Microdialysis as a tool for the management of diabetes mellitus

Abstract: Diabetes complications are the result of impaired metabolic control. A continuous glucose monitoring system could be a tool to improve metabolic control. Microdialysis is a minimal invasive method for investigating tissue metabolism in-vivo and provides a novel opportunity for glucose monitoring in patients with diabetes (DM). The general aim of this thesis was to investigate if microdialysis technique can be used for reliable monitoring of glucose and other metabolites in abdominal subcutaneous (sc) adipose tissue during everyday activity in patients with DM. Moreover, we wanted to investigate if the microdialysis technique can be used for assessment of insulin sensitivity in subcutaneous adipose tissue. Methodological studies Comparing the effect of different microdialysis flow rates (0.3, 1, 2 and 5 µL/min) on the interstitial metabolites measured in subcutis we found that at the basal fasting state the dialysate glucose obtained by 0.3 µL/min was equal to capillary glucose concentration. A decrease in dialysate glucose levels during the basal state was observed for higher flow rates but not for 0.3 µL/min when no glucose was added to the perfusion fluid. This indicates a depleting effect for higher flow rates (> 0.3 µL/min). The relative increase in glucose after OGTT was similar for capillary glucose and dialysate glucose measured with flow rate 0.3 µL/min but not for higher flow rates (I). In long term studies with microdialysis the changes in dialysate glucose and other metabolites over eight days differed significantly in rats and humans. Caution should therefore be used when extrapolating data from subcutaneous tissue in Sprague Dawley rat to human applications. In healthy subjects and in patients with DM significant increases in dialysate glucose levels and glucose recovery were observed over five days. Histological signs of local inflammation in sc adipose tissue were observed around the microdialysis catheters. However, when using a flow rate of 0.3 µL/min over a period of 5 days no changes were observed in dialysate glucose levels or glucose recovery. These data suggest that the measurements are not affected by inflammation around the catheter when using a microdialysis flow rate of 0.3 µL/min. The actual glucose concentration can be measured using a flow rate of 0.3 µL/min without any calibration adjustments that would be needed for 2 µL/min. Using a flow rate of 0.3 µL/min the dialysate glucose measured by microdialysis catheters which had been rinsed prior to the insertion were significantly higher compared to the levels measured by dry catheters. We recommend that the low flow rate should be used in a microdialysis-based glucose sensor (II, III). In fasting and hyperglycemic state the dialysate and capillary glucose levels correlated in healthy subjects and patients with type 1 DM but not in patients with type 2 DM. The correlation increased over time with the highest correlation being observed at the last measurements in all three groups. This indicates stronger correlation over time between capillary and interstitial glucose in type 2 DM (IV). Metabolic studies. Using a low flow rate (0.3 µL/min) the true concentrations of interstitial metabolites can be determined. We use the term interstitial (instead of dialysate) metabolite in our metabolic studies. Our studies showed that the microdialysis technique can be used for assessment of insulin sensitivity in sc adipose tissue. Moreover, there were significant correlations between insulin sensitivity in sc adipose tissue, whole body and liver (M. A mixed meal resulted in lower capillary and interstitial glucose as well as lactate levels compared to OGTT. There were no differences in relative glucose recovery after mixed meal compared to OGTT. The microdialysis technique was reliable also for studies after mixed meal on the insulin effect in sc adipose tissue. (V) In conclusion microdialysis technique can used for reliable monitoring of glucose and other metabolites in sc abdominal adipose tissue during everyday activity in patients with DM. Pre-rinsing the microdialysis catheter in combination with a low (0.3 µL/min) perfusion flow rate gave similar interstitial and capillary glucose levels during fasting state, after oral glucose test and standardized mixed meal and two hours after meals in healthy subjects and patients with type 1 and type 2 DM. The low flow rate is also recommended for long term (five days) measurements of sc interstitial glucose, since at this flow rate the measurements were not affected by the inflammation around the catheter. Furthermore, the microdialysis technique can be used for studying the effect of insulin on glucose utilization and lipolysis in abdominal sc adipose tissue.