Amy Sanghavi Shah, MD, MS

Years of epidemiological evidence showing an inverse relationship between high density lipoprotein cholesterol (HDL-C) and cardiovascular disease have driven the exploration of HDL-C-raising strategies to reduce this residual risk. Unfortunately, most attempts at raising HDL-C have failed to reduce CV disease. This is likely because “HDL-C” does not adequately reflect the range of distinct plasma HDL particles that vary widely in size, composition and. Our laboratory has found adolescents with type 2 diabetes compared to controls are deplete of a specific subpopulation of large apolipoprotein A-I containing HDL particles (LpA-Iarge) and the loss of this large HDL subpopulation is strongly associated with markers of premature atherosclerosis (vascular stiffness). Interestingly, this subpopulation is recoverable to levels that approach lean healthy adolescents just one year after weight loss surgery- despite these youth remaining quite obese. Importantly, HDL-C or even LDL-C concentrations do not capture these findings. These data are driving the exploration of the work in our laboratory that a specific HDL subspecies is deplete in T2D and contributes to CV risk. We have identified ways to isolate these particles from human plasma and work over the next year is focused on studying their structure, composition and function and determining whether alternative therapies (lifestyle and medications) have the potential to raise these particles without the need for surgery.

Jacob M. Redel, MD, and Amy Sanghavi Shah, MD, MS

There is an association of youth-onset type 2 diabetes with early development of cardiovascular risk factors—complications that affect the heart, kidney, and eye. Whether the adverse effects of youth onset type 2 diabetes also extend to the developing brain is less known. For that reason, Drs. Jacob Redel, MD, and Amy Shah, MD, MS, are evaluating for potential adverse outcomes of youth-onset obesity and type 2 diabetes on the brain. Recently, their group published data showing that youth with type 2 diabetes had lower cognitive scores on standardized tests and differences in total and regional gray matter volume on brain MRI compared to healthy controls. Now they are investigating whether these differences associate most strongly associated with obesity, type 2 diabetes, or other metabolic abnormalities such as insulin resistance. To do so, they are recruiting obese youth without diabetes, and comparing their cognitive scores and brain imaging with the findings in the type 2 diabetes group. Using the results of their pilot studies, they plan to apply for National Institutes of Health (NIH) grant funding to longitudinally evaluate for central nervous system changes that result from youth-onset obesity and type 2 diabetes.

Sarah D. Corathers MD

Dr. Sarah Corathers’ research focuses on psychosocial outcomes of adolescents and young adults with diabetes and health system based interventions to improve care. An intersecting of these interests is reliable implementation of patient reported outcomes, including depression screening of adolescents with diabetes. Given the potential lethality of insulin when taken in intentional overdose, the need for consistent identification of suicidality is an important feature of screening in this population. At Cincinnati Children's Hospital Medical Center, screening has resulted in referral and evaluation for treatment needs of approximately 20% of individuals screened who endorse moderate or high symptoms and immediate evaluation for 7% of individuals who endorse suicidal ideation. Following brief mental health intervention in the diabetes clinic, Dr. Corathers and colleagues (Kichler, Jones, Matlock) have shown reduction in depression symptoms and 78% no longer endorsing SI over time. Dr. Corathers is a faculty leader in the Type 1 Diabetes Exchange Learning Collaborative (T1Dx-LC), supported by funding from the Helmsley Charitable Trust, to build a quality improvement community for type 1 diabetes patients, families, clinicians, researchers, and advocates. In this role, Dr. Corathers has led efforts to spread reduction in depression nationally to participating sites.

Vivian Hwa, PhD

Dr. Vivian Hwa’s group continues to be involved in a number of projects stemming from genes/variants identified by WES (whole exome sequencing) analysis in patients with monogenic growth disorders. Highlights include (a) publication in Nature Communication (Nat Commun 9:2105, 2018) of the first dominant-negative STAT5B mutations in children with short stature and mild immune dysregulation. Dr. Hwa’s group spearheaded an international collaborative effort; (b) CRISPR/Cas knock-in mouse model of pathological human missense PAPPA2 mutation recapitulated patient growth phenotype – in collaboration with Dr. Andrew Dauber, manuscript in preparation; (c) CRISPR/Cas knock-in mouse model of a rare, in-frame, IGF1R homozygous mutation, the first germline Igf1r deficient mouse model to survive postnatally and recapitulates the severe growth are on-going to assess recapitulation of growth failure and insulin resistance phenotype observed in affected children; (d) human induced pluripotent stem cells (iPSC) lines are being generated from patient cells for liver organoid modeling to investigate the human hepatic GH-STAT5B-IGF-I growth axis, in collaboration with Dr. Takanori Takebe, MD; (e) published article describing dominant-negative mutations in GHR, GH receptor (J Endocr Soc 2017 1(4):345-358) selected for the national Endocrine Society’s thematic issue Neuroendocrinology 2018.

Takahisa Nakamura PhD

In a study funded by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Dr. Takahisa 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 has demonstrated that hepatic Argonaute 2-mediated RNA silencing regulates both intrinsic energy production and consumption and disturbs energy metabolism in the pathogenesis of obesity. This study provides a novel paradigm, in which RNA silencing plays an integral role in determining basal metabolic activity, and a therapeutic approach that alters energy balance in obesity and modulates the pathogenesis of obesity-associated sequelae.