Investigators Present Research at 2019 American Diabetes Association Meeting

Diabetes Association national conference held recently in San Francisco. Researchers from the HHDC presented promising results of cutting-edge studies to an international audience of providers, scientists and clinician educators, demonstrating the breadth and depth of diabetes research at the cellular level to the patient. The 2019 meeting drew more than 15,000 individuals including 12,000 professionals representing 115 countries.

Jed Friedman, Ph.D., Harold Hamm Diabetes Center director, said, “These studies emphasize that the ongoing work of the Harold Hamm Diabetes Center is focused not only on the early origins of diabetes in youth, but also is perpetually attuned to prevention, treatment and exploration of factors that contribute to long-term consequences of diabetes and its co-morbidities in adults.”

Researchers who presented their work include:

• David Fields, Ph.D., associate professor and CMRI Endowed Chair in Pediatric Diabetes;
• Yun Le, Ph.D., professor of Medicine, Section of Endocrinology and Diabetes, adjunct professor of Cell Biology and Ophthalmology, Harold Hamm Chair in Diabetes Research;
• April Teague, M.S., research associate;
• Jeanie Tryggestad, M.D., assistant professor, Department of Pediatrics, Section of Diabetes and Endocrinology; and
• Rui Cheng, Ph.D., research fellow, Department of Endocrinology and Diabetes.

Fields’ presentation, Maternal Obesity or Diabetes Effects on Milk Composition and Offspring Outcomes within the Got Milk? Variability in Milk Composition Symposium advances the field of human milk research. Intergenerational obesity and diabetes continue to be prominent factors that promote poor health throughout the United States. Exclusive breastfeeding may decrease risk of transmission from mother to child. This work demonstrates that milk hormone and cytokine concentrations, as well as novel milk-metabolomics signatures vary significantly with maternal body weight and adiposity. These milk “bioactives” predict altered early-infant growth. This study will be the largest and longest cohort study in the U.S., perhaps in the world, exploring the role of specific human milk bioactive compounds in the transmission of obesity and diabetes risk from mother to child. Results will inform possible maternal dietary or other behavioral targets to optimize breastfeeding outcomes for infant and child health.

Le presented Mechanism of Neurotrophin-mediated Neuroprotection in Diabetic and Hypoxic Conditions. Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of blindness in the US. Intensive effort in ocular pathobiology for the past 30 years has identified vascular endothelial growth factor (VEGF) as a major therapeutic target for vascular leakage and retinal and choroidal neovascularization in DR and AMD, resulting in development of anti-VEGF therapies for these disorders. However, long-term clinical trials suggest that anti-VEGF therapies may cause loss of retinal cells and neurons, which is not surprising as VEGF is also a survival factor. To address this issue, we investigated the mechanism of FEGF downstream neurotrophin-mediated neuroprotection. We are performing a preclinical study exploring the potential benefit of the in supporting viability of retinal cells and neurons under diabetic and hypoxic conditions, which will improve treatment of hypoxic retinal vascular diseases, including DR and AMD.

Coming to its end, Today and TODAY2 represent the longest-running study of Type 2 diabetes in young people. Tryggestad’s presentation, Pregnancy Outcomes (within the Longitudinal Outcomes in Youth with Type 2 Diabetes – The TODAY2 Study Symposium, showed that youth-onset Type 2 diabetes is more aggressive than adult-onset disease.

Summarized conclusions as reported by investigators across the span of the study, include:

Complications of heart, vascular, cerebrovascular and kidney disease accelerate with the transition to young adulthood, indicating serious personal and public health consequences. Early mortality is already occurring.

The 12-year cumulative incidence of low-density lipoprotein dyslipidemia was 26 percent

The event rate for all adjudicated heart, vascular, and cerebrovascular events was 6.41 per 1,000 patient-years, triple the cardiovascular event rate seen in the Diabetes Control and Complications Trial, which studied an older population with a longer duration of diabetes.

Half of TODAY participants had diabetic kidney disease markers, 40 percent with microalbuminuria and 11 percent macroalbuminuria. Both were associated with A1C levels of 8 percent and higher.

Retinopathy and neuropathy can be expected in youth-onset type 2 diabetes. Nearly half of TODAY participants had some degree of diabetic retinopathy. Loss of glycemic control, defined in the study as A1C of 8 percent or higher, carries a 19-fold risk for retinopathy; every percent of A1C increase doubles the risk of progression.

