In the September issue of Diabetes Care, Boden and Laakso (1) review various methods by which fatty acids and fat tissue promote the pathogenic process deteriorating to type 2 diabetes. They emphasize the effect of peripheral fat storage in muscle and liver on the development of insulin resistance and diabetes but neglect, however, to discuss the effect of fat deposition in and around the β-cell on β-cell function and apoptosis as a pathophysiologic event in the development of the disease.
In their review, Boden and Laakso mention only the increase in insulin secretion and glucose-stimulated insulin secretion (GSIS) in response to exposure to free fatty acids (FFAs). This response is said to be attenuated in diabetic patients and their relatives, thus demonstrating a tendency toward β-cell failure during the disease. This effect is a short-term effect. When obese individuals were exposed to high levels of FFAs for prolonged periods of time, a decline in GSIS was observed (2). The effect of chronically elevated FFAs highlights a major contribution of β-cell lipotoxicity to the pathogenic process deteriorating to type 2 diabetes . This β-cell lipotoxicity has been studied thoroughly. It has been shown that high levels of FFAs have a detrimental effect on β-cell survival and insulin secretion (3). In ZDF rats, these effects were related to enhanced accumulation of triglycerides in the islets and β-cells (4). A high FFA and triglyceride load in human islets induced caspase-mediated apoptosis, probably through the ceramide pathway (5). Furthermore, thiazoldinediones, which are known to improve insulin resistance through a reduction in fat content of muscle and liver, cause a dramatic improvement in insulin secretion in diabetic patients (6). Based on these effects, it would seem nearsighted to emphasize the role of FFAs in diabetes as mainly a peripheral one on muscle and liver tissue. Although type 2 diabetes is characterized by peripheral insulin resistance that might be related to deranged fat metabolism, it is becoming clear that it is not solely a disease of glucose-utilizing tissue but might also be a result of a lipotoxic effect on the β-cell.
Other areas that should be highlighted include the role of lipotoxic mitochondrial damage as a core process in the pathogenesis of type 2 diabetes and the role of mitochondrial uncoupling proteins (UCPs) as culprit proteins and a possible defense mechanism in diabetes. Mitochondrial dysfunction has been noted in diabetes and may result from an enhanced effect of lipid peroxides formed in the mitochondria as a result of FFA excess. This damage can then lead to further FFA accumulation through diminished oxidative capacity (7). The mitochondrial UCPs seem to play a role in the protection of the mitochondria from these harmful effects by preventing the formation of lipid peroxides (7). They were implied as culprit proteins in diabetes when a 50% reduction in UCP3 levels was found in diabetic patients (8), thus rendering them more susceptible to FFA-induced mitochondrial damage and the slippery slope that follows. Another uncoupling protein, UCP2, is suspected of playing a role in glucose sensitivity and insulin secretion in β-cells and is upregulated by chronically elevated FFAs (9). Genetic polymorphism in this protein was found to be associated with insulin resistance and increased risk of type 2 diabetes (10).
