Niddk Recent Advances & Emerging Opportunities January

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NIDDKRecent Advances &Emerging OpportunitiesJanuary 2021U.S. Department of Health and Human ServicesNational Institutes of HealthNational Institute of Diabetes & Digestive & Kidney Diseases

51423The NIDDK supports research to understand how the body’s organs and tissues—such as the pancreas, gut,liver, kidney, and bladder (1)—function in health and disease. Organs and tissues are made up of cells thatwork together to carry out the body’s functions. In the past, changes at the level of a single cell have beendifficult to tease out because of experimental limitations. Now, scientists are using new and sophisticatedtechnologies to analyze characteristics of individual cells (2), such as the proteins and metabolites that eachcell produces. The large amounts of data stemming from these analyses (3) are giving us unprecedentednew scientific insights and showing that the behavior and function of individual cells can vary greatly, evenbetween cells that are in close proximity to one another. This new knowledge is illustrating how differencesamong individual cells can play a role in determining health and disease. It is also helping to inform thedevelopment of new therapies, such as medicines and devices (4), to improve the health and quality of life ofpeople with diseases and disorders within the NIDDK mission, giving them hope for a healthier future. Manyof these diseases and disorders put people at high risk of severe illness from SARS-CoV-2 (5), the virus thatcauses COVID-19, so the NIDDK is also pursuing research to combat COVID-19 and find ways to reducethe additional dangers it poses for those with underlying health conditions. In parallel, as the virus disruptedresearch earlier in 2020, the NIDDK sought input from the scientific community and has taken action toreinvigorate research across the Institute’s mission.Image credits:1. Alfred Pasieka/Science Photo Library2. Steve Mabon, Tom Misteli, NCI, NIH3. Adapted from image created by Thomas Shafee. Image is licensed under the Creative Commons Attribution 4.0 International 0/deed.en).4. Shutterstock5. Centers for Disease Control and Prevention/Alissa Eckert, MSMI; Dan Higgins, MAMS

NIDDKRecent Advances &Emerging OpportunitiesJanuary 2021U.S. Department of Health and Human ServicesNational Institutes of HealthNational Institute of Diabetes & Digestive & Kidney Diseases

TABLE OF CONTENTSMESSAGE FROM THE DIRECTORResearch on Type 2 Diabetes.14Community-based Approach To ScreenBlack Men for Type 2 Diabetes.14CROSS-CUTTING SCIENCE.1Rare Genetic Variants Protect AgainstCOVID-19. 1Type 2 Diabetes by Promoting InsulinProcessing and Secretion.15NIDDK Efforts Toward AchievingHealth Equity. 3Combined Analysis of Studies withEast Asian Participants Yields aCelebrating the Past and Planning for theDramatic Increase in KnowledgeFuture: The 70 Anniversary of the NIDDK . 6of Type 2 Diabetes Genetics .15thDIABETES, ENDOCRINOLOGY, ANDMetabolic Regulators of Health and Disease .16METABOLIC DISEASES.9Fat Cell Signaling Molecules IdentifiedAssessing Diabetes Rates in Youth .11as Critical for Regulating MetabolicHealth in Mice .16Diabetes Continues To Rise AmongAmerican Youth.11A Factor in Fat Tissue That HelpsPreserve Insulin-producing BetaResearch on Type 1 Diabetes.11Cells in Mice.17New Artificial Pancreas SystemNew Tools and Surprising ResultsOutperforms Sensor-augmentedPave the Way to More ComprehensivePump Therapy for ManagingUnderstanding of Melatonin andType 1 Diabetes .11Circadian Rhythm .17Researchers Develop First Functional,Strides in the Treatment of Cystic Fibrosis.18Lab-generated Islets That EvadeImmune System Attack.12Therapies To Treat the MolecularCause of Cystic Fibrosis Now ApprovedInsights into the Autoimmune Process infor Ninety Percent of People withType 1 Diabetes .13the Disease .18Identification of Risk Factors for HeartCelebrating the Discovery andDisease in Type 1 Diabetes.13Development of Insulin.20

Seeing the Whole Picture: Two NIDDKYour Brain on High-fat Food:Workshops Aim To AdvanceWhy Diets May Fail .42Pancreatic Imaging.22Molecular Underpinnings of Exercise .42STORY OF DISCOVERY: How DifferentMedications for Diabetes and ObesityA Physiological Dance: How a Brief BoutEmerged from Basic Research on Oneof Exercise Initiates a MolecularPancreatic Hormone.24Choreography of Events.43PERSONAL PERSPECTIVE: Testing a NewThe Role of an Immune Protein inArtificial Pancreas System for ManagingMetabolic Conditioning ofType 1 Diabetes.29Muscle to Sustained Exercise.43PERSONAL PERSPECTIVE: Contributing toGut Microbiome and Body Weight.44Type 2 Diabetes Prevention Research .33How the Gut Microbiome Controls DailyOBESITY . 39Metabolic Rhythms .44Bariatric Surgery: New Insights into EffectsNIH Seminar Series: Obesity andon Weight Loss and Metabolism.39Women’s Health .45Comparing Surgical Treatment andDIGESTIVE DISEASES AND NUTRITION. 49Non-surgical Care for Long-termWeight Loss .39Gut Microbiome and Nutrition.51Diet Versus Surgery for Metabolic Health:Studies Show Role of Human GutWeighing the Benefits for People withMicrobiome in Nutrient Absorption .51Obesity and Type 2 Diabetes .40Toward Predicting Effective TreatmentsStimulating Beige Fat Formation.41for Inflammatory Bowel Disease.52Beige Is All the Rage: Drug TreatmentA Cellular Signature Reveals Why CurrentStimulates Beige Fat Formation ResultingCrohn’s Disease Therapy Does Notin Metabolic Health Benefits inWork for Some People.52People with Obesity.41A Common Fungus Sets the Stage forUnderstanding How High-fat FoodsSuccessful Fecal Microbiota TransplantationAffect Calorie Consumption .42in People with Ulcerative Colitis.53

