Glucose-induced insulin secretion from isolated, perifused rat islets is pulsatile with a period of about 5—10min, similar to the insulin oscillations that are seen in healthy humans but which are impaired in Type II diabetes. We evaluated the pattern of enhancement by the potent incretin, glucagon-like peptide 1 (GLP-1). GLP-1 increased the amplitude of pulses and the magnitude of insulin secretion from the perifused islets, without affecting the average time interval between pulses. Forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine had the same effect, suggesting that the effect was due to elevated cAMP levels. The possibility that cAMP might enhance the amplitude of pulses by reducing phosphofructo-2-kinase (PFK-2) activity was eliminated when the liver isoform of PFK-2 was shown to be absent from β-cells. The possibility that cAMP enhanced pulsatile secretion, at least in part, by stimulating lipolysis was supported by the observations that added oleate had a similar effect on secretion, and that the incretin effect of GLP-1 was inhibited by the lipase inhibitor orlistat. These data show that the physiological incretin GLP-1 preserves and enhances normal pulsatile insulin secretion, which may be essential in proposed therapeutic uses of GLP-1 or its analogues.

Abbreviations used: FFA, non-esterified ('free') fatty acids; F(1,6)P2, fructose 1,6-bisphosphate; F(2,6)P2, fructose 2,6-bisphosphate; GLP-1, glucagon-like peptide 1; HSL, hormone-sensitive lipase; IBMX, isobutylmethylxanthine; LC-CoA, long chain acyl-CoA; PFK-1, phosphofructo-1-kinase; PFK-2, phosphofructo-2-kinase; PKA, protein kinase A; RT, reverse transcriptase.

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