Neuropathy is even more common, with 73 percent of participants testing positive. Loss of glycemic control is again the primary risk factor.

Pregnancy outcomes in patients with youth-onset type 2 diabetes are grim. Of 236 pregnancies with known outcomes,12 percent ended in miscarriage, 3.8 percent in stillbirths, and 9.7 percent in unknown losses.

Of live births, 23.7 percent were pre-term, more than double the expected pre-term rate. The average birth weight was 2,138 grams, well below the typical 3,389 grams. Macrosomia was seen in 18.9 percent and very low birth weight in 15.9 percent, double reference study levels.

Neonatal hypoglycemia was reported in 28.7 percent of newborns, respiratory distress in 14 percent, shoulder dystocia in 3.1 percent, cardiac anomaly in 8.5 percent, and other complications in 12.2 percent. These rates are two to 19 times reference study levels.

A third of mothers were hospitalized, versus an expected 14 percent. Preeclampsia was seen in 18.1 percent, hypertension in 37.5 percent, microalbuminuria in 7.5 percent, and A1C of 8 percent or higher in 32.5 percent.

In general, the outcomes are worse, especially for the babies born to mothers with T2DM diagnosed in youth.

The conclusion overall: T2DM diagnosed in youth is a much more severe disease that requires early treatment intensification to prevent complications.

Tryggestad’s poster presentation, Circulating Adhesion Molecules and Relationships to Micro and Macrovascular Outcomes: The TODAY Study featured a secondary analysis, which explored circulating vascular adhesion markers. In adults, these markers are predictive of future cardiovascular disease. Findings showed the markers were associated with A1C, and along with two of them associated with diabetic kidney disease. Several also were associated with later finding on cardiac echo. It appears that these markers are associated with glycemic control and complications; further follow-up may determine their predictive power for future cardiovascular events.

Tryggestad also presented miRNA-126-3p Impacts Insulin Signaling in Smooth Muscle Cells, co-authored with Teague. Proper function of vasculature (the system of blood vessel structure) depends on communication between endothelial and smooth muscle cells (SMC). Diabetes is a causal factor in cardiovascular disease and affects vasculature through several mechanisms, including the disruption of critical communication within blood vessels. MicroRNA (miRNA), non-coding RNA that alter gene function, is one way in which diabetes may modify this intercellular communication. Previous work in our lab found increased miRNA-126 in umbilical cord endothelial cells (HUVEC) exposed to maternal diabetes. HUVEC are known to secrete miRNA-126 into the extracellular space. Furthermore, SMC take up miRNA-126 when cultured with endothelial cells. Using a cell culture model, the study demonstrated that uptake of miRNA-126 by SMC reduces crucial insulin-signaling pathway protein by up to 65 percent, potentially altering insulin sensitivity in the contractile cells of the vasculature. This study forms the basis for future research on the impact of miRNA-126-3p on SMC function.

Loss of Neuropilin 1 in Podocytes Aggravates Diabetic Nephropathy, presented by Rui Cheng, Ph.D., showed how the loss of a key protein in kidney cells aggravates diabetic nephropathy, a complication of diabetes.

Podocyte injury is a crucial pathological event in diabetic nephropathy. Neuropilin 1 (NRP1) is a multi-functional transmembrane protein and functions as a co-receptor of extracellular ligands (an ion or molecule that binds to a central metal atom to form a complex. Previous studies have shown that significant decreases in NRP1 levels occur in kidneys of diabetic patients, and advanced glycation products down-regulate NRP1 in podocyte cell lines of mice. The function of NRP1 in podocytes is not well understood. This study found the NRP1 level was significantly lower in glomeruli of the diabetic mouse; loss of NRP1 in the podocyte leads to morphological and functional changes in vivo. In diabetic conditions, the podocyte-specific NRP1-deficient mice developed severe proteinuria and disturbed glomeruli. Phosphorylation of MAPKP38 was significantly elevated in the NRP1-deficient glomeruli, suggesting podocyte stress and injury from the NRP1 loss. These results suggest that NRP1 ablation impairs renal function and worsens diabetic nephropathy and NRP1 is essential in the regulation of podocyte function and survival.