, fat mass, and insulin resistance. These data suggest a potential role for kidney hypoxia in the early kidney damage of diabetes that leads to the development of diabetic kidney disease.
In collaboration with the University of Michigan and Princeton University, we conducted a molecular network analysis using our kidney tissue expression data to determine how COVID-19 might disproportionately affect individuals with diabetic kidney disease. We focused on the ACE2 receptor because it is the primary cell-entry receptor for the SARS-CoV-2 virus responsible for COVID-19. We found that ACE2 expression in the kidneys was predominantly localized to proximal tubular epithelial cells and we linked ACE2 expression to innate immune response and viral entry machinery, suggesting that ACE2-coregulated proximal tubular epithelial cell expression programs in type 2 diabetes may interact with the SARS-CoV-2 infection process. Upregulation of viral infection pathways by this process could explain the higher susceptibility of patients with type 2 diabetes to severe COVID-19.
In collaboration with the University of New Mexico, we conducted a post-hoc analysis of clinical trial data that linked a home-based kidney care program to greater patient involvement in the care of their chronic kidney disease. In the post-hoc analysis, we found that the effectiveness of the home-based program was most prominent in patients who also had type 2 diabetes suggesting that this program was most effective in ameliorating the progression of kidney disease attributable to diabetes.
In collaboration with the University of Michigan, we reported that in American Indian patients with long-standing type 2 diabetes, neuropathy and kidney disease worsened during follow-up despite stable or improving metabolic syndrome components, suggesting that early metabolic intervention may be necessary to prevent the complications of type 2 diabetes.
In collaboration with the University of Bristol, we examined IGF binding protein (IGFBP) expression in American Indians with diabetic kidney disease and identified a novel role for this protein in the regulation of podocyte function. IGFBP expression is reduced in early diabetic kidney disease in type 2 diabetes and strategies to maintain glomerular IGFBP expression may be beneficial in maintaining and preserving podocyte function in early diabetic kidney disease.
In collaboration with Peking University, we combined human and mouse data to demonstrate that intracellular annexin A1 modulates the inflammatory state, suggesting that it may be a promising therapeutic approach to treating or reversing diabetic kidney disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Active Follow-up><Adolescent><Adolescent Youth><Adult-Onset Diabetes Mellitus><Affect><Albuminuria><American Indian><American Indians><Annexin A1><Annexin I><Biological Markers><Body Tissues><Brittle Diabetes Mellitus><COVID-19><COVID-19 infection><COVID-19 virus><COVID19><COVID19 infection><COVID19 virus><CV-19><CV19><Calpactin II><Caring><Cell Body><Cells><Chromobindin 9><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><CoV-2><CoV2><Collaborations><Conduct Clinical Trials><Data><Developing Countries><Developing Nations><Development><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Disease Management><Disorder Management><Dysfunction><Effectiveness><Epidemiology><Epithelial Cells><Exhibits><Fats><Fatty acid glycerol esters><Functional disorder><Genetic><Glomerular Filtration Rate><Home><Human><Hypoxia><Hypoxic><IDDM><IGF-Binding Proteins><IGFBP><Incidence><Individual><Inflammatory><Innate Immune Response><Insulin Resistance><Insulin-Dependent Diabetes Mellitus><Insulin-Like Growth-Factor-Binding Proteins><Intervention><Intervention Strategies><Iothalamate><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Less-Developed Countries><Less-Developed Nations><Link><Lipocortin 1><Lipocortin I><Maturity-Onset Diabetes Mellitus><Measures><Medicine><Meta-Analysis><Metabolic><Metabolic syndrome><Mice><Mice Mammals><Michigan><Minnesota><Modern Man><Molecular><Murine><Mus><NIDDM><Nephropathy><Network Analysis><Neuropathy><New Mexico><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Oxygen Deficiency><Pathway Analysis><Pathway interactions><Patients><Pattern><Persons><Physiopathology><Predisposition><Prevalence><Process><Proteins><Publishing><Receptor Protein><Regulation><Renal Disease><Renal Failure><Renal Insufficiency><Renal Plasma Flow><Renocortin><Reporting><Risk Factors><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Slow-Onset Diabetes Mellitus><Somatomedin-Binding Proteins><Stable Diabetes Mellitus><Structure><Sudden-Onset Diabetes Mellitus><Susceptibility><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Therapeutic><Therapeutic Agents><Third-World Countries><Third-World Nations><Tissues><Tubular><Tubular formation><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Under-Developed Countries><Under-Developed Nations><Universities><Up-Regulation><Upregulation><Viral><Viral Diseases><Virus><Virus Diseases><Visceral Epithelial Cell><Work><Wuhan coronavirus><active followup><adult onset diabetes><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><bio-markers><biologic marker><biomarker><chronic kidney disease><clinical trial analysis><cohort><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><damage to kidney><developing country><developing nation><developmental><diabetes><epidemiologic><epidemiological><follow up><follow-up><followed up><followup><glomerular visceral epithelial cell><hCoV19><hemodynamics><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insulin dependent diabetes><insulin resistant><insulinlike growth factor binding protein><interventional strategy><juvenile><juvenile diabetes><juvenile diabetes mellitus><juvenile human><ketosis prone diabetes><ketosis resistant diabetes><kidney biopsy><kidney damage><kidney disorder><kidney hypoxia><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><maturity onset diabetes><nCoV2><neuropathic><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathophysiology><pathway><podocyte><preservation><prevent><preventing><programs><protein expression><receptor><renal><renal biopsy><renal damage><renal disorder><renal hypoxia><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><trend><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><urinary><viral infection><virus infection><virus-induced disease>