New Mouse Model of Celiac Disease .54STORY OF DISCOVERY:Porphyrias Research .63New Mouse Model MimicsCeliac Disease in People .54PERSONAL PERSPECTIVE: DevelopingNew Diagnostic and Treatment OptionsClinical Research on Biliary Atresia.54for Children with Biliary Atresia.67Testing a New ScreeningKIDNEY, UROLOGIC, ANDApproach for Early Diagnosis ofHEMATOLOGIC DISEASES. 73Biliary Atresia.54Chronic Kidney DiseaseGene Activity Signature PredictsProgression in Children .75Survival in Young Children withBiliary Atresia.55Identifying Children at IncreasedRisk of Chronic Kidney DiseaseDietary Contributors to NonalcoholicProgression .75Fatty Liver Disease .56New Insights into Kidney Development.76How High Fructose Intake MayTrigger Fatty Liver Disease.56New Kidney Mapping CouldLead to Health Gold .76New Insights into Basic LiverCell Biology.56Unraveling the Molecular Nature of BloodVessel Specialization in the Kidney.76Insights into How Immune CellRecruits Are Programmed ToResearch on Lower UrinaryDefend the Liver .56Tract Symptoms .77Strategic Plan for NIH Nutrition Research.58Symptom-based Clustering in Menwith Lower Urinary Tract Symptoms .77Consortium Advancing ChildhoodPancreatitis Research .59Immune System Responses toUrinary Tract Infections.78Recent Advances from the GastroparesisClinical Research Consortium: TowardImmune System Response CouldBetter Understanding, Diagnosis,be Undermining Ability To Fightand Treatment .61Urinary Tract Infections.78

Progress Toward Treating Urinary Stones .79Moving Objects with UltrasoundBeams—Potential Application toUrinary Stone Disease .79New Insights into Blood Disorders.79Putting the “Brakes” on Adult BloodStem Cell Proliferation.79Identification of Small MoleculeCompound that Reverses ExperimentalTelomere-related Diseases .80Training Reimagined: Cultivating the NextGeneration of Innovative and CollaborativeKUH Researchers .81STORY OF DISCOVERY: AdvancingUnderstanding of Lower Urinary TractSymptoms and Associated Conditions .83PERSONAL PERSPECTIVE: Paving a Pathto Personalized Kidney Care ThroughParticipation in Research.88NIDDK EXTRAMURAL FUNDINGTRENDS AND SUPPORT OF GUIDINGPRINCIPLES . 93ACKNOWLEDGMENTS

Message from the DirectorAs the Director of the National Institute of Diabetesand Digestive and Kidney Diseases (NIDDK), I ampleased to present this annual report highlightingthe research efforts and programs supported bythe Institute. The NIDDK has a broad researchresponsibility that includes some of the most common,debilitating, and costly conditions affecting Americans.These conditions include diabetes and other endocrineand metabolic diseases; liver disease and otherdigestive diseases and conditions, such as inflammatorybowel disease and irritable bowel syndrome; nutritionaldisorders; obesity; kidney diseases, such as polycystickidney disease and glomerular disease; urologicdiseases and conditions, such as interstitial cystitis/painful bladder syndrome, prostatitis, and urinary tractinfection; and blood diseases.In view of the profound effects that COVID-19(Coronavirus Disease 2019) has had on our Nationand the world, and the ways in which the disease hasexacerbated some of the existing health disparitiesin the NIDDK’s mission diseases, the “Cross-CuttingScience” chapter of the 21st edition of this reporthighlights our Institute’s multi-pronged effortstoward the goal of health equity. In addition, thereport describes recent NIDDK-supported scientificadvances on topics such as: An innovative approach from NIDDK intramuralresearchers shows the potential importance ofspeech in transmitting the virus responsible forCOVID-19; Lab-generated cell clusters that can produceinsulin in mice while avoiding destruction by theimmune system, a step toward a possible longterm treatment for type 1 diabetes; A dramatic increase in knowledge of type 2diabetes genetics from combining analyses ofstudies in people of East Asian descent; Finding that community barbershops arepromising venues for screening Black men fortype 2 diabetes; Demonstration of health benefits in peoplefrom a treatment that converts energy-storingfat cells into an energy-burning form of fat; Testing of medications that now make it possibleto partly restore the function of the proteinmissing in 90 percent of people with cysticfibrosis; The weight-loss and metabolic effects ofbariatric surgery compared to non-surgicalweight-loss approaches; The physiological effects of exercise; The role of the microbiome, including itsregulation of circadian rhythms and its effectson nutrient absorption; Development of a new mouse model thatmimics the immune system features and glutendependent intestinal damage seen in peoplewith celiac disease; Insights into the way high fructose consumptionmay promote nonalcoholic fatty liver disease; Kidney development and function, as novelinsights bring us closer to new strategies toaddress kidney diseases; Development of a noninvasive techniquewith potential application to treat urinarystones; and

Identification of a compound that may one daylead to improved treatment for dyskeratosiscongenita, a rare blood disease.In addition to reporting on recent advances, thispublication traces the multi-step path to researchachievements through several “Stories of Discovery.”These essays illustrat