The UC Denver DRC P&F Program funds diabetes researchers distributed across the basic science, translational, and clinical spectrum who investigate T1D, T2D, and/or diabetes complications and is a key element in recruiting and training promising diabetes research scientists. Applications will be considered from both junior and established investigators.
Srividhya Iyer, PhD--Assistant Professor, Department of Orthopedics
Title: ER stress in prediabetes-associated skeletal fragility
Project Summary: People with diabetes who are obese and people with prediabetes are predisposed to higher fracture incidence and poor bone healing outcomes, but the basis of impaired osteogenesis remains unclear. Accumulation of misfolded proteins results in ER stress and mediates progression of multiple diabetic comorbidities. In preliminary studies, we found that the hyperglycemic obese mice had reduced bone mass and diminished bone healing following fracture. Osteoblast cultures obtained from marrow of obese mice exhibited elevated bioenergetics concomitant with higher respiratory complex V protein levels. Additionally, obese mice had dilated ER in the osteoblasts as well as elevated PERK and ATF6 activity in cortical bone. These findings suggest that impaired osteogenic response partly due to disruption of ER homeostasis could impede fracture repair in the setting of obesity. Studies in Aim 1 will examine the effect of obesity-associated diabetes on osteoprogenitors that contributes to delayed healing in vivo, using reporter mice by flow sorting and histologic imaging. Additional bioenergetic and transcriptomic studies will reveal changes to pathways affected by obesity in osteoblast progenitors. In Aim 2 we will test the therapeutic efficacy of the ER stress inhibitor TUDCA in improving fracture deficits of the obese mice.
Jordan Jacobelli, PhD--Associate Professor, Department of Immunology and Microbiology
Title: Cytoskeletal regulation of self-reactive T cell restimulation and effector functions in the pancreatic islets
Project Summary: Islet-specific T cell entry in the islets and antigenic restimulation at the disease site are key steps leading to islet destruction in type 1 diabetes (T1D). The T cell cytoskeleton plays a crucial role in regulating T cell migration and interaction with Antigen Presenting Cells (APC) and target cells. However, there is a key knowledge gap about the mechanism by which specific cytoskeletal effectors regulate T cell functions at the autoimmune disease site. Formin-like-1 (FMNL1) is a cytoskeletal effector highly expressed in T cells. Our data show that FMNL1 knock-out (KO) T cells are significantly impaired in inducing T1D in a mouse T cell transfer model. Furthermore, our preliminary data show that FMNL1-deficient T cells have impaired motility within lymph nodes and reduced T cell-APC interactions. Based on these data, we hypothesize that FMNL1-deficient islet-reactive T cells are less pathogenic due to reduced migration, activation and effector functions within the pancreatic islets. We will employ a multi-pronged approach, including genetic, immunological, and in vivo imaging techniques, to determine the role of FMNL1 in auto-reactive T cell pathology in T1D. Our work will also validate FMNL1 as a potential target to inhibit T cell mediated pathogenesis as a treatment for T1D.
Laurel Messer, PhD, RN--Assistant Professor of Pediatrics, Barbara Davis Center
Title: Development of a “Cognitive Awareness Artificial Pancreas Enhancement” (CAPE) to Help Adolescents with Type 1 Diabetes Optimize their use of Artificial Pancreas Systems
Project Summary: Adolescents with type 1 diabetes (T1D) demonstrate suboptimal glycemic control and self management behaviors, even when using sophisticated artificial pancreas (AP) systems. The purpose of this proposal is to develop a “cognitive awareness” AP enhancement (CAPE) to “nudge” adolescents, via adaptive prompts based on current cognitive resources and behavioral tendencies, to improve their diabetes self-care with AP system, ultimately improving glycemic control. This will be done by first collecting real-time physiological, psychological, and behavioral inputs from adolescents who use AP systems. Next, these data will be used to create mental models based on the user’s awareness of their blood glucose levels, their ability to plan near-term actions around insulin boluses and meals and their overall cognitive load. Finally, we will use these mental models to create and pilot the CAPE algorithm, which will provide the AP user with carefully designed “nudges” to enhance self-management behavior. Nudges are environmental design factors or that affect people’s behavior outside their awareness, which can be used to encourage healthy choices by children and adolescents. A cognitively aware AP system is needed because effective “nudging” depends on optimal timing and situational awareness of the user, and current systems lack this level of modeling.
Kalie Tommerdahl, MD--Instructor, Department of Pediatrics, Section of Endocrinology
Title: Metformin and Automated Insulin Delivery System Effects on Renal Vascular Resistance and Vascular and Endothelial Function in Youth with Type 1 Diabetes Pilot Study
Project Summary: Diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading causes of morbidity and mortality in people with type 1 diabetes (T1D) and are exacerbated by longer diabetes duration and time outside goal glycemic range. Yet, T1D pathophysiology extends beyond beta cell injury and insulin deficiency and includes insulin resistance (IR), possibly secondary to excess peripheral insulin exposure, and renal vascular resistance (RVR), factors that accelerate CVD risk. We demonstrated metformin improved peripheral insulin sensitivity (IS) and vascular stiffness in youth with T1D on insulin injections or standard insulin pumps. However, metformin's effects on kidney and endothelial outcomes, and the effects of advanced diabetes technologies plus metformin on any cardiovascular or kidney outcome, remains unknown. Automated insulin delivery (AID) systems combine an insulin pump, continuous glucose monitor, and control algorithm to modulate background insulin, decrease peripheral insulin exposure, improve time in target range, and reduce hypoglycemia. We hypothesize that AID systems plus metformin may modulate RVR and vascular/endothelial function, thereby affecting cardiometabolic function, and propose an open label pilot study of 3 months metformin 2,000mg daily in 12 youth (12-21 years) with T1D on AID systems to evaluate for changes in gold-standard measures of RVR, arterial stiffness, and endothelial function.
