Abstract
A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.
Highlights
Type 2 diabetes mellitus (T2D) is characterized by a dysfunction in glucose, lipid, and protein metabolism caused by a combination of impaired insulin secretion and insulin sensitivity, resulting in overt hyperglycemia
fatty acids (FAs) represent an important source of ATP, and they are transported to mitochondria or peroxisomes to be oxidized in acetyl-CoA, in a process known as βoxidation [23]
Despite the beneficial acute effects in Glucose-Stimulated Insulin Secretion (GSIS) potentiation, various studies have shown that T2D patients present high levels of plasma free fatty acids (FFAs) [49,50,51] and that deleterious parameters related to this condition, such as impaired insulin secretion and glucose intolerance are associated with the elevated levels of saturated FAs, including palmitic acid (C16:0) and stearic acid (C18:0) [52,53,54]
Summary
Type 2 diabetes mellitus (T2D) is characterized by a dysfunction in glucose, lipid, and protein metabolism caused by a combination of impaired insulin secretion and insulin sensitivity, resulting in overt hyperglycemia. In persons with prediabetes (impaired fasting glucose, impaired glucose tolerance, without overt hyperglycemia), insulin resistance is compensated by insulin secretion to maintain normoglycemia. It is only when pancreatic β-cell’s capacity is overwhelmed and insulin secretion fails—via either loss of β-cell function or mass (discussed later)—that overt hyperglycemia and T2D ensue [6,7]. Two main stresses are strongly correlated to this condition, namely the oxidative stress and the endoplasmic reticulum (ER) stress [9] Of note, both stresses are involved in the pathogenesis of diabetic complications. We will discuss the different types of fatty acids (FAs) and their effect on β-cells dysfunction and death, with special interest in the role of one main source of oxidative stress, the NADPH oxidase, and the ER stress
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