Rat islets express several isoforms of adenylyl cyclase (AC), and the regulation of AC activity in isolated islets by Ca 2؉ and protein kinase C (PKC) was investigated. At basal 2.8 mmol/l glucose, the muscarinic receptor agonist carbamylcholine chloride (CCh) evoked a concentration-dependent increase in cAMP generation with a maximum increase at least 4.5-fold above control.
erified fatty acids such as oleate and palmitate acutely potentiate insulin secretion from pancreatic islets in a glucose-dependent manner. In addition, recent studies show that fatty acids elevate intracellular free Ca 2ϩ and increase voltage-gated Ca 2ϩ current in mouse -cells, although the mechanisms involved are poorly understood. Here we utilized a heterologous system to express subunit-defined voltage-dependent L-type Ca 2ϩ channels (LTCC) and demonstrate that -cell calcium may increase in part from an interaction between fatty acid and specific calcium channel subunits. Distinct functional LTCC were assembled in both COS-7 and HEK-293 cells by expressing either one of the EYFP-tagged L-type ␣ 1-subunits (-cell Cav1.3 or lung Cav1.2) and ERFP-tagged islet -subunits (i 2a or i3). In COS-7 cells, elevations in intracellular Ca 2ϩ mediated by LTCC were enhanced by an oleate-BSA complex. To extend these findings, Ca 2ϩ current was measured in LTCC-expressing HEK-293 cells that revealed an increase in peak Ca 2ϩ current within 2 min after addition of the oleate complex, with maximal potentiation occurring at voltages Ͻ0 mV. Both Cav1.3 and Cav1.2 were modulated by oleate, and the presence of different auxiliary -subunits resulted in differential augmentation. The potentiating effect of oleate on Cav1.2 was abolished by the pretreatment of cells with triacsin C, suggesting that long-chain CoA synthesis is necessary for Ca 2ϩ channel modulation. These results show for the first time that two L-type Ca 2ϩ channels expressed in -cells (Cav1.3 and Cav1.2) appear to be targeted by nonesterified fatty acids. This effect may account in part for the acute potentiation of glucose-dependent insulin secretion by fatty acids.-cell calcium; free fatty acids; insulin secretion DURING THE LAST DECADE, the rise in the incidence of type 2 diabetes has occurred concomitant with epidemic obesity (20,39). The relationship between diabetes and obesity is now established, as the two disorders share common features, including insulin resistance, hypercholesterolemia, and hypertriglyceridemia or increased plasma levels of free fatty acids (FFAs) (6,19,21,51). Several human studies show that elevation of circulating FFA levels leads to an increase of peripheral insulin resistance in a dose-dependent manner in both obese nondiabetics and type 2 diabetics (7,53,57). Moreover, obese individuals show insulin resistance and are at high risk for diabetes; most eventually become diabetic. In addition, several studies show that obesity and insulin resistance usually precede the development of diabetes (7,12,22). Therefore, it has been proposed that diabetes is both a lipid disorder and a disease of glucose intolerance and that a converging metabolic signal may be a link between diabetes and obesity (46).Despite the relationship between obesity and diabetes, several reports demonstrate that lipid-derived signals are actually necessary for normal insulin secretion (34, 62) and advance the idea that long-chain CoA, malonyl-CoA (47), and d...
The endothelial differentiation gene (EDG) receptors are a class of G protein-coupled receptors. EDG-1, -3, -5, -6, and -8 bind the bioactive lipid sphingosine-1-phosphate (SPP) as the primary signaling ligand. EDG-2, -4, and -7 bind the ligand lysophosphatidic acid. EDG-1, -2, -3, -5, -6, and -7, but not -8, mRNAs were expressed in isolated rat pancreatic islets, whereas INS-1 insulinoma cells expressed only EDG-1, -2, -3, and -5 mRNAs. EDG-4 mRNA was expressed in mouse islets. EDG-1 mRNA but not EDG-3 mRNA was rapidly induced relative to 18S rRNA after stimulation of isolated islets with phorbol 12-myristate 13-acetate (PMA) or cholecystokinin-8S for 2 h. The protein kinase C inhibitor GF 109203X blocked the EDG-1 induction by PMA. Similarly, in islets stimulated for 2 h with 17 mmol/l glucose, the relative EDG-1 mRNA levels increased almost twofold compared with levels in control islets at 5.5 mmol/l glucose. In contrast, after 11 mmol/l glucose stimulation for 7 days, the relative levels of rat islet EDG-1 mRNA were significantly reduced to 54% below that of islets cultured at 5.5 mmol/l glucose. There was no change in relative EDG-3 mRNA levels. Stimulation of EDG receptors in islets and INS-1 cells with SPP inhibited glucagon-like peptide 1 (GLP-1)-stimulated cAMP production and insulin secretion in a concentration-dependent manner. Pertussis toxin antagonized the SPP effects on insulin release. Thus, EDG receptors are expressed in pancreatic islet -cells and G i seems to mediate the inhibition by SPP of adenylyl cyclase and cAMP formation and inhibition of the stimulation of insulin secretion by GLP-1. Diabetes
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