Amy Sanghavi Shah, MD MS; Nancy Crimmins, MD, MS; Ryan Brady, MD

Inflammation and Cardiovascular Disease in Adolescents with Type 1 Diabetes and Celiac Disease

Celiac disease and type 1 diabetes are chronic, autoimmune diseases that independently increase the risk to develop cardiovascular disease. However, when present together, cardiovascular risk is much higher than that seen in any one disease alone. Data in adults suggests cardiovascular risk is not due to differences in traditional cardiovascular risk factors, instead inflammation and oxidative stress in the gut systemically appear to compound this cardiovascular risk. In a project led by Ryan Brady, MD, a fellow at Cincinnati Children’s Hospital, and investigators in the Division of Endocrinology (Amy Shah, MD, MS, and Nancy Crimmins, MD); Division of Gastroenterology, Hepatology and Nutrition (Daniel Mallon, MD); and Division of Allergy and Immunology (Senad Divanovic, PhD) the goal is to determine if youth with celiac disease and type 1 diabetes have greater cardiovascular risk beyond that observed in adolescents with type 1 diabetes, and whether cardiovascular risk differs by control of celiac disease. This project will help to answer critical questions about whether there is a need for more aggressive interventions, beyond those currently recommended for type 1 diabetes, for adolescents with both diseases. Additionally, if cardiovascular risk differs by celiac disease control, not only is adherence to a gluten-free diet critical to improve long-term outcomes, but screening should be aggressive to identify undiagnosed or asymptomatic celiac disease in youth with type 1 diabetes.

Amy Sanghavi Shah, MD, MS

Surgical or Medical Treatment for Pediatric Type 2 Diabetes (ST)

As a result of the increase in childhood obesity, type 2 diabetes (T2D) emerges as a growing health concern for teenagers. Unlike T2D in adults, youth-onset T2D leads to rapid deterioration in pancreatic beta-cell function resulting in early dependence on exogenous insulin and progression of co-morbidities, including cholesterol, blood pressure, liver and kidney disease. Current treatment approaches are inadequate for youth. Because of this, exploration of innovative approaches to reduce co-morbidities is critical. Metabolic bariatric surgery (MBS) significantly improves multiple outcomes in adults with T2D. Initial small uncontrolled studies of Roux-en-Y gastric bypass also suggest beneficial effects in youth with type 2 diabetes, but definitive studies and understanding of mechanisms in youth-onset T2D are lacking, especially with the now more common form of MBS, vertical sleeve gastrectomy (VSG). Investigators in the Division of Endocrinology (Dr. Shah) and Center for Bariatric Research and Innovation (Michael Helmrath, MD) received recent funding to conduct an NIH clinical trial to examine outcomes after VSG compared to the best currently available medical treatment: advanced medical therapy (AMT) in teenagers with type 2 diabetes. This is a multicenter study conducted with investigators at Denver Children’s over the next five years. The result of this study will determine whether VSG is more effective than AMT in promoting glycemic control and reducing co-morbidities in youth-onset type 2 diabetes. Such an outcome would dramatically improve the lives of youth who are at risk for early co-morbidities and complications. Finally, the design of this project is to study the mechanisms underlying improvements of diabetes with VSG in youth to guide the development of future treatments that could target these same pathways without the need for surgery.

Nana-Hawa Yayah Jones, MD

Identifying & Eliminating Health Disparities in Youth Living with T1D

Funded by Cincinnati Children's Office of Faculty Development, the Diversity and Health Disparities Research Awards provides funding to faculty members with a strong commitment to health disparities research. In partnership with the Division of General and Community Pediatrics, the Diabetes Center’s, Nana-Hawa Yayah Jones, MD, and her team will characterize the sociodemographic characteristics of children with poorly controlled type 1 diabetes (T1D) as defined by elevated hemoglobin A1c (HbA1c) and acute healthcare utilization. Recent studies demonstrate significant and rising disparities in how different racial and ethnic groups experience T1D-related morbidity. The first aim is to assess patient- and neighborhood-level factors that are of relevance to T1D morbidity and glycemic control. The second aim pulls together a multidisciplinary team including endocrinologists, primary care providers, a psychologist, a consultant from the James M. Anderson Center for Health Systems Excellence, data analyst specializing in geospatial analytics, and most importantly a community health worker to develop a multi-disciplinary, multi-component approach to reduce HbA1C levels and T1D-related emergency department visits and hospitalizations for children residing in at risk neighborhoods. Using a novel approach to patient and community-centered care called CareMapping, the project will utilize quality improvement methodology to take a deep dive into the barriers that result in the increased morbidity experienced by this patient population. This deep dive will inform future novel interventions within the chronic care model to reduce health disparities across all chronic disease across Cincinnati Children's.

