Earlier on this forum I had raised the question of why the finding among type 2 diabetics, that lowering blood sugar values toward but not all the way to normal levels was actually counterproductive if taken too far, had not been extended to type 1 diabetics. The answer usually given was that since this phenomenon had not yet been studied in type 1 patients, the opposite effect should be assumed to be the result of very strict blood sugar control in them, though the physiological reasons for this difference were never adequately explained.
But now, finally, the logic of extending these implications to type 1 diabetics are being recognized, and once they are more generally accepted, they could have a revolutionary effect on treatment regimens. This is especially the case since there is some evidence indicating that lower blood sugar levels might actually cause some of the same vascular complications traditionally associated with high blood sugar, so that when you see a patient with diabetic vascular disease, it could well have been caused by both high and low blood sugar.
See, for example, the article by N. Kajihara, et al., “Low Glucose Induces Mitochondrial Reactive Oxygen Species in Bovine Aortic Endothelial Cells,” Journal of Diabetes Investigation, vol. 8, no. 6, pp. 750-761 (2017):
"Hypoglycemia, mediated by intensive glucose‐lowering interventions, is a common side‐effect in patients with diabetes, and might increase the risk of poor outcomes. Additionally, ECs play important roles not only as vessel barriers, but also in the regulation of vascular tone, coagulation, leukocyte adhesion and vascular permeability. Vascular tone is modulated by various factors, such as NO. The earliest and most important factor mediating endothelial dysfunction is a reduction in NO bioactivity, which is mediated by ROS. Therefore, ROS generation in vascular cells plays a key role in endothelial dysfunction and subsequent atherosclerotic lesion formation. Furthermore, hypoglycemia induces endothelial dysfunction through the production of several inflammatory factors, including VCAM‐1, ICAM‐1, vascular endothelial growth factor, interleukin‐8, interleukin‐6, endothelin‐1 and tumor necrosis factor‐alpha, resulting in increased risk of diabetic macro‐angiopathy. In particular, Jin et al. reported that hypoglycemia increases serum adrenaline and levels of adhesion molecules, such as VCAM‐1 and ICAM‐1, in the endothelium of the rat aorta. In addition, increased ROS also activates nuclear factor‐κB, which mediates the overexpression of adhesion molecules, such as VCAM‐1, ICAM‐1 and E‐selectin. In the present study, we observed that LG stimulation decreased the bioavailability of NO, and increased the expression of VCAM‐1 and ICAM‐1 in ECs. Furthermore, blockade of FAO or suppression of mtROS ameliorated the LG‐induced bioavailability of NO, and expression of VCAM‐1 and ICAM‐1. These results suggested that hypoglycemia‐induced reduction of NO bioactivity, and overproduction of VCAM‐1 and ICAM‐1 messenger RNA were mediated by the overproduction of mtROS and activation of FAO in ECs.
The present findings might have implications in both diabetic macro‐angiopathy and diabetic micro‐angiopathy. In fact, our preliminary data showed that etomoxir decreased ROS generation and prevented vascular permeability caused by recurrent hypoglycemia in the retinas of diabetic mice (unpubl. data). Interestingly, Schoors et al.33 reported that etomoxir also reduces pathological angiogenesis in a model of oxygen‐induced retinopathy. We therefore speculate that mtROS and FAO might be involved in the progression of microvascular complications caused by recurrent hypoglycemia."