Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

Abstract

OBJECTIVE-An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease ␤-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in ␤-cell function. RESEARCH DESIGN AND METHODS-We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells.RESULTS-Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P Ͻ 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P Ͻ 0.01) and induced oxidative stress (P Ͻ 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour infusion of olive oil induced oxidative stress (P Ͻ 0.001) and decreased the insulin response of isolated islets similar to oleate (P Ͻ 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P Ͻ 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. T ype 2 diabetes is characterized by both insulin resistance and defective insulin secretion (1). Obesity is the major predisposing factor for type 2 diabetes and is associated with excessive release of fatty acids from the expanded adipose tissue mass, leading to elevated plasma free fatty acids (FFAs), which are known to induce insulin resistance (2,3). Acute FFA exposure stimulates insulin secretion (4), but studies in vitro and in situ have shown that prolonged FFA exposure decreases glucose-stimulated insulin secretion (GSIS) (5). The effect of prolonged FFA elevation on ␤-cell function in vivo has been more controversial, as absolute GSIS was found to be increased (6 -8), unchanged (9,10), or decreased (11-13) by FFA. However, in most of these studies ␤-cell function was inadequate to compensate for FFA-induced insulin resistance (9 -13), at least in predisposed individuals (14). Although the mechanisms behind FFA-induced decrease in ␤-cell function are unclear, one possibility points toward oxidative stress. Pancreatic ␤-cells have low antioxidant defenses (15) and are thus susceptible to reactive oxygen species (ROS)-induced decrease in function and viability (16,17). Oxidative stress has been implicated in the decrease in GSIS induced by prolonged exposure to glucose (18,19), which is in many respects similar to that induced by prolonged exposure to FFA (4,20). However, whether oxidative stress plays a role in FFA-...

Short-term low carbohydrate/high-fat diet intake increases postprandial plasma glucose and glucagon-like peptide-1 levels during an oral glucose tolerance test in healthy men

“…Although the effects of elevated plasma FFA on insulin secretion are controversial, prolonged elevation of FFA levels impaires insulin secretion. 34 In the current study, the increase in fasting FFA levels was similar between ND and LC/HFD, but they negatively correlated with firstphase insulin release indexes. Therefore, it is likely that FFA levels are a contributing factor in the regulation of first-phase insulin release.…”

A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS)

“…Since FFA has been shown to generate ROS in beta cells and anti-oxidants have been reported to prevent FFA-induced GSIS-inhibition [27,28], oxidative stress was postulated to be a key mediator in the induction of FFAinduced beta cell dysfunction. Although the mechanisms by which oxidative stress affects beta cell function have not been well-defined, reduced production of ATP, possibly through UCP-2 induction, was reported to be a plausible mechanism for explaining FFA-induced beta cell dysfunction [5].…”

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…Interestingly, the beta cell is especially sensitive to oxidative stress owing to its low levels of antioxidant enzymes [45], and so the balance between free radical production and detoxification could easily be thrown in the direction of oxidative stress. Incubation of islets or beta cells in high glucose and NEFA has been shown to cause impaired insulin secretion, which can be improved with antioxidant treatment [46,47]. Increased markers of oxidative stress have also been measured in islets from patients with type 2 diabetes, and improvements were seen when the islets were treated with the antioxidant glutathione [48].…”