Philippe Backeljauw, MD

Optimizing care in individuals with Turner syndrome

Dr. Backeljauw’s research continues in the area of Turner syndrome. Since the development of new international Turner syndrome care guidelines, via a consensus meeting in Cincinnati, this last year has seen the introduction of additional recommendations through several publications, including a key paper on estrogen replacement in Turner syndrome in the Journal of Clinical Endocrinology and Metabolism. In addition, through a nationwide patient survey study of more than 1,100 individuals with Turner syndrome, there is documentation of the prevalence of increased bone fragility in Turner syndrome associated with impaired balance as an underrecognized risk factor for fracture in this population. Ongoing research in the Cincinnati Center for Pediatric and Adult Turner Syndrome care includes the characterization of aortic disease in individuals with Turner syndrome in collaboration with the University of Cincinnati College of Engineering (PI: Iris Gutmark-Little, MD).

Vivian Hwa, PhD

Dr. Hwa’s research continues to focus on the molecular basis of severe growth failure in children who respond poorly to growth hormone, with publications including the first report of dominant-negative STAT5B mutations in patients with short stature but lacking immune complications normally associated with STAT5B deficiency (Nature Communications, 2018), DNMT3A gain-of-function mutations that change the epigenetic landscape and associated with microcephalic primordial dwarfism (Nature Genetics, 2019), and a review of non-classical growth hormone insensitivities (Endocrine Review, 2019). With their translational research experience and repository of unique patient-derived cells, Dr. Hwa’s group has taken advantage of cutting-edge, human 2D and 3D stem cell-based modeling for assessing growth disorders, supported by a recent NIH R21 grant.

Takahisa Nakamura, PhD

In a study funded by NIH-NIDDK, Dr. Nakamura’s research group investigates the role of hepatic RNA silencing in obesity-associated pathophysiology. In general, RNA silencing inhibits mRNA translation. While mRNA translation accounts for the majority of cellular energy expenditure, it is unclear if RNA silencing regulates energy homeostasis. The group previously demonstrated that hepatic Argonaute 2-mediated RNA silencing regulates both intrinsic energy production and consumption, and disturbs energy metabolism in the pathogenesis of obesity. A new study indicates that hepatic Argonaute 2 also plays a critical role in the regulation of glucose metabolism post-bariatric surgery. This study provides a novel concept about RNA silencing regulates glucose metabolism in the pathogenesis of obesity-associated sequelae and bariatric surgery outcomes.

Juan Sanchez Gurmaches, PhD

Brown fat organogenesis and maintenance requires AKT1 and AKT2

Understanding the signaling mechanisms that control brown adipose tissue (BAT) development is relevant to understand energy homeostasis and obesity. The AKT kinases are critical insulin effectors; however, their role in adipocyte development remains poorly understood. In a new study from our lab, we investigated AKT function in BAT development. Contrarily to previously thought, we found that AKT1 is dispensable in vivo for adipose tissue development. In contrast, AKT2 is essential for adipose tissue growth, not because it controls differentiation per se, but rather because it promotes lipid accumulation, and its loss results in body fat redistribution. We additionally find that deleting both Akt1 and Akt2, either in precursors or mature brown adipocytes, causes severe BAT lipodystrophy without having any obvious effect on muscle development. These findings contribute significantly to understanding the complex relationship between the AKT isoforms and their regulators in adipose tissue development and maintenance on the pathogenesis and prevention of obesity and insulin resistance.