R01DK124344

Role of Microvascular Insulin Resistance and Cardiorespiratory Fitness in Diabetes - Project Summary

The goal of this two-site proposal is to determine whether and by what means insulin resistance, in the form of impaired insulin regulation of microvascular perfusion, leads to decreased functional exercise capacity (FEC) in type 2 diabetes (T2D). Data from our two research teams suggest that the cardiac and skeletal muscle microvascular dysfunction present in people with T2D contributes to limitations in cardiac and skeletal muscle oxygenation and function associated with impaired function exercise capacity (a major predictor of cardiovascular and all-cause mortality).

Insulin action is a potent predictor of the FEC impairment in T2D. The exact relationship between insulin action, cardiac and muscle dysfunction, cardiac and skeletal muscle perfusion, and decreased FEC in T2D remains unclear. Here, we propose to address this gap in knowledge by defining the roles of impaired insulin-mediated cardiac and skeletal muscle perfusion and exercise performance in people with T2D.

Hypothesis: Decreased insulin-mediated muscle perfusion found in T2D contributes to the development of cardiac and skeletal muscle dysfunction and subsequent impairment in exercise capacity. We further hypothesize that exercise training attenuates insulin resistance and restores insulin-mediated perfusion to the skeletal and cardiac muscle, leading to improved exercise performance.

Specific Aim 1: To test the hypothesis that impairment in insulin-mediated cardiac perfusion limits exercise performance through its effect on cardiac function in people with T2D. We will examine the relationship between insulin-mediated cardiac perfusion, other measures of cardiac function, and VO2 peak at rest and with exercise in subjects with and without T2D. Given that there is a sex disparity in diabetes outcomes and exercise impairment with a lack of mechanistic insights on sex differences, we will analyze all parameters for differences by sex on an exploratory basis in the three aims.

Specific Aim 2: To test the hypothesis that impaired insulin-mediated skeletal muscle perfusion limits exercise performance through its effect on oxidative capacity in people with T2D. We will examine the relationship between insulin-mediated skeletal muscle perfusion, muscle oxygenation, skeletal muscle mitochondrial function and in vivo skeletal muscle oxidative flux, and VO2 peak in subjects with and without T2D.

Specific Aim 3: To test the hypothesis that the improvement in FEC subsequent to exercise training operates via action on cardiac and muscle function in T2D. These experiments will test whether the improvements in VO2 peak observed with exercise training correlate with improvements in insulin-mediated perfusion, cardiac and skeletal muscle function, and the impact of T2D on these changes.

Understanding the role of microvascular disease in the diabetes-mediated exercise impairment may offer novel targets for intervention to improve exercise capacity, functional status, and longevity in people with diabetes. Together, our two groups will employ complementary theoretical backgrounds and research methods in a synergistic approach to address the innovative hypothesis posed to improve health in T2D.

The Regents Of The University Of Colorado

(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]

Aurora, Colorado 800452595 United States

Single Zip Code

Investigator-Initiated Clinical Trials Targeting Diseases within the Mission of NIDDK (R01-Clinical Trial Required) (PA-18-330)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 406% from $695,115 to $3,514,350.