Amy Sanghavi Shah, MD, MS, Mark DiFrancesco, PhD, and Ryan Brady, MD

Diabetes Related Vascular Disease May Extend to the Brains in Teens

Type 2 diabetes in teens continues to increase. There is a desperate need for studies dedicated to children with type 2 diabetes as childhood-onset type 2 diabetes differs dramatically from type 2 diabetes in adults making extrapolation of adult data impossible. The onset of type 2 diabetes in youth is more insidious and shows a poorer response to medications, rapid progression to insulin dependence, and risk of multisystem complications by early adulthood. Our team, Shah, DiFrancesco, and Brady, are documenting the effects of type 2 diabetes on peripheral vasculature and the heart. A new study with funding from NIH will evaluate whether these youth are at risk for vascular disease that extends to the brain. Using advanced magnetic resonance imaging (MRI) methods, we will assess youth cross-sectionally and then again at three years. This project will comprehensively determine brain impairment in teens with type 2 diabetes by looking at changes to the structure and function of blood vessels in the brain and how that may relate to tissue loss and cognitive problems. This project will drive the optimal design of treatment approaches to prevent or reverse brain complications that could otherwise extend to adulthood.

Amy Sanghavi Shah, MD, MS, FNLA

Understanding the Initial Steps of Heart Disease

Plaque buildup (or the development of atherosclerosis) begins when a retainment of low-density lipoproteins (LDL) enter the blood vessels around the heart. Data from our laboratory show that high-density lipoproteins (HDL) can inhibit LDL entry and retention, the initial steps of atherosclerosis. With funding from the National Institutes of Health, a Shah laboratory study aims to define how the balance between LDL and HDL influences plaque buildup in the artery wall and how type 2 diabetes alters this. Specific studies will focus on whether certain types of LDL are more likely to enter the vessel wall and whether certain types of HDL are best at preventing LDL entry and retention. These results can potentially inform future therapeutic strategies to block atherosclerosis initiation, which currently do not exist. This work can potentially benefit both youth and adults, particularly individuals with type 2 diabetes at an accelerated risk for cardiovascular disease.

Amy Sanghavi Shah, MD, Lawrence M. Dolan, MD, and Elaine M. Urbina, MD, MS

Arterial Vessel Stiffness Progresses Over Time in Teens with Youth with Diabetes 

Arterial stiffness is a marker of early cardiovascular disease and predicts future cardiovascular-related events. Investigators at Cincinnati Children’s along with others, sought to understand if arterial stiffness worsens over time in teens with diabetes and whether this differs by type of diabetes. Work performed as part of a multicenter collaboration called the SEARCH for Diabetes in Youth Study studied 1,159 youth twice over five years (949 with type 1 diabetes and 210 with type 2 diabetes). Participants with both types of diabetes had worsening vessel stiffness, but those with type 2 diabetes vs type 1 diabetes had greater vascular stiffness at initial and follow-up assessment and a greater change over time (all p<0.05). Risk factors associating with worse arterial stiffness, regardless of diabetes type, includes higher blood pressure, hemoglobin A1c, waist circumference, and triglycerides, all of which relate to metabolic syndrome. This data suggest that targeting healthy lifestyles, limiting high blood pressure and weight gain, and targeting optimal glycemic control for all youth with diabetes may be important. This work receives funding from the NIH and CDC. It is a collaboration between investigators Shah and Dolan in the Division of Endocrinology, Urbina in the Division of Cardiology, and three other sites in the US (Seattle, Colorado, and South Carolina).

Takahisa Nakamura, PhD

Role of Extracellular Vesicles in Obesity-Associated Inflammatory Responses

In studies receiving R01- and R21-funding, Nakamura and colleagues investigate extracellular vesicles (EVs) that are membrane-enclosed EVs. EVs are emerging as important transducers of intercellular communication in the pathogenesis of obesity-associated chronic inflammatory diseases, including type 2 diabetes and non-alcoholic steatohepatitis (NASH). This study aims to determine how EVs regulate immunometabolism in obesity and contribute to the development of chronic inflammatory diseases to develop novel therapeutic approaches targeting EVs for these diseases.

