Mechanisms should be established to support research on drug and biologic development that will not be supported by industry. For example, expansion of programs such as the NIH-supported Type 1 Diabetes Rapid Access to Intervention Development (T1D-RAID) program, and establishment of clinical trial networks, would allow potential therapies to be developed and tested in early Phase I and II trials that could lead to NIH ...more »
MicroRNAs are short ribonucleotides that bind to messenger RNA to modify protein translation or promote RNA degradation. Knowledge of the function and regulation of miRNA is rapidly expanding. They appear to be sensitive to the extracellular environment and could be important regulators of a cell’s response to diabetes. Can miRNA signatures detect early signs of DN? Can knowledge of miRNA signatures be translated ...more »
Tissue injury in diabetes results from cell damage and death, impaired communication among cells, dysfunction of nerves and blood vessels, and detrimental responses to systemic signals, such as inflammation. The development of the clinical manifestations depends on tissue-specific responses to injury and impairments in repair and regenerative processes. The knowledge base of the pathologic process in different tissues ...more »
Normally, metabolic and ischemic insults stimulate repair and regeneration. In diabetes, however, these processes are impaired. Recent advances in cell reprogramming hold great promise for future cell replacement therapies. How are specific populations of stem/progenitor cells affected by diabetes? Are these abnormalities reversible through optimal diabetes treatment or therapies targeted to stem/progenitor cells? ...more »
Translation of the knowledge of the molecular consequences of diabetes to effective therapies requires better measures of disease progression, faithful models of the molecular and cellular pathology, and application of cutting-edge technologies. Validated biomarkers and surrogate end points will allow rapid screening of clinical interventions prior to larger clinical trials, and can assess risk factors and treatment adequacy ...more »
One explanation for the discordant response of agents that treat complications in rodents versus humans is that deleterious pathways that are responsive to a certain drug may be widely expressed in inbred animal models, but expressed in only a small number of individuals. Should some agents be tested in primates or some other larger mammal? Pharmacogenomic, pharmacometabolomic, and pharmacoproteomic approaches could ...more »
Genetic mutations in mitochondrial fission/fusion proteins and changes in ROS production have been linked to diabetic complications. Why does the apparently global pathogenic mechanism of increased mitochondrial activity have variable consequences in different cell types? Can we develop better tools to assess mitochondrial function, transport, number, and fission/fusion states? Can we improve mitochondrial function ...more »
The abundance of molecular pathways affected by diabetes presents the challenge of understanding complex interactions among the pathways, but also the opportunity of providing multiple and potentially complementary targets for drug development. How do the identified molecular pathways associated with diabetic nephropathy interact within each cell and does this vary for different cell types? Are there undiscovered molecular ...more »
Autophagy was discovered in yeast as a stress response and may contribute to the excess of cell death and progression of complications. The human homologues of yeast autophagy genes and drugs known to affect autophagy are available to test the role of autophagy in diabetic nephropathy.
The value of currently available urine biomarkers that identify those at risk for diabetic nephropathy is increasingly called into question. The development of new urine and plasma biomarkers to predict diabetic nephropathy may shed light on disease mechanisms. Also, rational clinical trial design will be made possible by such markers.
While the mouse has many advantages, the human diabetic nephropathy phenotype has been difficult to faithfully replicate in the mouse using candidate gene approaches. Future work should focus on developing "humanized mice," in which loci associated with human diabetic complications are knock-in to the mouse. These animals could then be used to study mechanisms and therapeutics using systems biology approaches.
Non-mammalian model organisms have been underutilized to understand diabetic nephropathy pathogenesis. These simple model organism systems that permit ease of genetic manipulation, rapid throughput and precise measurement of phenotypes. Work published earlier this year (PNAS 107: 775, 2010) demonstrated that type 2 DM risk loci could be characterized in zebrafish. Interestingly, this study demonstrated this study shows ...more »