Hormonal FM: what's the frequency?

Abstract

Recently, Peter Bergsten and co-workers measured slow oscillations (∼0.2 min−1) in the oxygen tension (pO2) and cytosolic calcium concentration {[Ca2+]} that correlated with the frequency of pulsatile insulin secretion into the portal vein [1xPrimary in vivo oscillations of metabolism in the pancreas. Bergsten, P. et al. Diabetes. 2002; 51: 699–703Crossref | PubMedSee all References[1]. Given the roles of [Ca2+] and pO2 in stimulating insulin secretion, these data provide strong evidence that secretion from individual islets, located at various distances from the portal vein, is coordinated throughout the pancreas. The frequency signature can only be maintained if the hormone moves through the pancreas quickly; the authors estimated the passage rate of insulin by measuring that of glucose. Although these studies targeted the portal vein, others have reported oscillations of approximately the same frequency in human plasma insulin [2xCyclic oscillations of basal plasma glucose and insulin concentrations in human beings. Lang, D.A. et al. N. Engl. J. Med. 1979; 301: 1023–1027Crossref | PubMedSee all References[2]. Similar to other blood-borne signaling molecules, the pulsatile nature of plasma insulin is important for promotion of the hormone's action.Bergsten's results raise many questions regarding the mechanisms, not only for coupling the fluctuating levels of cytosolic signals to the exocytosis of insulin, but also for coordinating secretion from individual islets. Citing the lack of synchronous electrical oscillations between islets within the same pancreas, the authors suggest that the rapid passage of glucose through the pancreas implies that coordination might be achieved by a blood-borne agent. The relationships between cellular carbohydrate metabolism, cytosolic [Ca2+] and secretion of insulin, are well studied. However, that these parameters also oscillate in response to glucose in cultured cells is less well appreciated. These in vivo findings suggest that the pulsatile nature of signaling molecules – be they blood-borne compounds (e.g. insulin and non-esterified fatty acids) or intracellular signals {e.g. [Ca2+] and ADP/ATP} – should be considered when describing the machinery that uses them to regulate fuel metabolism. The relevance of this work to the highly popular metabolic clamp approach, in which the blood and/or tissue content of select molecules is held constant, remains to be determined. Even so, the metabolic clamp has provided significant advances in our understanding of in vivo regulatory mechanisms.Although not discussed by the authors, the in vivo oscillation of insulin levels raises the possibility that some portion of the blood-borne insulin signal is carried by the frequency of the pulses, not simply by the level of insulin. The ability of extra-pancreatic tissues to receive this putative frequency-modulated (FM) signal has not been sufficiently investigated. Even so, oscillations of fructose-1,6-bisphosphate (F16P2) and ADP/ATP have been reported in skeletal muscle extracts [3xFructose-2,6-bisphosphate and glycolytic oscillations in skeletal muscle extracts. Tornheim, K. J. Biol. Chem. 1988; 263: 2619–2624PubMedSee all References[3]. If such an FM signaling system is actually functioning in vivo, then it might constitute another regulatory mechanism for coordinating whole-body fuel metabolism.