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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) a mouse model to study the mechanisms underlying the pancreatic beta cell destruction underlying T1D.  The model was based upon rat insulin promoter driven beta cell specific expression of the costimulatory receptor CD80.  Its main advantage was that diabetes was inducible with predictable kinetics.  We could induce diabetes by virus infection, low dose beta cell toxins, and by immunizing with beta cell autoantigens.  My model continues to be used today.  Our lab has utilized 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.  My laboratory also explored other potentially safer approaches to transplant isolated islets, the detailed metabolic function promoted by islet allografts, and continue to study approaches that may obviate immunosuppression following an islet allograft.

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.  My 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, my lab reported that many human alpha cells transcribe high levels of insulin mRNA.  We’ve recently moved to the study of islets isolated from donors with T2D and even 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 have 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 within the hospital and community providers

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.