Clinical Characterization and Therapy of Patients with Aggrecan Deficiency

Philippe Backeljauw, MD, and Gajanthan Muthuvel, MD, and colleagues describe in detail the clinical phenotype of aggrecan deficiency in a relatively large cohort of patients with this novel growth disorder. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease. Their studies show that, even though the early manifestations of joint disease may be difficult to ascertain, the association of short stature with joint problems such as osteochondritis dissecans should raise the possibility of aggrecan deficiency as a diagnosis. In a second protocol, treatment with recombinant human growth hormone shows improved linear growth in a cohort of ten patients with short stature due to ACAN deficiency, and an extension trial is underway. Novo Nordisk, Inc. sponsors both studies.

Fluorescent Genetic Tools for Studying Brown Fat Development and Function in Mice

In mice and probably humans, brown adipose tissues (BAT) use high amounts of nutrients to generate heat. Because of this, harnessing BAT energy consumption as therapy for metabolic disease is an important goal. Over the last decade, we can draw an association between the presence and activation of BAT in humans and the improvement or prevention of the primary and secondary effects of overweight and obesity, osteoporosis and cardiovascular diseases (independently of obesity). Techniques to trace and isolate brown adipocyte precursor and adipocytes during development and disease are essential to fully understand and manipulate brown adipose tissue development and function. Our recent publication in Methods in Molecular Biology reports several protocols in thermogenic tissues using the Cre-dependent Rosa26 located dual-fluorescent membrane-targeted tomato, membrane-targeted GFP, or R26R-mTmG reporter mouse reporter mice. In this, we include a protocol for isolation and separation of brown adipocyte precursor and a whole mount preparation method not requiring sample processing between dissection and data acquisition. Additionally, we also describe dilapidation methods for whole tissue 3D imaging with a basis on the use of antibodies specific to reporters or that allows the analysis of endogenously expressed fluorescent proteins. These techniques may be useful to understand the influence of genetic or environmental alterations in brown adipocyte precursors and adipocyte biology.

Nana-Hawa Yayah Jones, MD

Equity in Healthcare

In pursuing equity in healthcare delivery for patients with type 1 diabetes (T1D), Jones and the Diabetes Center partnered nationally and locally to attack the health disparities that plague childhood's third most common chronic disease. With funding from the Type 1 Diabetes Exchange, a cross-clinical national consortium aimed to improve the quality of life for all patients living with T1D, this project targets reducing inequities in diabetes technology device use. In the past decade, advancements in diabetes technology are progressing with overwhelming speed, leaving behind the most vulnerable patients – patients experiencing social determinants of health (SDoH). Using quality improvement methodology, a diabetes-centered yet multidisciplinary team see increases in diabetes technology usage in at-risk patients; however, gaps still persist. To further narrow gaps, Jones and the Diabetes Center now screen for SDoH, increasing screening from 0% to > 80%, and are spreading this learning model to other ambulatory departments within the hospital, working with Cincinnati Child Health-Law Partnership (Child HeLP) to refine legal aid interventions. Jones also leads an integral team in the Cincinnati Children's Health Equity Network (HEN) to pursue excellent and equitable health outcomes for children in Greater Cincinnati.

Sarah D. Corathers, MD

Quality Improvement in Type 1 Diabetes

Corathers’ research focuses on the psychosocial aspects of adolescents and young adults with type 1 diabetes (T1D) and health system-based interventions to improve care delivery and outcomes. Recent work includes collaboration with Avani Modi, PhD, from the Division of Behavioral Medicine and Clinical Psychology on a multi-site study with R01 funding, Diabetes Journey. The study objective is to use patient-reported barriers to diabetes adherence to guide the integration of a novel mHealth intervention to improve executive functioning skills in adolescents with T1D. In the Pediatric Safety Learning Lab with AHRQ funding, Corathers works with colleagues to reduce harm due to medication and treatment errors across two conditions (diabetes and autism spectrum disorders). The focus of intervention for T1D is prompt recognition and management of serious illness at home with tools to enhance sick day guidance and the use of simulations for families to practice skills. Through the Place Outcomes Research Award, Corathers and team are completing a pilot study of artificial intelligence decision support to guide glucose pattern review and insulin dose titration between clinical encounters. Contributions from findings from the pilot led to a successful proposal for a Diabetes Clinic Innovation award from Helmsley Charitable Trust. The project, CONNECT1D, aims to redesign care to address the needs of medically and socially vulnerable youth with T1D by increasing access to diabetes technology, more frequent communication between visits, enhanced community and mental health partnerships, and investment in clinical information systems that integrate diabetes device data with electronic health records.

