Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. In the present review, we focus on exogenous and endogenous effects of NEFAs, including the polyunsaturated fatty acid, arachidonic acid (or its metabolites generated from cyclo-oxygenase activity), on β-cell metabolism, and have explored the outcomes with respect to β-cell insulin secretion.

Utilization of β-cell lines for assessment of β-cell function

In writing the present review, we are fully aware that most of the studies cited have utilized rat-, mouse- or hamster-derived primary islet cells or insulinoma β-cell lines to study function in vitro. This is due to the inherent difficulty in maintaining primary rodent islet β-cell mass and function for more than a few days in vitro and of course the scarcity of human islets for research purposes. There are as yet no suitable human β-cell lines available for unrestricted in vitro studies. However, the major rodent β-cell lines have provided substantial data and insights into cell function in normal or pathogenic situations. The most widely used cell lines include INS-1, MIN-6, RINm5F and BRIN BD11.

Modulation of insulin secretion by NEFAs (non-esterified fatty acid)

In vivo studies

Insulin secretion is influenced, at any given time, predominately by the blood glucose concentration and by the prevailing fatty acids in the circulation [1]. Gut-derived incretins and other hormones and neurotransmitters may also exert an influence. Many groups have investigated the effect of fatty acids on the process of glucose-induced insulin secretion (e.g. [26]). The rapid effect of NEFAs in potentiating GSIS (glucose-stimulated insulin secretion) in vitro, while having little effect on secretion at non-stimulatory glucose concentrations, would suggest that they act to amplify metabolic stimulus–secretion coupling mechanisms [7,8]. The potency of fatty acids to promote glucose-induced insulin release increases with the chain length and decreases with the degree of unsaturation [9,10]. Long-chain fatty acids (such as palmitate, linoleic and α-linolenic acids) potentiate insulin secretion in response to basal glucose concentrations [11].

Acute lowering of plasma fatty acid levels is associated with a decreased insulin response to glucose [2,12], but full secretory function can be restored by inclusion of fatty acids during perfusion of pancreas from fasted rats [5,6,13]. GSIS by perifused islets of 24 h fasted rats is reduced when compared with the response of islets from fed rats [5,6,13,14]. In rats deprived of food for 18–24 h, the ability of the β-cell to secrete insulin in response to a glucose load is fully dependent on the elevated levels of circulating NEFAs characteristic of the fasted state [5]. In fact, circulating fatty acids are essential for an efficient glucose stimulation of insulin release after prolonged fasting in humans and rats [15,16].

A recent advance in the understanding of the mechanism(s) by which NEFAs modulate insulin secretion in vivo is the discovery of high levels of expression of the membrane-bound G-protein-coupled receptor GPR40, a putative NEFA receptor in human and animal islet β-cell preparations [17]. The GPR40 mRNA level was positively correlated with the insulinogenic index [18]. The potential signalling mechanism(s) by which GPR40 regulates insulin secretion are still under investigation but are likely to involve changes in intracellular calcium mobilization [17,19,20].

In vitro studies

Pancreatic islets exposed to high concentrations of NEFAs for periods of 24–48 h [21,22] display enhanced basal insulin secretion, decreased insulin synthesis, depletion of stored insulin and an impaired response of the β-cell to stimulation by glucose, all of which are characteristics seen in Type 2 diabetes. Other studies using pancreatic islets have demonstrated that palmitate increased cytosolic Ca2+ [7]. Rat and human islets exposed to fatty acids for 48 h demonstrated increased insulin release at basal glucose concentration (3 mM) but decreased release at an elevated (stimulatory) glucose concentration (27 mM) [23].

The effects of high concentrations of NEFAs on isolated islets and clonal pancreatic insulin-secreting cells are dependent on the period of exposure during cell culture. Acute exposure (1–3 h) of pancreatic islets to NEFAs enhances insulin secretion [24] and plays a critical role in modulating the stimulatory effect of glucose on insulin release [7,25]. Acute removal of exogenous NEFAs may however result in excessively high rates of GSIS. After incubation of rat pancreatic islets for 4 h with a high concentration of fatty acid-free BSA, they responded to glucose with extraordinarily high rates of secretion, without changing the typical biphasic pattern of the response [26]. The latter results may argue in favour of a buffering role for NEFAs, such that they siphon off some glucose (in the form of a downstream metabolite, glycerol 3-phosphate) for formation of TAG (triacylglycerol) so as to ensure that excessively high rates of insulin secretion do not occur. The TAG stores may subsequently release NEFAs on appropriate stimulation via specific TAG lipases. Expression of UCP-2 (uncoupling protein-2) in β-cells is increased by NEFAs. UCPs are located in the inner mitochondrial membrane and act as proton channels. They uncouple the electrochemical gradient produced by the respiratory chain from ATP synthesis [27,28]. Up-regulation of UCP-2 or overactivity of UCP-2 leads to inhibition of ATP synthesis. Fatty acids increase UCP-2 mRNA and protein levels in several cells including β-cells. As a result, ATP synthesis is reduced and GSIS is blunted. UCP-2-knockout mice have lower fasting blood glucose and elevated insulin levels when fed with a high-fat diet as compared with WT (wild-type) mice [29]. Exposure to palmitate reduced GSIS in WT islets, whereas UCP2−/− islets had enhanced GSIS [30].

