U01DK134975

The priority study: From prediction to prevention of youth-onset type 2 diabetes - project summary/abstract

Increases in pediatric obesity have led to an increased burden of youth-onset (YO) type 2 diabetes (T2D), disproportionately affecting vulnerable youth. YOT2D is characterized by extreme insulin resistance, insulin hypersecretion, rapid B cell failure, and increased complications compared to adult T2D, raising concern for significant morbidity very early in life. However, the mechanism(s) and risk factors that cause some adolescents with prediabetes (PREDM) to progress to YOT2D while others do not, remain poorly understood.

This proposal will study early pubertal youth at risk for YOT2D, to develop more precise prediction paradigms of progression to YOT2D, and to investigate pathophysiologic drivers. YOT2D disproportionately affects racial and ethnic minorities, often with multiple socioeconomic stressors, and the impact of social determinants of health (SDOH) on progression to YOT2D must be clarified.

Dr. Sheela N. Magge (PI) has assembled a highly-experienced team from Johns Hopkins sites in Baltimore and Florida, including primary care pediatricians (Perrin, Polk, Showell, Hernandez) at clinics serving large Black and Hispanic populations with socioeconomic disadvantage. Participation in research by minoritized groups is influenced by the trustworthiness of the health system, and study recruitment will be aided by leveraging these trusted care providers.

Dr. Magge proposes an innovative approach, recruiting from 3 distinct sources:
1. Pediatric subspecialty clinics (endocrinology and obesity)
2. General pediatric clinics serving low-income children of color
3. Offspring of adults with early onset (£40yrs) T2D

The study will longitudinally follow this cohort (total N=2250) of 9-13 year old girls and 10-14 year old boys (site N=150) with BMI = 85%ile and PREDM, as defined by HbA1c, fasting glucose, and/or 2-hr glucose on oral glucose tolerance test (OGTT), over 3 years or diagnosis of T2D, whichever occurs first. They will collect anthropometric, cardiovascular, behavioral, and genetic risk factors, as well as SDOH measures. Physiologic testing, including mathematical modelling of insulin kinetics and free fatty acid flux (FFA) using a 3-hour OGTT, in vivo continuous glucose monitoring (CGM), and body composition, will be collected.

Aims:
1) To develop reliable estimates of YOT2D risk in youth with PREDM, overall and according to risk factor profiles that differentiate groups based on their risk of progression to YOT2D.
2) To characterize the early pathophysiologic drivers of YOT2D.
A. To study differences in insulin kinetics (secretion, sensitivity, clearance), FFA flux, CGM, ectopic fat (visceral, hepatic), and cardiovascular risk between youth who progress to YOT2D and those who do not.
B. To determine whether these pathophysiologic differences differ by risk factor groups identified in Aim 1.

This proposal employs a multidisciplinary team with a novel mix of expertise in SDOH, stakeholder engagement, and metabolic pathophysiology, an innovative recruitment approach, and cutting-edge, novel methodologies to investigate the risk factors and pathophysiologic drivers that predict and cause YOT2D, in order to inform future prevention and treatment strategies.

The Johns Hopkins University

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Maryland United States

State-Wide

Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes Clinical Centers (U01 Clinical Trial Not Allowed) (RFA-DK-21-002)

Amendment Since initial award the total obligations have increased 1079% from $127,554 to $1,503,510.