Nationally, Corathers is a faculty leader in the Type 1 Diabetes Exchange Quality Improvement Collaborative (T1Dx-QI), a growing network for patients, families, clinicians, researchers and advocates dedicated to accelerating improved outcomes and lived experiences for people impacted by T1D.

Mansa Krishnamurthy's, MD, MSc

Congenital Hyperinsulinism

Krishnamurthy's, research focuses on identifying and modeling novel genetic mutations that cause congenital hyperinsulinism, diabetes and digestive disorders using translational and basic science approaches. Her recent work demonstrates the utility of organoids in diagnosing patients with uncovered pathologies. Deep analysis of the stomach and intestine using organoids derived from PDX1 mutation patients demonstrate intestinal and gastric metaplasia, respectively. This prompted a re-examination of gastric and intestinal biopsies from PDX1 mutation patients, which recapitulated the organoid phenotypes. The number of endocrine cells in the stomach and intestine reduced in PDX1 mutation patient organoids and biopsies. Monitoring these patients will now look for the progression of metaplasia and gastrointestinal complications that may relate to the reduced gastric and intestinal endocrine cells. Study findings are in a recent publication of Gastroenterology.

Sarah Lawson, MD

Continuous Glucose Monitor for Inpatient Use

Diabetes technology is advancing rapidly. Admittance to the hospital often requires patients to remove their equipment, leaving them dissatisfied and with initial large glucose swings. To improve patient satisfaction and stay relevant in the diabetes world, Cincinnati Children’s works to be consistently proactive with diabetes technology. Through the work of the Insulin Safety Committee, Cincinnati Children's is successful in the continuance of insulin pumps during inpatient stays. We are one of a limited number of pediatric hospitals in the nation to create a working protocol to ensure the continuance of high patient satisfaction while maintaining our high hospital standard for medication documentation, staff knowledge of high-risk drugs, and most importantly, patient safety. We are moving towards approving continuous glucose monitors (CGM) for inpatient care. We currently allow home CGMs to remain on a patient upon admittance, but must do any intervention with insulin or hypoglycemia correction after checking point-of-care glucose. We do this as formal testing accuracy of CGMs during severe illness is limited. After discussions with the Centers for Medicare and Medicaid, we are working on devising a safe and easy method for validating home CGMs to continue their use during hospitalizations. This is a national problem in both adult and pediatric institutions. The Insulin Safety Committee at Cincinnati Children's hopes to be a leader in solving this problem.

Meilan M. Rutter, MD

Research to improve the care of patients with Differences of Sex Development (DSD)

Differences of Sex Development (DSD) or congenital conditions in which chromosomal, gonadal or anatomic sex development is atypical. Clinical care of individuals with DSD is complex, challenging and controversial, and there are disagreements within and between professional, advocacy and patient communities regarding optimal health care delivery. The Defining Successful Outcomes and Trade-offs study seeks to identify stakeholder perspectives surrounding clinical practices and outcomes in DSD care. The ongoing mixed methods study comprises three phases: 1) assessing what constitutes successful clinical practices and outcomes through semi-structured interviews (N = 110 stakeholders); 2) identifying trade-offs through a field survey and best-worst scaling methods (N = 497 stakeholders); and 3) creating evidence-based curricula to inform shared decision-making in DSD clinical care. This research receives support from the NICHD (R01HD086583) and represents a collaboration between three centers: the University of Michigan, Phoenix Children's Hospital and Cincinnati Children's. Rutter, and the DSD team at Cincinnati Children's, also participate in the national DSD Translational Research Network (DSD TRN). With dedication, the DSD TRN is establishing evidence-based standards to improve clinical care for patients with DSD and their families. It includes a central registry (720 families) for clinical research, and a biobank (582 biological samples) for genetic discovery. The DSD TRN receives support from the NICHD (R01HD093450) and currently comprises a network of 14 interdisciplinary pediatric teams across the US.