In contrast with chronic exposure to saturated fatty acids, reports suggest that non-esterified AA (arachidonic acid) is critical for normal pancreatic β-cell function. Studies that inhibited the release of endogenous AA by inhibiting PLA2 (phospholipase A2) activity resulted in a significant reduction of GSIS from human islets [31]. With respect to intracellular regulation of GSIS in the β-cell, the release of endogenous AA from the plasma membrane via PLA2 hydrolysis of phospholipids has been identified as an important event [3234]. Additionally, exogenous AA has been reported to augment insulin secretion from pancreatic β-cells [35,36].

The positive effects of AA on insulin secretion could be the result of its own actions as a second messenger or it could be the result of AA metabolism to biologically active metabolites. Metabolism of non-esterified AA by COX (cyclo-oxygenase) enzymes produces PGs (prostaglandins), whereas LOX (lipoxygenase) enzymes generate LTs (leukotrienes) and HETEs (hydroxyeicosatetraenoic acids) [37] (Figure 1). Previous experiments evaluating the β-cell functional effects of PGs (most notably PGE2) implicated these lipid mediators in the inhibition of GSIS [38,39]. However, initial reports demonstrated that the HETEs and LTs produced from LOX enzyme activity augmented GSIS [4042]. Confusingly, more recent experiments have reported that PGE2 does not inhibit insulin secretion from human islets [37].

Endogenous non-esterified AA formation and metabolism in the pancreatic β-cell

Figure 1
Endogenous non-esterified AA formation and metabolism in the pancreatic β-cell

Glucose metabolism will lead to the formation of ATP and closure of the K+ATP channel, thus depolarizing the plasma membrane. This will result in activation of the VDCC (voltage-dependent calcium channel) and calcium influx, thus activating cPLA2 (cytosolic PLA2), thereby releasing endogenous AA from membrane phospholipids. AA metabolites can subsequently be formed by the action of either COX or LOX enzyme activity.

Figure 1
Endogenous non-esterified AA formation and metabolism in the pancreatic β-cell

Glucose metabolism will lead to the formation of ATP and closure of the K+ATP channel, thus depolarizing the plasma membrane. This will result in activation of the VDCC (voltage-dependent calcium channel) and calcium influx, thus activating cPLA2 (cytosolic PLA2), thereby releasing endogenous AA from membrane phospholipids. AA metabolites can subsequently be formed by the action of either COX or LOX enzyme activity.

Importantly, few studies have attempted to explore the interplay between glucose, amino acids and fatty acids with respect to β-cell mass and functional integrity in vitro. In a key recent study, culture of clonal BRIN BD11 β-cells for 24 h with the polyunsaturated fatty acid, AA, increased β-cell proliferation and enhanced amino acid (alanine)-stimulated insulin secretion. Conversely, 24 h exposure to the saturated fatty acid, PA (palmitic acid), was found to decrease β-cell viability (by increasing apoptosis) and increase the intracellular concentration of TAG, while inhibiting alanine-stimulated insulin secretion [43]. We have now expanded on these studies by probing the effects on exogenously added AA in the presence of COX1 or COX2 inhibitors or by probing the effects on endogenous AA by the addition of PLA2 inhibitors.

Recently, we demonstrated that inhibition of the COX-1 pathway of AA metabolism resulted in an inhibition of D-glucose- and L-alanine-stimulated insulin secretion from BRIN BD11 cells, in the presence of exogenously added AA [43]. This may indicate that COX-2 metabolites (which will be preferentially generated under these conditions) are inhibitory to nutrient-stimulated insulin secretion. In contrast, selective inhibition of COX-2 using NS-398 (100 μM) in combination with 100 μM of exogenously added AA significantly (P<0.05) enhanced both basal and nutrient-stimulated insulin secretion compared with BRIN BD11 cells incubated with control medium (Table 1). This may indicate that COX-1 metabolites (which will be preferentially generated under these conditions) are stimulatory to basal and nutrient-stimulated insulin secretion.

