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Figure 2 Sorbitol signaling pathway proposed for high-glucose–mediated enhanced collagen production in fibroblasts. Increases in intracellular glucose concentrations can activate an enhancer sequence in the collagen promoter, yielding enhanced collagen production and fibrosis. Increases in diacylglycerol can occur secondary to the altered transcription of enzymes involved in its synthesis or degradation (e.g., diacylglycerol kinase). The enhanced entry of glucose into the fibroblasts can also occur independently of transporter proteins yielding the stimulation of sorbitol and the production of 3-deoxyglucosone and glyoxal (intracellular advanced glycosylation end-product [AGEs]), both of which are direct stimulants of protein kinase C-beta. The production of aldose reductase (AR) also can be favored by an enhanced transcription of the gene. The sorbitol pathway can also increase production of reactive oxygen species (ROS), further stimulating PKC-beta. GLUT-1 = glucose transporter-1; PKA = protein kinase A.