Executive Summary This proposal is focused on developing a treatment for Type II Diabetes Mellitus (T2DM). The treatment design is based on the premise that T2DM is caused by a systematic mitochondrial defect. One goal will be the development of a mitochondrial resuscitation cocktail that stimulates mitochondrial function and optimizes mitochondrial activity. A second goal will be to replace lost or damaged pancreatic islet cells with patient-specific cells derived via induced pluripotency followed by in vitro differentiation and maturation. The efficacy and safety of these approaches will be tested first in mouse models. The proposal is focused on a very significant disease, with an incidence that has been increasing rapidly in California and throughout the world. The proposed approach is directed at both correcting systemic metabolic defects associated with T2DM and replacing lost pancreatic beta cells. Although reviewers felt that the proposal outlined an interesting and innovative approach, they had strong doubts about the underlying premise that most T2DM is caused by a mitochondrial defect reversible by mitochondrial resuscitation, even though T2DM is associated with significant oxidative stress. Considerable published clinical evidence supports the heterogeneous, complex nature of the disease and reviewers felt that the complexity would not be captured by a purely mitochondrial pathophysiological focus. Consequently, the proposed therapeutic intervention was not viewed as likely to cure most cases of T2DM. Furthermore, the major focus of the proposal could be achieved independent of stem cell biology, by developing mitochondrial cocktails for diabetes independent of stem cells; stem cells are not the foundation of the proposal. Reviewers had two additional concerns that limited their enthusiasm for the proposal. First, the development, optimization, potential side effects, and regulatory approval for the resuscitation cocktail were viewed as serious obstacles. Second, the generation of mature pancreatic islet cells from patient-specific induced pluripotent stem cells has yet to be achieved, with a variety of steps in the process and appropriate conditions for development unknown. The prospect for these challenges being addressed within the five year time-frame was judged highly unlikely. The PI is a widely recognized leader in the field of mitochondrial disease. He/she has a superb record of productivity and collaboration and has substantial experience in assembling and managing team-based research programs. The PI is a clear strength of the proposal. The planning approach is well organized and structured. Prospective team members with appropriate expertise are identified. Seven subcommittees are assigned distinct responsibilities in formulating and guiding the planning process. Reviewer Synopsis The premise of this proposal is that Type II Diabetes Mellitus (T2DM) is caused by a systemic mitochondrial defect that could be corrected by developing a mitochondrial resuscitation cocktail that up-regulates OXPHOS, reduces oxygen radicals, inhibits apoptosis, and optimizes mitochondrial autophagy. Then to replace the lost  cells, the applicant proposes to genetically induce patient cells into pluripotent stem (iPS) cells and use the Novocell differentiation procedure to generate immature  cells, and to apply insights from mouse studies to induce the maturation of the human  cells. The efficacy and safety of the cocktail and  cells will be tested in mouse models of T1DM and mitochondrially-induced T2DM. Preclinical testing of the mitochondrial cocktail will be performed on patients with known mtDNA defects and on IR and NIDDM patients. Preclinical tests of the iPS cell-derived  cells will apply the Edmonton transplantation protocol to IDDM patients in combination with mitochondrial resuscitation. Reviewer One Comments Concept: The proposal focuses on a very significant disease (T2DM), even though the clinical definition seems to capture a number of diseases with different pathophysiological etiology. The concept underlying this proposal is that mitochondria cause T2DM. This is an interesting idea; however this is unlikely to be ultimately the sole cause of T2DM. Thus treatment with iPS cured for mitochondrial defects is a very preliminary idea, especially since T2DM is treatable with other approaches. Another important consideration is that it is unclear and unknown how well the Novocell protocol works for the production of pancreatic islet-like cells. Principal Investigator: The PI is a pioneer in the field of mitochondrial disease. He is not an MD. Planning Approach: The planning approach is divided up into individual planning committees. It seems very organized and structured. The host institution is an excellent environment for the project. Reviewer Two Comments Concept: The premise of this proposal is that type 2 diabetes is a mitochondrial disease in that insulin resistance is the result of the inability of the mitochondria to oxidize all the calories consumed leading to ROS that cause mitochondrial damage;  cells are then stressed by the extra glucose causing their dysfunction and loss. Thus, the concept is that a cure for type 2 diabetes would be two pronged: a cocktail to resuscitate the mitochondria and then replacement of  cells using a patient’s own induced pluripotent stem (iPS) differentiated to functional mature  cells ex vivo. While a small proportion of type 2 diabetes patients clearly have a mitochondrial defect (along with deafness), type 2 diabetes is a heterogeneous disease that may arise from many different genes contributing to  cell inability to compensate for the functional demand of insulin resistance. Two arguments against the mitochondrial basis of type 2 diabetes as defined here are : 1) most obese persons have significant insulin resistance but are not diabetic (actually have normal glucose tolerance); 2) 70% of type 2 patients who undergo gastric bypass become non diabetic within a week of surgery. The generation of a mitochondrial resuscitation cocktail is imaginative and based on the research of the PI and his collaborators. As suggested it might include resveratrol (to increase SIRT1 activation and OXPHOS energy output), bezefibrate (to increase fatty acid metabolism), natural or catalytic antioxidants (to ameliorate mitochondrial oxidative damage), a modified cyclosporine (to inhibit apoptosis) and PI3K antagonists and agonists to regulate mitochondrial turnover. It is frightening what side effects could be seen from these numerous drugs. While there are mouse models to test the effectiveness of the variations of this cocktail, it is hard to conceive of FDA approval for all within the desired time frame. The second prong is equally problematic: generation of patient specific-induced pluripotent stem cells, then using the Novocell protocol to generate  cells from these and some yet to be discovered protocol for inducing functional maturity in these cells. Each of these steps is unproven and will need extensive development. Thus the feasibility in the time frame for this prong is doubtful. Principal Investigator: Dr. Wallace is Director of the Center for Molecular and Mitochondrial Medicine and Genetics and Professor of Molecular Medicine, of Biological Chemistry and of Ecology and Evolutionary Biology UC Irvine. A member of the National Academy of Sciences, he is a well recognized expert on mitochondrial dysfunction and disease. He not only is an excellent scientist but he has many years of experience in building and managing a group of basic, translational and clinical researchers. He and several of the other involved already have CIRM grants. He is clearly a strength of this proposal. Planning Approach: The planning approach is for 7 subspecialty groups with specific responsibilities to meet together monthly to define the goals and plans to achieve those goals. The groups include: mitochondrial medicine, hES cells,  cell development, mouse diabetes models, patient recruitment and evaluation, transplantation and evaluation, and regulatory and commercial. The individuals who are core to these groups are named and provide a large range of necessary expertise. It is likely that these committees will be able to define the goals and steps to get to clinical trials.