Petter Bjornstad, MD--Assistant Professor of Pediatrics and Medicine
Title: Spatial metabolomics for human kidney interrogation of early diabetic kidney disease
Project Summary: Kidney hypoxia, stemming from a mismatch between increased renal energy demand and impaired substrate metabolism, is emerging as a unifying early pathway in the development of diabetic kidney disease (DKD) and a potential therapeutic target. In our JDRF-funded CROCODILE study we are quantifying kidney O2 consumption by 11C-acetate PET, kidney oxygenation by blood oxygen level dependent MRI, glomerular filtration rate and renal plasma flow by iohexol and p-aminohippurate clearances, morphometric and transcriptomic analyses of kidney tissue from research biopsies, insulin sensitivity by hyperinsulinemic-euglycemic clamp and mitochondrial function by plasma and urine metabolomics in young adults with and without type 1 diabetes (T1D). However, plasma and urine metabolomics are not kidney-specific and identified compounds may not be representative of the intrarenal milieu. Accordingly, metabolic phenotyping of the kidney tissue to interrogate tissue-specific metabolic perturbations of early DKD in T1D would enhance our study design. The DRC P&F Grant would provide support to add spatial metabolomics analyses of kidney tissues by matrix-assisted laser desorption/ ionization mass spectrometry imaging from young adults with (n=20) and without (n=20) T1D. Our central objective is to quantify metabolite data in discrete kidney compartments in order to define the metabolic pathways that may drive early DKD in T1D.
Sridharan Raghavan, MD, PhD--Attending Physician, Rocky Mountain Regional VA Medical Center; Assistant Professor, University of Colorado School of Medicine
Title: Evaluating Genetic Tools for Diabetes Precision Medicine in Clinical Biobanks
Project Summary: Diabetes mellitus is heterogeneous, making it an ideal disease for precision medicine that individualizes treatment to maximize benefit and minimize harm. One axis of heterogeneity is the distinction between type 1 (T1D) and type 2 diabetes (T2D). Failure to recognize the disease subtype can lead to delays in treatment intensification and eventually to diabetes complications. A second important context for heterogeneity in diabetes care is in response to medications where favorable glycemic response must be balanced against the risk of hypoglycemia, a treatment-related adverse event. Recent advances in the genetics of T1D, T2D, response to metformin and sulfonylureas, and hypoglycemia have set the stage for studies evaluating how genetic information can be applied to clinical care using clinical biobanks with data representative of the real world diabetes patient population. In this study, we will complete two aims: 1) Test whether T1D and T2D genetic risk scores predict diabetes type and time to insulin dependence in two clinical biobanks; and 2) Evaluate metformin-, sulfonylurea-, and hypoglycemia-associated genetic variants as tools to guide oral diabetes medication choice. By exploring the relationships of diabetes-related genetic loci with aspects of patient care, we aim to make a translational research impact on precision diabetes care.
Mia Smith DVM, PhD--Assistant Professor, Department of Pediatrics and the Barbara Davis Center for Diabetes
Title: Decoding the B cell endotype in early onset T1D
Project Summary: Recent studies indicate the existence of two forms of type 1 diabetes distinguished by the age of onset. Importantly, one of the major defining characteristics between the two forms of disease is the presence of increased numbers of B cells in early onset T1D (<7 years) compared to late onset (>13 years). The increased numbers of B cells is associated with, and can even predict, rapid progression of disease as evidence by increased loss of C-peptide. Despite the compelling evidence for a role of B cells in an aggressive form of T1D, it remains unknown which B cell subset(s) is the pathogenic offender, as well as its phenotype, activation, and functional status. This application seeks to address this deficit in our knowledge by comparing the B cell compartment in early onset to late onset and healthy controls using the most comprehensive B cell panel (>35 markers) used to date and high-dimensional mass cytometry (CyTOF). The significance of this proposal is that it aims to improve human health by developing fundamental knowledge in our understanding of the molecular mechanism of B cell involvement in rapid rate of progression, which may translate into future novel therapeutic targets to treat disease.
Clyde Wright, MD--Associate Professor of Pediatrics
Title: Pathogenic Role of IκBβ/NFκB signaling in ER Stress Induced β-cell Injury and Death
Project Summary: Intrauterine growth restriction (IUGR) is defined as a failure of the developing fetus to reach its genetic growth potential. IUGR is a well-established independent risk factors for the development of Type II diabetes (T2DM) in adulthood. It is increasingly recognized that T2DM is a chronic inflammatory disease. The transcription factor NFκB has been termed the “master regulator the inflammatory response,” and is a well-studied mediator of innate immunity. Multiple studies have implicated NFκB activity as a central mediator of β-cell apoptosis downstream of ER stress. Our lab is new to the study of diabetes, but the rigor of published research, together with our preliminary data, have led us to develop our overarching hypothesis that IUGR β-cell IκB expression favoring IκBβ/NFκB signaling increases sensitivity to ER stress and contributes to an increased risk of developing T2DM.
The primary objective of the UC Denver DRC P&F Program is to fund young investigators. As such, applications from junior faculty will be given priority. Applicants who hold or have held NIH R01 or higher- level research awards in diabetes-related areas as a principal investigator are not eligible except as noted below. However, investigators who hold NIH K or R21 awards, and/or career development or young faculty awards from JDRF, ADA or AHA are encouraged to apply. Applications will only be considered from established investigators if those investigators are new to diabetes research OR if those investigators propose innovative, high-risk projects that would not be competitive through the usual granting agencies. In the latter categories, priority will be given to interdisciplinary projects.