Cells in focusHepatocytes: critical for glucose homeostasis
Introduction
Compounds absorbed in the gut pass through the liver where they can be absorbed and metabolized. To accomplish this, mature hepatocytes are arranged into irregular folded sheets surrounding the sinusoids where blood flows, separated only by a single layer of endothelial cells, interspersed Kupffer cells, and hepatic stellate cells. Hepatocytes also maintain a connection to the gut via the formation of canaliculi and larger ducts into which bile is secreted. While all hepatocytes are capable of carrying out the necessary metabolic and secretory tasks attributed to liver parenchymal cells, there are some differences that exist in subcellular structure and function of hepatocytes with respect of localization within in the liver (Tosh, Alberti, & Agius, 1988). Afferent periportal hepatocytes reportedly have higher gluconeogenic activity, whereas the efferent perivenous hepatocytes have been shown to possess higher activity of some glycolytic and lipogenic enzymes. Together, hepatocytes play a critical role in maintaining blood glucose levels within a narrow range while responding to the changing demands of the body. The focus of this review will be on hormonal regulation of mature hepatocytes to accomplish glucose homeostasis, and hepatic-specific impairments in this process that are related to obesity, insulin resistance, and type 2 diabetes (Fig. 1).
Section snippets
Hepatocytes in the fasted state: net glucose production
During fasting, increased glucagon release by the α cells residing in the pancreatic islets of Langerhans leads to a rise in plasma glucose levels. The binding of glucagon to its cognate receptor on hepatocytes activates the serine/threonine kinase PKA which results in phosphorylation and activation of glycogen phosphorylase kinase (GPK) and glycogen phosphorylase (GP), increasing the rate of glycogenolysis. Glycogen reserves, however, provide only a short term supply of glucose.
Hepatocytes in the fed state: insulin-dependent glucose utilization
Postprandially, the liver removes glucose from the circulation and stores it in the form of glycogen or metabolizes it through glycolysis. The GLUT2 transporter mediates the diffusion of glucose across of plasma membrane of the hepatocyte. This transporter differs from GLUT4 glucose transporters found in the muscle and adipose in that it is constitutively present at the plasma membrane and secondly has a low affinity and high Vmax for glucose compared to other glucose transporters. Thus, GLUT2
Dysregulation of hepatic glucose metabolism: insulin resistance and type 2 diabetes
The liver plays a major role in glucose homeostasis. Clearly, dysregulation of insulin action will have profound effects on hepatic glucose homeostatic pathways and circulating glucose levels. This is abundantly apparent in western society which is experiencing an epidemic of impaired insulin action in the form of insulin resistance and type 2 diabetes.
Type 2 diabetes is caused by a combination of genetic and environmental influences. While the genetic contribution to type 2 diabetes is not
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