During this year, we have developed several tools required for the conduct of diabetes clinical trials. Infrastructure for inpatients and outpatients will be described separately. ? ? For Clinical Center inpatients with hyperglycemia, we have established a new Blood Glucose Management Service (abbreviated BGMS). Any primary care team interested in turning over all insulin-based blood glucose management decisions to our multidisciplinary team can do so by submitting a consult. The team, consisting of an attending physician, 2 nurse practitioners, a pharmacist, a certified diabetes educator, and both pediatric and adult endocrine fellows, assumes 24 hour/day and 365 day/year responsibility for insulin orders and glycemia control for such patients. The team rounds daily, reviews patient status and blood glucose values, then writes insulin orders and daily notes (all in the electronic medical record) to maintain near-normal glycemia. The team has already been successful with its teaching mission, i.e. diabetes treatment objectives and strategies are being clearly communicated to patients, nursing staff, and physicians. Physician providers have demonstrated their support for the service by the number of patients referred; our monthly census has increased from 61 patient care days in February 2007 to over 180 in September 2007. We are developing tools to capture research relevant data from the patients we follow, and management questions are uncovered as good research questions. For instance, we are presently testing how much insulin can safely be added to total parenteral nutrition (TPN) used to support a bone marrow transplant recipient with graft-versus-host disease requiring high dose glucocorticoids. We are attempting to develop other research tools designed to measure the services impact on inpatient morbidity and mortality, as we continue to support other NIH protocol participants with difficult to control hyperglycemia. Further, we are developing intervention protocols for this next fiscal year for obese subjects with type 2 diabetes mellitus, and such patients will be hospitalized as part of that evaluation and treatment. The proper management of such protocol recipients often requires considerable and multidisciplinary diabetes treatment expertise.? ? For our outpatient clinical protocols, we focus on preserving or even promoting pancreatic beta cell function is individuals with T1DM. Data from several studies have now clearly demonstrated that in 2007, the safest and most effective way to preserve beta cell function is to maintain blood glucose concentrations within normal (or near-normal) ranges. Further, for protocols designed to assess a treatments ability to preserve beta cell function, power analyses mandate enrolling approximately 80 to 120 individuals with recent onset T1DM. Enrolling that protocol participant pool in a reasonable time means casting broadly (geographically speaking), and (sadly) diabetes care delivery in the general community is not geared to adequately support patients to promote near-normal glycemia. We can easily highlight the compromises required to date by citing our recently completed protocols: we either referred patients to their local health providers for diabetes care (and glycemia control subsequently fell below modern treatment goals), or the protocol enrolled sufficiently small patient numbers that we could provide intensive-insulin management advice using e-mail and telephone contact. For all these reasons, we have worked to develop systems allowing our NIH team to mass produce diabetes care delivery such that all protocol participants could enjoy intensive-insulin managements benefits. We generated a request for proposals for a web-based blood glucose reporting system that will allow all outpatients we follow with diabetes to automatically download finger-stick blood glucose values from their meters to a centralized, secure data base that both they and their health care team can access 24 hours a day, 365 days a year. Further, the RFP mandates that the secure website allow secure communication between the patient and the health care team via the web, allowing for the frequent dose modifications inherent in any intensive insulin management regimen. The RFP received several bids currently being evaluated, and we anticipate awarding the contract this fiscal year.? ? We have also developed assays to detect anti-GAD and anti-IA2 autoantibody titers relevant for our T1DM immunotherapeutic clinical trials. We participated in the international Diabetes AutoAntibody Standardization Program (DASP) workshop in 2006 to validate our laboratory's assays, and for one of the two assays (IA2) the NIH lab scored best in the world for sensitivity/specificity. A manuscript reporting the 2006 DASP workshop results has been submitted for publication and is currently under review. This year too, we participated in a new DASP workshop (we submitted our results in September 2007) with results of this years workshop still pending.? ? Last, since T1DM is a T cell mediated autoimmune illness, we recruited a cellular immunologist to the Branch in 2007, Dr. Kristin Tarbell. Dr. Tarbells immunology pedigree is top-notch, with background in both Hugh McDevitts laboratory (for her Ph.D.), and she did her post-doctoral work with Ralph Steinman, recipient of a 2007 Lasker Award. Dr. Tarbell will participate in our clinical trials by working to develop assays to monitor the anti-beta cell T cell response.? ? Along with some extra-mural collaborators (who will be listed on next year's report) we are currently putting together a protocol enrolling individuals with recent onset T1DM to test whether intensive insulin management coupled with a glucagon-like-peptide 1 (GLP1) receptor agonist plus a proton pump inhibitor, with or without immunosuppression, will (alone or in combination) prolong or even promote beta cell function. The trials central hypothesis is supported by considerable rodent data, and we anticipate enrolling our first patients in 2008.
| Liu, Eric H; Siegel, Richard M; Harlan, David M et al. (2007) T cell-directed therapies: lessons learned and future prospects. Nat Immunol 8:25-30 |