We also assessed the effect of inhibition of BRIN BD11 PLA2 enzyme activity with 1 μM AACOCF3 (arachidonyltrifluoromethane) for 24 h. BRIN BD11 cells were incubated for 24 h with exogenous AA±AACOCF3 followed by acute (20 min) determination of insulin secretion (Table 2). After incubation with 1 μM AACOCF3 in combination with 100 μM AA, significant (P<0.01) inhibition of nutrient (glucose plus alanine)-induced insulin secretion was observed (Table 2).

Table 1
Effect of 24 h culture in 100 μM AA alone or in combination with various COX inhibitors on subsequent acute (20 min) basal and nutrient (16.7 mM D-glucose and 10 mM L-alanine)-stimulated insulin secretion by BRIN BD11 cells

NS-398, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide. *P<0.05 compared with BRIN BD11 cells cultured in control medium and stimulated with 1.1 mM D-glucose. #P<0.05, ##P<0.01 compared with BRIN BD11 cells cultured in AA alone and stimulated with D-glucose and L-alanine.

 Insulin secretion (ng of insulin/mg of protein per 20 min) 
Treatment Basal stimulation (1.1 mM D-glucose) Nutrient stimulation (16.7 mM D-glucose and 10 mM L-alanine) 
Control 3.29±0.48 13.89±2.79 
100 μM AA 4.63±0.91 12.36±1.97 
100 μM AA and 100 μM acetaminophen 4.11±0.82 6.02±1.77# 
100 μM AA and 100 μM NS-398 7.38±0.82* 39.82±4.13## 
 Insulin secretion (ng of insulin/mg of protein per 20 min) 
Treatment Basal stimulation (1.1 mM D-glucose) Nutrient stimulation (16.7 mM D-glucose and 10 mM L-alanine) 
Control 3.29±0.48 13.89±2.79 
100 μM AA 4.63±0.91 12.36±1.97 
100 μM AA and 100 μM acetaminophen 4.11±0.82 6.02±1.77# 
100 μM AA and 100 μM NS-398 7.38±0.82* 39.82±4.13## 
Table 2
Effect of 24 h culture in the absence (control) or presence of 100 μM AA in combination with various cytosolic PLA2 inhibitors on subsequent acute (20 min) basal and nutrient (16.7 mM D-glucose and 10 mM L-alanine)-stimulated insulin secretion by BRIN BD11 cells

**P<0.01 compared with BRIN BD11 cells cultured in control medium and stimulated with D-glucose and L-alanine.

 Insulin secretion (ng of insulin/mg of protein per 20 min) 
Treatment Basal stimulation (1.1 mM D-glucose) Nutrient stimulation (16.7 mM D-glucose and 10 mM L-alanine) 
Control 2.76±0.44 12.24±2.25 
100 μM AA 4.63±0.91 12.36±1.97 
100 μM AA and 1 μM AACOCF3 3.89±1.49 4.82±0.98** 
 Insulin secretion (ng of insulin/mg of protein per 20 min) 
Treatment Basal stimulation (1.1 mM D-glucose) Nutrient stimulation (16.7 mM D-glucose and 10 mM L-alanine) 
Control 2.76±0.44 12.24±2.25 
100 μM AA 4.63±0.91 12.36±1.97 
100 μM AA and 1 μM AACOCF3 3.89±1.49 4.82±0.98** 

We conclude that exogenous AA is metabolized by COX-1 and COX-2 enzymatic activities, leading to the formation of modulators of insulin secretion. AA may be generated also by an endogenous β-cell PLA2 activity, leading to modulation of stimulus–secretion coupling essential for insulin secretion. It is clear that further work needs to be performed on the mechanisms of AA (and its metabolites) modulation of insulin secretion in the β-cell. This may reveal novel therapeutic options for the treatment of Type 2 diabetes.

Molecular Mechanisms of Glucolipotoxicity in Diabetes: A Biochemical Society Focused Meeting held at University College Dublin, Ireland, 25–26 March 2008. Organized and Edited by Tony Corfield (Bristol, U.K.), Mark Holness (Barts and the London School of Medicine and Dentistry, U.K.) and Philip Newsholme (University College Dublin, Ireland).

Abbreviations

     
  • AA

    arachidonic acid

  •  
  • AACOCF3

    arachidonyltrifluoromethane

  •  
  • COX

    cyclo-oxygenase

  •  
  • GSIS

    glucose-stimulated insulin secretion

  •  
  • HETE

    hydroxyeicosatetraenoic acid

  •  
  • LOX

    lipoxygenase

  •  
  • LT

    leukotriene

  •  
  • NEFA

    non-esterified fatty acid

  •  
  • PGs

    prostaglandins

  •  
  • PLA2

    phospholipase A2

  •  
  • TAG

    triacylglycerol

  •  
  • UCP-2

    uncoupling protein-2

  •  
  • WT

    wild-type

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