Abstract
Type 2 diabetes is caused by chronic insulin resistance and progressive decline in beta-cell function. Optimal beta-cell function and mass is essential for glucose homeostasis and beta-cell impairment leads to the development of diabetes. Elevated levels of circulating fatty acids (FAs) and disturbances in lipid metabolism regulation are associated with obesity, and they are major factors influencing the increase in the incidence of type 2 diabetes. Chronic free FA (FFA) treatment induces insulin resistance and beta-cell dysfunction; therefore, reduction of elevated plasma FFA levels might be an important therapeutic target in obesity and type 2 diabetes. Lipid signals via receptors, and intracellular mechanisms are involved in FFA-induced apoptosis. In this paper, we discuss lipid actions in beta cells, including effects on metabolic pathways and stress responses, to help further understand the molecular mechanisms of lipotoxicity-induced type 2 diabetes.
Highlights
Type 2 diabetes is a heterogeneous syndrome that is related to both defective insulin secretion and peripheral insulin resistance
Chronic increases of plasma free fatty acid (FA) (FFA) concentrations result in disturbances in lipid metabolism regulation, which contribute to decreased beta-cell function and viability, and induce type 2 diabetes [3] (Figure 1)
Compared to untreated rat islets, rat islets cultured for 7 days in the presence of high levels of FFAs exhibit the hallmark events of apoptosis such as DNA fragmentation, increased caspase activity, ceramide formation, and expression of apoptotic genes [16]
Summary
Type 2 diabetes is a heterogeneous syndrome that is related to both defective insulin secretion and peripheral insulin resistance. There is some evidence that elevated fasting and postprandial FFA concentrations increase the risk of developing type 2 diabetes and obesity [1, 2]. Chronic increases of plasma FFA concentrations result in disturbances in lipid metabolism regulation, which contribute to decreased beta-cell function and viability (lipotoxicity), and induce type 2 diabetes [3] (Figure 1). The effects of a specific fatty acid (FA) on insulin secretion and betacell survival are related to the degree of saturation and carbon chain length of the FA. Prolonged exposure to palmitate (PA), an ester of the saturated palmitic acid, inhibits the secretory capacity of beta cells, impairs insulin gene expression, and increases beta-cell apoptosis [15]. This review discusses mechanisms, such as expression of receptors, synthesis of de novo ceramide, lipid droplet (LD) formation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and autophagy, that regulate beta-cell death and dysfunction with a focus on development of type 2 diabetes
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