Glucolipotoxicity: fuel excess and beta-cell dysfunction

Abstract

Glucotoxicity, lipotoxicity, and glucolipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the beta-cell. In addition to their contribution to the deterioration of beta-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for lipotoxicity to occur, the term glucolipotoxicity, rather than lipotoxicity, is more appropriate to describe deleterious effects of lipids on beta-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucolipotoxicity on insulin secretion, insulin gene expression, and beta-cell death, and the role of glucose in the mechanisms of glucolipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of beta-cell compensation, decompensation, and failure during the course of type 2 diabetes.

Figure 1

Biochemical pathways through which elevated levels of glucose can form excessive levels of reactive oxygen species (ROS), which cause oxidative stress and lead to β-cell dysfunction. Under normoglycemic conditions, glucose metabolites flow primarily through oxidative phosphorylation, but during exposure to excessive glucose levels, metabolites also overflow into alternative pathways. The β-cell contains very low levels of antioxidant enzymes and consequently is exquisitely sensitive to ROS. This is consistent with physiological regulation of β-cell function when ROS levels are low, but deleterious effects on the β-cell when ROS levels are abnormally high.

Figure 2

Molecular mechanisms of action for glucotoxicity and glucolipotoxicity at the level of insulin gene expression. Under physiological conditions, MafA and PDX-1 are two critically important regulators of the insulin promoter, and respectively bind to the C elements and the A boxes (upper panel). Glucotoxicity greatly diminishes protein levels of PDX-1 and MafA, the former through a posttranscriptional mechanism and latter through a posttranslational mechanism. These abnormalities lead to decreased insulin mRNA, insulin content, and glucose-induced insulin secretion, and are reversible only in the early stages of glucose toxicity (middle panel). Under glucolipotoxic conditions, MafA expression is inhibited, whereas PDX-1 is affected at the post posttranslational level in its ability to translocate to the nucleus. This results in decreased insulin gene expression (lower panel).

Figure 3

Effects of glucose on lipid partitioning in the β-cell. In the presence of elevated glucose and fatty-acid (FA) levels, the increase in cytosolic malonyl-CoA resulting from glucose metabolism inhibits the enzyme CPT-1. Transport of LC-CoA in the mitochondria is reduced, and the esterification pathway is activated, leading to cytosolic accumulation of lipid-derived signaling molecules such as ceramide, diglycerides (DG), phosphatidic acid (PA), phospholipids (PL), and triglycerides (TG).

Figure 4

Contribution of glucotoxicity and glucolipotoxicity to the development of type 2 diabetes. In this hypothesis, lean and obese individuals who develop type 2 diabetes primarily have polygenic defects that predispose them to the disease. Because of genetic abnormalities the lean phenotype develops impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), which exposes the β-cell to chronic hyperglycemia. Hyperglycemia generates ROS which cause oxidative stress and worsened β-cell dysfunction. Alternatively but not exclusively, abnormally high blood glucose concentrations cause increased cellular lipid synthesis and glucolipotoxicity, which also causes deterioration in β-cell function. The obese phenotype has intrinsically elevated blood free fatty acid (FFA) levels which causes the β-cell to switch to preferential fatty-acid metabolism (glucolipoadaptation). Over time, however, the β-cell can no longer adapt and glucolipoadaptation evolves toward glucolipotoxicity. This in turn leads to hyperglycemia, which eventually overwhelms the β-cell and leads to its frank dysfunction. FA, Fatty acid.