Hyperlipidemia Is Toxic to b-Cells, but Only in the Presence of Hyperglycemia

Both hyperglycemia and hyperlipidemia have been implicated as contributors to b-cell failure in type 2 diabetes. The authors of a recent review article believe that chronic hyperglycemia, by itself, is toxic to b-cells, whereas chronic hyperlipidemia is only toxic to beta-cells in the presence of hyperglycemia. They summarize the results from their laboratories at the Pacific Northwest Research Institute and the University of Washington in Seattle that support this belief.

Hyperglycemia can have several adverse effects on the b-cell. When present for a short time, it may cause b-cell desensitization-a physiological and reversible phenomenon that impacts the b-cell's ability to secrete substances, including insulin. Chronic hyperglycemia can lead to glucotoxicity-the irreversible loss of b-cell function, reduction of b-cell mass, b-cell exhaustion, and b-cell apoptosis. Glucotoxicity depends, at least in part, on chronic oxidative stress working on several b-cell transcription factors, including pancreatic-duodenum homeobox?1, leading to decreased insulin gene expression. Glucotoxicity can occur even in the absence of hyperlipidemia.

Concerning lipotoxicity, the authors focus on fatty acids as playing an important role in b-cell failure when chronically present in high concentrations, and they believe that it is the accumulation in the b-cell of metabolites formed in the fatty acid esterification process that causes lipotoxicity. Although fatty acids are a normal source of energy for b-cells, in high concentration they increase the basal release of insulin while inhibiting glucose-induced insulin secretion.

In support of the hypothesis that hyperglycemia is required for lipotoxicity to occur, the authors point out that most hyperlipidemic persons do not have diabetes. They cite in vitro and in vivo studies that are consistent with this clinical observation. They also suggest that obesity or dyslipidemia is not sufficient to cause b-cell dysfunction, on the basis of the fact that b-cell function is usually normal in patients with disorders of lipid metabolism.

The authors refer to specific in vitro and animal studies to support their hypothesis. When pancreatic islets in vitro are exposed for prolonged periods to fatty acids, there is a decrease in insulin gene expression, but only in the presence of a high glucose concentration. Further, the concentration of glucose limits the rate at which fatty acids are incorporated into neutral lipids. In Zucker diabetic rats, the accumulation of triglycerides and impairment of insulin gene expression in pancreatic islets are prevented by normalization of blood glucose but not by normalization of plasma lipid levels, and feeding a high-fat diet to hyperglycemic Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro whereas a similar diet has no effect in normoglycemic animals.

The above summary is adapted from the cited reference. 

Poitout V, Robertson RP. Minireview: Secondary Beta-Cell Failure in Type 2 Diabetes-A Convergence of Glucotoxicity and Lipotoxicity. Endocrinology. 2002;143:339-342.


Last Modified: 2/1/2013