In This Issue of Diabetes

摘要

Although the kidney is known to play a crucial role in glucose homeostasis and metabolism, the underlying mechanisms of regulation of gluconeogenesis in the proximal tubule are surprisingly little understood. On that basis, Sasaki et al. (p. 2339) describe a series of mouse experiments that systematically try to uncover the mechanisms involved, revealing that gluconeogenesis is likely regulated by both insulin signaling and glucose reabsorption in the proximal tubules. They report that this likely affects gluconeogenic gene expression variously, depending on whether there was a fasted or fed state. Using different models, including tissue-specific knockout mice, they then unravel the pathways involved. They go on to suggest that various factors including PGC1a, Fox0I, sirtuin 1, and sodium-glucose cotransporter (SGLT) may be involved. Specifically, in mice with proximal tubule-specific knockout of insulin receptor substrates, they found impaired insulin signaling and upregulated gluconeogenesis gene expression, with corresponding increases in renal gluconeogenesis and insulin resistance. The hint that two pathways might be involved came from experiments involving mice given streptozotocin. Further experiments in cells then helped unravel what might be going on. In addition to insights into the mechanisms involved, the authors point out that some of the findings might have clinical significance, including consequences for the use of the SGLT2 inhibitors. Author Naoto Kubota told Diabetes: "We assumed that insulin is the dominant regulator of glucose metabolism regardless of particular tissues. However, our data show that this is unlikely to apply to the proximal tubules of the kidney, at least in some conditions. We also find it curious that the proximal tubules do not seem to care for blood glucose levels: they sense primary urine glucose levels instead, via SGLTs on the luminal side. As is revealed in this paper, glucose metabolism in the kidney does have unique aspects, which should be addressed in detail in future research."