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Individual Abstracts for the
Lester Wolfe Workshop in Laser Biomedicine
Optical Methods for Managing Diabetes:
Will Technology or Biology Succeed First?

Tuesday, November 16, 2004 4:00-6:00 PM
MIT Grier Room * 34-401
50 Vassar Street * Cambridge, MA

Challenges and Opportunities in Managing Diabetes
Dr. David Nathan
Director, Diabetes Center and General Clinical Research Center
Massachusetts General Hospital
Diabetes mellitus represents the most common, severe chronic disease in the US and much of the world. There are 1,200,000 new cases of diabetes annually in the US. The long-term complications of diabetes cause more blindness, kidney failure and amputations than any other disease and contribute to as much as 40% of all heart disease. Fortunately, we have effective interventions to prevent or limit the long-term complications of diabetes and to prevent the epidemic form of diabetes, Type 2 diabetes. In order to manage diabetes effectively requires frequent glucose monitoring. Advances in such monitoring should improve the chronic levels of glycemia experienced by diabetic patients, lessen the burden of self-care, and ultimately decrease the morbidity and mortality of the disease.

Imaging Islet Cell Function – From Single Cells to Intact Islets
Prof. David Piston
Department of Molecular Physiology and Biophysics
Vanderbilt University
The convergence of newly developed instrumentation and optical probes allows us to examine quantitatively dynamic processes within ever more complicated biological systems. By using quantitative fluorescence imaging methods such as fluorescence recovery after photobleaching (FRAP) and Förster resonance energy transfer (FRET) of multi-colored GFPs fused to the glucose sensing enzyme glucokinase (GK), we have discovered that the location and activity of beta cell GK is acutely regulated by insulin. These findings provide a mechanism whereby the glucose sensing ability of the beta cell is tightly coupled to insulin signaling. We have also measured pancreatic ?-cell metabolism during glucose stimulation of pancreatic islets by quantitative two-photon NAD(P)H imaging. We have developed methods to delineate quantitatively the NAD(P)H signals from the cytoplasm and mitochondria, and show that the metabolic response of these two compartments are differentially stimulated by glucose and other metabolites. Absolute levels of NAD(P)H were determined using two-photon excited fluorescence lifetime imaging (FLIM). These findings elucidate the relative contributions of glycolytic and citric acid cycle metabolism in the normal and diabetic insulin secretion pathways.

Diabetic Retinopathy: From Basic Science to Clinical Studies
Dr. Sven-Erik Bursell
Joslin Diabetes Center
Diabetic retinopathy is the leading cause of new blindness in working age persons and leads to annual federal health care expenditures of $639 million. Results from the ETDRS study showed that laser panretinal photocoagulation (PRP) was clinically effective in reducing the risk of vision loss to less than 5%. Despite this clinical benefit PRP destroys retina in an attempt to maintain vision with a number of associated adverse effects such as reduction in peripheral vision. Because PRP is a destructive therapy it becomes attractive to consider non-invasive-non-destructive therapies for the treatment of diabetic retinopathy.
The Joslin Diabetes Center’s basic research has focused on identifying potential novel therapeutic agents such as protein kinase C-? inhibitors. Results have shown that protein kinase C (PKC) activation plays an important role in the development of early retinal abnormalities in diabetes and that PKC inhibitors are effective in ameliorating these physiological abnormalities. Results have shown that PKC activation mediates increased endothelin-1 expression resulting in early reductions in retinal blood flow. Retinal blood flow reduction has been measured in early diabetes in diabetic rats and mice and in diabetic patients with less than 10 years duration of diabetes. Additionally, in a transgenic mouse model over-expressing PKC-?? retinal blood flow is reduced, endothelin-1 expression is increased, and diabetic retinopathy lesion development in these animals is accelerated compared to wild type diabetic mice.
Inhibition of PKC activation has been evaluated clinically a phase I b single center, randomized, parallel, double masked placebo controlled trial. Twenty-nine patients with disease duration less than 10 years participated in the study with oral treatment of the PKC inhibitor for 30 days. The results from this study showed that treatment significantly ameliorated associated reductions in retinal blood flow and did not adversely affect retinal vascular leakage in diabetic patients with normal retinal vascular permeability. The potential beneficial results using PKC inhibition have now been extended into phase III clinical trials.

Optical Methods for Noninvasive Blood Glucose Analysis
Dr. Mark Arnold, University of Iowa
Department of Chemistry * Optical Science & Technology Center
Optical methods are under consideration as a means to measure blood glucose noninvasively in human subjects. The concept is to pass a selected beam of light into the human body and then determine the level of glucose from an analysis of the resulting spectrum. This approach is noninvasive in the sense that no sample is required, which means there is no need to collect a sample of blood or interstitial fluid.
Clinically, noninvasive methods offer a number of critical features that render this approach attractive for monitoring glycemia in the treatment of diabetes. Specifically, pain-free and reagent-less noninvasive measurements will likely improve tight glycemic control by encouraging frequent measurements through the elimination of pain associated with collecting a sample of blood and reduction in the cost per test. In addition, an optical noninvasive glucose monitor offers the potential for continuous glycemic measurements while avoiding the complications associated with implantable glucose biosensor technologies. These features drive the development of this technology.
The ability to determine the concentration of glucose from an analysis of spectra collected noninvasively from human subjects is not trivial. A high degree of selectivity is required to distinguish glucose from the large number of endogenous molecules within the human body. The chemical structure of the glucose molecule does not provide a uniquely distinguishing spectral feature over the wavelengths of light that can be used to probe inside the human body. Optical signals from glucose overlap with those from other endogenous substances, thereby demanding sophisticated methods to extract the glucose information selectively.
Successful noninvasive blood glucose monitoring represents a great challenge and requires a detailed understanding of the chemistry, physics, physiology, and optics associated with the measurement. The features of different approaches will be reviewed and the current state-of-the art will be discussed.