David M. Harlan, MD
Selected Diabetes Research Accomplishments
Developed a mouse model to study pathogenic mechanisms underlying diabetes
Developed and patented for the US Navy, this mouse model was designed to investigate pancreatic beta cell destruction in autoimmune T1D. It's based on rat insulin promoter driven beta cell specific expression of the costimulatory receptor CD80 and continues to be used today. Its main advantage was that diabetes was inducible with predictable kinetics. We could induce diabetes by viral infection, low dose beta cell toxins, and by immunizing with beta cell autoantigens. The Harlan lab has used the model to study islet biology during the processes leading to diabetes, and to develop new analytical techniques which have transitioned to the study of human islets.
Employed non-human primate models to evaluate novel immunomodulatory approaches to prevent allograft rejection and transplanted pancreatic islet biology
Recognizing the advent of new immunomodulatory therapies and the growing interest in islet transplantation, we developed non-human primate models to test safety and efficacy. We’ve reported the remarkable efficacy of anti-CD154 to prevent allograft rejection (kidney, islets, and skin), and a novel means of inducing diabetes in the non-human primate. The Harlan lab also explored potentially safer approaches to transplant isolated islets, the detailed metabolic function promoted by islet allografts, and continues to investigate approaches to eliminate the need for immunosuppression following an islet transplantation.
Studied isolated human islets to disclose important structural and functional biology, and to develop new analytical tools
Recognizing the unique resource isolated human islets afforded for discovery, we were first to report that hyperglycemia induces beta cell TXNIP expression and transcription of a novel insulin mRNA which is preferentially translated. The Harlan lab was also the first to report the very different cellular structure of human compared to rodent islets, and that adult human beta proliferation rates are very low to minimal. Using techniques developed through our mouse studies, we reported that many human alpha cells transcribe high levels of insulin mRNA. We now study islets isolated from donors with T2D and T1D, with the latter helping to identify novel T cell epitopes involved in the anti-beta cell immune response.
Conducted clinical trials to test novel therapies and elucidate important human biology as it relates to diabetes and its treatment
As an active diabetes clinician, I've tested novel diabetes treatments for safety and efficacy. I was involved in testing immunotherapies (e.g. anti-CD3, oral interferon-alpha), led the NIH islet transplantation efforts, and tested various approaches to promote pancreatic insulin producing capacity after T1D diagnosis, and in studies to elucidate the mechanisms underlying diabetes complications.
Led efforts to improve diabetes care delivery for inpatients and outpatients by creating better care systems
One example of this was reporting that solitary pancreas transplantation worsens survival. Solitary pancreas transplantation has steadily decreased since that report, potentially saving many lives.