Fatty Acids As Insulin Secretagogues
Fatty acids trigger secretion of insulin in a glucose-dependent manner (3,44). Fatty acids serve as an important endogenous fuel of islet tissue incubated with low glucose
or in the absence of glucose. The possibility has been considered that a high level of fatty acids may inhibit the glucokinase glucose sensor because acyl-CoA, the first metabolite in fatty acid catabolism, is a very potent inhibitor of this enzyme (3). However, this inhibition is competitive with glucose and is therefore significant only when glucose levels are less than 5 mM. It is also not clear whether free levels of acyl-CoA are ever high enough for a fuel effect to take place. If the glucose level is high (approx 7.5 mM), as seen after a mixed meal, fatty acids can stimulate insulin release. On the other hand, fatty acid oxidation is effectively blocked by high glucose (i.e., by about 75%). This is probably the result of the accumulation of malonyl-CoA (28,29,45). The increase in malonyl-CoA, acting via its capacity to inhibit CPT-I (30), results in inhibition of fatty acid oxidation, increased de novo lipid synthesis, and a rise in diacylglyc-erol content. Vara and Tamirit-Rodriquez (46,47) noted that the insulin secretagogues glucose and leucine share the ability to divert fatty acids from the oxidation pathway into esterification products. Note, however, oral superphysiological levels of leucine are needed. It has been also shown that the starvation-induced blunting of glucose-stimulated insulin secretion (GSIS) in perifused rat islets and in the perfused rat pancreas (48-50) could be largely offset by addition of 2-bromostearate (2-BrS), an inhibitor of CPT-I. Thus, alterations of the transferase activity or significant changes of its malonyl-CoA sensitivity could greatly modify this regulatory switch. Because it is hypothesized that increases in the levels of malonyl-CoA and cytosolic LC-CoA esters are signal transduction intermediates in glucose-stimulated insulin secretion and may serve as critical factors in P-cell function, such a change could be physiologically or pathologically relevant. This concept has come to be known as the "long-chain acyl-CoA hypothesis" (24,28,29). Possible sites at which increased LC-CoA could influence insulin secretion include conversion to bioactive metabolites such as diacylglycerol or inositol trisphos-phate (IP3), contribution to plasma membrane or secretory granule membrane lipid turnover, or direct acylation of proteins involved in secretory granule trafficking. Although the proposed mechanisms are plausible, direct evidence for any of these actions of lipids on insulin secretion has not been provided to date.
Consistent with an important role of P-cell lipids in glucose sensing, lowering of circulating fatty acids via administration of nicotinic acid or adenovirus-induced hyperleptine-mia completely abrogates insulin secretion in response to glucose, amino acids, or sulfonylureas (51,52). These experimental manipulations may lower lipid stores in P-cells, but full secretory function can be restored by provision of fatty acids to the pancreas of such animals. However, in contrast to the positive acute effects of lipids on islet function, long-term exposure to hyperlipidemic conditions results in a condition that has been characterized as "lipotoxicity," wherein lipid overstorage is thought to lead to the syndrome of P-cell dysfunction associated with insulin-resistant and diabetic states, including P-cell hyperplasia, basal hyperinsulinemia, and loss of glucose responsiveness (53). Exposure of islets to palmitic acid for 1 h reduced glucose-stimulated proinsulin biosynthesis in a dose-dependent manner (54). Sprague-Dawley rats fed a diet with 40% fat for 3 wk were glucose intolerant, and in vitro insulin secretion at high glucose was only increased 8.5-fold over basal, compared with 28-fold in control rats (55). Decreased insulin release was associated with a twofold increase of islet uncoupling protein-2 mRNA (UCP-2) expression. UCP-2 catalyzes a mitochondrial inner-membrane H+ leak that bypasses ATP synthase, thereby reducing cellular ATP content (55). It is extrapolated that UPC-2 induction may deenergize P-cell mitochondria, an effect yet to be proven.
