Transient receptor potential melastatin 7 (TRPM7) channels are novel Ca 2؉ -permeable non-selective cation channels ubiquitously expressed. Activation of TRPM7 channels has been shown to be involved in cellular Mg 2؉ homeostasis, diseases caused by abnormal magnesium absorption, and in Ca 2؉ -mediated neuronal injury under ischemic conditions. Here we show strong evidence suggesting that TRPM7 channels also play an important role in cellular Zn 2؉ ] i measurement have been questionable. For example, previous studies reported that some indicators commonly used for calcium imaging, e.g. Calcium Green-1 and fura-2, are responsive to zinc with an extremely high affinity, and that specific zinc chelators reduced the intensity of calcium indicators (4 -7). These findings suggest that some of the biological effects previously assumed to be mediated by Ca 2ϩ may be mediated, at least partially, by zinc ions. Like calcium, recent studies have demonstrated that zinc ions play an important role in neuronal injuries associated with various neurological conditions (8, 9). The exact pathways mediating intracellular zinc accumulations and toxicity are, however, not clear.Zinc is one of the most crucial trace metals in cells. For example, zinc is required for the function of a broad range of enzymes involved in transcription, protein synthesis, and signal transductions (10). Although there are low levels of free zinc in cells, most zinc ions are bound to intracellular proteins (11). The mechanisms that affect the free zinc concentration are, therefore, pivotal for maintaining normal brain function. Although the extracellular fluid may contain up to several micromolar of zinc, intracellular zinc concentration ([Zn 2ϩ ] i ) is generally maintained at 10 Ϫ9 -10 Ϫ10 M (10, 12, 13). This steep gradient across the cell membrane is maintained primarily by zinc extrusion systems such as zinc transporters (ZnTs). At least 10 members of ZnTs, with different tissue distribution, have been identified in the ZnTs family. They promote the efflux of intracellular zinc into extracellular space or uptake of zinc into vesicles (14,15). In contrast to ZnTs, Zrt-and Irt-like proteins, or ZIPs, are known to transport zinc into the cells (14, 15). In addition, some calcium channels, e.g. voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate (NMDA) receptors, and amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA)/kinate receptors have been reported to be zinc permeable (16,17). The activities of these channels thus affect intracellular zinc homeostasis and toxicity. Unfortunately, clinical trials using the antagonists of these channels failed to provide satisfactory neuroprotection (2, 3).Transient receptor potential melastatin 7 (TRPM7) is a member of the large TRP channel superfamily expressed in * This work was supported, in whole or in part, by National Institutes of Health Grants R01NS47506 and R01NS49470 and American Heart Association Grant 0840132N.

The addition of glucagon delivery to a closed-loop system with automated exercise detection reduces hypoglycemia in physically active adults with type 1 diabetes.

Aims Exercise increases risk of hypoglycemia in type 1 diabetes (T1D). An artificial pancreas (AP) can help mitigate this risk. We tested whether adjusting insulin and glucagon in response to exercise within a dual-hormone AP reduces exercise-related hypoglycemia. Materials and Methods In random order, 21 adults with T1D underwent three 22 h sessions: AP with exercise dosing adjustment (APX), AP with no exercise dosing adjustment (APN), and sensor-augmented pump therapy (SAP). After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP, subjects could adjust dosing before exercise. The two primary outcomes were percent of time in hypoglycemia (<3.9 mmol/L) and percent of time in euglycemia (3.9–10 mmol/L) from the start of exercise to the end of the study. Results The mean times spent in hypoglycemia (<3.9 mmol/L) after the start of exercise were 0.3% [−0.1, 0.7%] for APX, 3.1% [0.8, 5.3%] for APN, and 0.8% [0.1, 1.4%] for SAP. There was an absolute difference of 2.8% less time in hypoglycemia in APX versus APN (p =0.001) and 0.5% less time in hypoglycemia for APX versus SAP (p = 0.16). Mean time in euglycemia was comparable across conditions. Conclusions Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycemia compared with no adjustment and performs similarly to SAP when insulin is adjusted before exercise.

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In this article, we present several important contributions necessary for enabling an artificial endocrine pancreas (AP) system to better respond to exercise events. First, we show how exercise can be automatically detected using body-worn accelerometer and heart rate sensors. During a 22 hour overnight inpatient study, 13 subjects with type 1 diabetes wearing a Zephyr accelerometer and heart rate monitor underwent 45 minutes of mild aerobic treadmill exercise while controlling their glucose levels using sensor-augmented pump therapy. We used the accelerometer and heart rate as inputs into a validated regression model. Using this model, we were able to detect the exercise event with a sensitivity of 97.2% and a specificity of 99.5%. Second, from this same study, we show how patients’ glucose declined during the exercise event and we present results from in silico modeling that demonstrate how including an exercise model in the glucoregulatory model improves the estimation of the drop in glucose during exercise. Last, we present an exercise dosing adjustment algorithm and describe parameter tuning and performance using an in silico glucoregulatory model during an exercise event.