The incidence of adult-onset Diabetes Mellitus (DM)(T2DM) has been rapidly increasing in California and throughout the world. T2DM commonly runs in families, indicating a genetic predisposition, but human genes do not change as fast as the incidence of T2DM is increasing. Therefore, much of the increase in T2DM incidence must be the result of the faulty interaction between ancient genes and recent changes in our environment. DM patients have high levels of sugar (glucose) in their blood. This glucose comes from our food and is used as fuel to generate energy by the power plants of our cells, the mitochondria. If an individual that eats a higher sugar diet than the mitochondria can burn, glucose builds up in the blood. Mitochondrial deficiencies have been found in T2DM patients, thus limiting their capacity to metabolize today’s rich diets. Like industrial power plants, our mitochondrial power plants contain their own blueprints located inside the mitochondrion, the mitochondrial DNA. Damage to the mtDNA means that damaged power plants can not be repaired and go offline. In a number of instances, T2DM has been associated with defects in the mtDNA blueprints. Therefore, T2DM is associated with an underlying mitochondrial defect. When we eat a high sugar meal, our blood sugar level rises. Cells in the pancreas, the beta cells, sense the high blood glucose and secrete a hormonal signal, insulin. Insulin enters the blood stream and instructs the cells in our body to start burning the glucose. However, if the mitochondrial furnace is damaged, the glucose fuel can not be burned and both glucose and insulin build up in the blood. As long as the blood glucose is high, the beta cells will keep producing and secreting insulin. However, this puts an enormous stress on the beta cells, and eventually they burn out and die. Consequently, the patient’s cells are not informed when fuel is available and thus don’t burn it. This leads to end stage T2DM. If we wish to effectively treat people for T2DM, we must first correct the mitochondrial defect so that the cells can again convert the glucose into energy. Then we can replenish the patient’s beta cells using stem cells so that the rest of the body’s cells know when to burn the glucose. Therefore, we propose to develop a drug and neutriceutical procedure to repair and reactivate the mitochondria throughout the body. In addition, we propose to create individualized replacement Beta cells by converting the patient’s skin cells into stem cells. These patient stem cells will then be converted into functional beta cells for introduction back into the liver of the patient. The new beta cells should colonize the liver, secreting insulin and regulating blood glucose.
Diabetes Mellitus (DM) currently affects 4 to 5% of the world population and the incidence of DM has been projected to increase 50% between 2000 and 2030. By 2010, approximately 350 million individuals will suffer from DM (1, 2). DM patients are also at increased risk of developing renal, visual, and peripheral neuropathy symptoms, and the relative risk of developing DM and the associated complications varies among California’s ethnic groups (3). Hence, the health burden of DM in California is enormous. Diabetes is traditionally divided into two classes: an early-onset, HLA class I associated form presenting with a complete absence of endogenous insulin production (Type I DM, T1DM) and a later-onset, non-HLA associated form frequently associated with the retention of some endogenous insulin production (Type II DM, T2DM). In the U.S. T1DM patients account for about 5 to 10% of DM. T2DM patients then account for the remaining 90 to 95% of cases (2). Since T1DM is assumed to result from the autoimmune destruction of the pancreatic beta cells, it is thought that this disease might be treated by suppression of the immune system and infusion of functional pancreatic islets into the liver (4). By contrast, the etiology of T2DM is less well understood, and its treatment might be more complex. Still, the health burden of T2DM vastly overshadows that of T1DM. Hence, the search for a cure for T2DM must be a high priority. A recent series of discoveries may have brought T2DM into the realm of treat-ability. A rising tide of evidence has appeared that indicates that most T2DM patients have an underlying defect in mitochondrial oxidative phosphorylation (OXPHOS) (5-10). Moreover, the discovery of T2DM cases caused by mtDNA mutations (11, 12) has stimulated the active search of pharmacological and neutraceutical approaches to treat mitochondrial dysfunction (13-19). Therefore, it follows that T2DM could be effectively treated by a combination of metabolic treatment to resuscitate faltering mitochondria plus replacement of lost beta cells through stem cell-derived beta cell replacement, which is what we proposed here. However, the significance of this project goes far beyond treatment of T2DM. Certainly, the beta cells could be used to treat T1DM patients. More importantly, however, it is becoming increasingly clear that mitochondrial dysfunction underlies the etiology a broad spectrum of metabolic, neurological, and cardiovascular diseases as well as cancer and aging (13, 20, 21). Hence, an effective mitochondrial resuscitation cocktail might be an essential adjunct of many of the cell based therapies that are being considered by CIRM including those for treating Parkinson Disease, Alzheimer Disease, Amyotrophic Lateral Sclerosis (ALS), retinal degeneration, deafness, cardiomyopathy, etc.