A new study using molecular and pharmacological tools suggests that the LC-CoA hypothesis may require re-evaluation (56). Recombinant adenovirus containing the cDNA-encoding malonyl-CoA decarboxylase (AdCMV-MCD), an enzyme that decar-boxylates malonyl CoA to acetyl-CoA, was employed in this approach. Treatment of INS-1 cells with AdCMV-MCD prevented the normal glucose-induced rise in malonyl-CoA levels, such that its concentration in AdCMV-MCD-treated cells at 20 mM glucose was lower than control cells at 3 mM glucose. That the normal link between glucose and lipid metabolism had been significantly disrupted by this approach was shown by the fact that in the presence of 20 mM glucose, AdCMV-MCD-treated cells were less effective at suppressing [1- 14C] palmitate oxidation, and incorporated 43% less labeled palmitate and 50% less labeled glucose into cellular lipids than controls. In spite of the large metabolic changes caused by expression of malonyl-CoA decarboxylase (MCD), insulin secretion in response to glucose was unaltered relative to controls. On the other hand, treatment of INS-1 cells or fresh rat islets of Langerhans with triacsin C, an inhibitor of LC-CoA synthetase caused potent attenuation of palmitate oxidation and glucose or palmitate incorporation into cellular lipids in both INS-1 cells and fresh rat islets, but had no effect on glucose-stimulated insulin secretion in either group. Thus, neither overexpression of MCD nor treatment with triacsin C had any effect on the rate of glucose usage in the P-cell preparations. Based on these data, the authors concluded that there is no direct correlation between the extent to which lipids are directed toward oxidative or esterification pathways and insulin secretion. However, there is evidence that whereas triacsin C is almost completely effective in blocking triglyceride and phos-pholipid synthesis from glycerol, incorporation of oleate or arachidonate into phospho-lipids was less impaired (56). Similarly, it has been observed that triacsin C inhibits conversion of [1-14C] palmitate into triglycerides by more than 90%, whereas incorporation of the same substrate into phospholipids is reduced by 50% (56). Thus, although the effects of MCD expression or triacsin C treatment on lipid fluxes in the cited studies were large, they were not complete, and it remains possible that the residual flux of substrate into specific esterification or biosynthetic pathways is sufficient for the maintenance of glucose responsiveness. Note also that complete depletion of islet triglycerides by experimental hyperleptinemia results in abrogation of fuel-mediated insulin secretion in rats (57), apparently indicating that at least a minimal pool of lipids must be present in P-cells in order for normal fuel sensing to take place.
Based on these results, the following modification of the LC-CoA hypothesis was suggested (4). Because the normal link between glucose and lipid metabolism can be markedly disrupted with no effect on glucose usage or insulin secretion, attention is refocused on a coupling factor produced as an immediate byproduct of the glycolytic and mitochondrial pathways. The data are consistent with the tenants of the basic model highlighted in Fig. 1A, in which a primary signal is the glucose-driven increase in ATP to ADP ratio, leading to inhibition of ATP-sensitive K+ channels and influx of extracellular Ca2+. The abrogation of glucose-stimulated insulin secretion by lipid depletion may then be explained by the absence of essential modulators of secretory granule trafficking and/or exocytosis. Examples of distal sites at which lipids may be acting include generation of signaling molecules such as diacylglycerol or IP3, or via contribution to secretory granule or plasma membrane turnover. That lipids are acting at a distal rather than a proximal site is supported by the finding that lipid-depleted islets not only fail to respond to glucose but also show no response to arginine, leucine, or the sulfonylurea glibenclamide (58). The mechanism by which fatty acids exert these important modulatory effects on insulin secretion remains to be established. Finally, it should be underlined that the data do not discount the possibility that the malonyl CoA/CPT-I metabolic signaling network may play important roles in long-term processes related to insulin secretion (i.e., P-cell growth, apoptosis, regulation of important metabolic genes, and toxic effects related to chronic exposure of P-cells to high concentrations of fatty acids, a phenomenon termed "lipotoxicity") (24-27,53).
Recent data by Sugden et al. (59) suggest that the pyruvate dehydrogenase complex (PDC) may occupy a pivotal position in coordinate fuel utilization governing the contribution of glucose and fatty acids as metabolic fuels. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g., mal-onyl-CoA and citrate) that reflect fuel abundance. Fatty acids oxidation suppresses the PDC activity. PDC inactivation by phosphorylation is catalyzed by pyruvate dehydro-genase kinases (PDKs 1-4). The hypothesis was developed (59) that PDK4 is a "lipid status"-responsive PDK isoform facilitating fatty acids oxidation and signaling through citrate formation. Thus, substrate interactions at the level of gene transcription may extend glucose-fatty acids interactions over a longer time period.
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