John Buse leads the diabetes clinical trials operation
Dr. Buse was key to high profile work published last year in the New England Journal of Medicine and JAMA that will improve care for diabetics both in achieving glucose control, and limiting cardiovascular disease. They continue to enroll diabetics in many studies and make more progress in this burgeoning disease.
The UNC Diabetes Care Center continues to work on NIH and industry funded studies in type 1 and type 2 diabetes. In 2016, the team of investigators: Sue Kirkman, Laura Young, Beth Harris, Jean Dostou, Kate Bergamo, April Goley, John Buse, along with 6 research coordinators and 3 research assistants, published more than 20 manuscripts. Studies were featured in the NEJM, JAMA and premier specialty journals with a similar number of manuscripts under review. We continue to follow more than 5,000 participants in registries and 321 randomized participants in 18 trials. We are actively recruiting for 7 studies:
- The NIH GRADE trial is randomizing patients on metformin monotherapy in the first 10 years since diagnosis with an A1C between 6.8 and 8.5% to liraglutide, sitagliptin, glargine or glimepiride.
- FIDELIO and FIGARO are two trials with finerenone, an oral non-steroidal mineralocorticoid receptor antagonist, for patients with type 2 diabetes and albuminuria or proteinuria.
- The Bexagliflozin Efficacy and Safety Trial (BEST) trial is randomizing patients with type 2 diabetes at high risk for cardiovascular events to a novel SGLT2 inhibitor.
- PIONEER-7 is randomizing patients with type 2 diabetes on two oral agents to oral semaglutide – the first oral GLP-1 receptor agonist – or sitagliptin, a marketed DPP-4 inhibitor.
- Onset®5 is randomizing patients with type 1 diabetes on Medtronic insulin pumps to “faster-acting insulin aspart” versus commercially available insulin aspart.
- TrialNet is an NIH effort to recruit family members of patients with type 1 diabetes for studies studying prevention and reversal of type 1 diabetes.
The most exciting studies coming up over the next year are a pivotal dual-hormone bionic pancreas trial and pig studies (hopefully a prelude to human studies) of Zhen Gu’s “smart insulin patch.” We are developing protocols for studies of:
- a completely novel class of antihyperglycemic agents – liver-specific glucokinase activators,
- continuous glucose monitoring approaches in type 1 and type 2 diabetes, and
- patient-centered outcomes research having established the Diabetes and Obesity Collaborative Research Group for PCORnet.
Researchers at UNC Diabetes continue to work closely with collaborators at Duke, Wake Forest University and East Carolina University to develop a pan-NC approach to diabetes studies in partnership with many of the approximately 200 investigators at UNC with funded research projects in diabetes and obesity. We hope to be successful in efforts to recruit new diabetes/obesity investigators to the Department of Medicine and look forward to partnering in that regard.
Eric Klett has a new RO1 to study mechanisms of insulin production
Dr. Eric Klett who calls both Medicine and Nutrition his homes, was awarded an RO1 from the NIH in 2016 to study the role of dietary fatty acid and intra-pancreatic beta-cell fatty acid metabolism on glucose-stimulated insulin secretion (GSIS). Insulin secretion is a complex process initiated by nutrient secretagogues, including glucose and fatty acids. GSIS is augmented by saturated long-chain fatty acids, but is impaired by ω-6 polyunsaturated fatty acids (PUFA). Glucose and fatty acids are essential to GSIS, though the exact molecular mechanism by which specific fatty acids alter GSIS remains unclear.
Dr. Klett has examined the role of one of the rate-limiting enzymes in glycerolipid synthesis on beta-cell function, acyl-CoA synthetase (ACSL). Specifically, exposing beta-cells to ω-6 PUFAs (arachidonate or linoleate) not only impairs GSIS, but also reduces ACSL isoform-4 (ACSL4) mRNA and protein expression. Further, reducing ACSL4 specific activity decreases GSIS. The reduction in insulin secretion is due to the accumulation of unesterified epoxyeicosatrienoic acids (EETs). Dr. Klett’s R01 project will specifically examine the mechanisms that underlay EETs inhibitory role on GSIS and to further characterize the effects of dietary ω-6 PUFAs on whole body glucose homeostasis. The hypothesis that ACSL4 plays a key role in eicosanoid metabolism has significant implications in all disease processes that involve eicosanoid metabolism, including diabetes, cardiovascular disease, and cancer.
Research into skeletal metabolism the labs of Janet Rubin and Maya Styner
In the “Bone Labs,” RO1s and a KO8, as well as a new DOM Junior Faculty Development Award (to Dr. Styner) support the collaborative work of Drs. Janet Rubin and Maya Styner to understand how exercise regulates bone marrow mesenchymal stem cell (MSC) differentiation; they are co-authors on a study published in Frontiers in Endocrinology in June of 2016.
In the coming year Dr. Styner will study how bone fat cells provide energy to support bone formation, and how this can go awry – for instance, anorexia nervosa is associated with fat deposition in bones, and yet bones become fragile. Using underfed mice, she will try to figure out why these fat cells appear in the bone, yet are consumed in other depots.
Dr. Rubin’s laboratory group is working on how actin polymerization within the nucleus controls gene expression patterns in bone stem cells. They have found that such polymerization within the nucleus (see graphic where driving actin into the nucleus forces polymerization) is key to jumpstarting differentiation programs.
David Clemmons, MD, makes progress in pharmaceuticals to prevent vascular disease in diabetics
Vascular Pharmaceuticals, Inc., a biopharmaceutical company spun out of UNC Department of Medicine, is conducting work to address the complications of diabetes, specifically diabetic nephropathy. There is a serious unmet need for effective treatments for this patient population since it is the leading cause of end stage renal disease. Founded in 2005, the company is advancing their lead therapeutic candidate, VPI-2960B, a monoclonal antibody that blocks ligand occupancy of the c-loop region of the αVß3 integrin receptor. This receptor is stimulated when a patient has high blood sugar and this aberrant stimulation leads to irreversible cellular damage in the nephron. Initial studies have shown that this novel approach inhibits early manifestations of the disease in experimental animal models. The company is currently completing a Phase 2 clinical trial (one year duration) that has enrolled 160 patients. The results to date show that the drug is safe and an interim analysis of efficacy at 6 months demonstrated a definite trend toward estimated glomerular filtration rate preservation at higher doses.