Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion

Abstract

of insulin secretion from the ␤-cells of the pancreatic islets of Langerhans is central to the development of type 2 diabetes mellitus and has therefore been the subject of much investigation. Great advances have been made in this area, but the mechanisms underlying the pulsatility of insulin secretion remain controversial. The period of these pulses is 4 -6 min and reflects oscillations in islet membrane potential and intracellular free Ca 2ϩ . Pulsatile blood insulin levels appear to play an important physiological role in insulin action and are lost in patients with type 2 diabetes and their near relatives. We present evidence for a recently developed ␤-cell model, the "dual oscillator model," in which oscillations in activity are due to both electrical and metabolic mechanisms. This model is capable of explaining much of the available data on islet activity and offers possible resolutions of a number of longstanding issues. The model, however, still lacks direct confirmation and raises new issues. In this article, we highlight both the successes of the model and the challenges that it poses for the field.pancreatic ␤-cells; mathematical model; diabetes IN THE CONSENSUS MODEL for glucose-stimulated insulin secretion (GSIS) from pancreatic ␤-cells (Fig. 1A), glucose enters the cell through GLUT2 glucose transporters and is metabolized to increase the ATP/ADP ratio, which in turn closes ATP-sensitive K ϩ (K ATP ) channels. This depolarizes the membrane, which opens L-type Ca 2ϩ channels and promotes Ca 2ϩ influx. The resulting increase in the cytosolic Ca 2ϩ concentration evokes exocytosis of insulin granules. The development of this model represented a major achievement that overturned early, more orthodox suggestions that glucose acted through a receptor, like many other signals for hormone secretion. This model has not been reversed by subsequent findings, although it has been extended by consideration of noncalcium amplifying factor(s) of yet undetermined identity (35). Nonetheless, the consensus picture is essentially a static view, as it fails to account for important dynamic features of GSIS, in particular, its pulsatile nature. Oscillations in insulin secretion have been measured in vivo (59, 65), in the perifused pancreas (76), and in isolated islets (4,27,46,70). The oscillations typically have two components; the faster component has a period of tens of seconds (6,27,59), and the slower component has a period of 4 -6 min (59,65,66). This latter component appears to play an important physiological role in insulin action (54) and is lost in patients with type 2 diabetes and their near relatives (53,60,64,87). In this article we discuss a nascent model that includes the consensus mechanism but also offers an integrated account of both the "fast" (tens of seconds) and "slow" (4 -6 min) insulin oscillations in secretion and their interactions. We propose that the fast oscillations result from electrical mechanisms, predominantly feedback of cytosolic free calcium on plasma membrane ion channels, and that ...

Direct Measurements of Oscillatory Glycolysis in Pancreatic Islet β-Cells Using Novel Fluorescence Resonance Energy Transfer (FRET) Biosensors for Pyruvate Kinase M2 Activity

“…In addition, slow oscillations are intrinsic to metabolism, as oscillations in NAD(P)H and O 2 can be shown to persist in the absence of islet Ca 2ϩ oscillations (20,21). Some of these studies (19,21) were motivated by a model in which metabolic oscillations are driven by oscillations in glycolysis (22), and the experiments confirmed predictions made by the model. However, alternate theories for islet metabolic oscillations have been proposed by other workers in the field (23)(24)(25)(26)(27), and oscillations in glycolytic intermediates have not been directly measured.…”

Oscillatory control of insulin secretion

“…Also elevation of cAMP promotes irregular Ca 2+ spiking that is superimposed on top of the slow oscillations or on a stably elevated [Ca 2+ ] i level Liu et al, 1996;Dyachok and Gylfe, 2004), reflecting facilitation of Ca 2+ -induced Ca 2+ release (CICR) via IP 3 Rs (Dyachok and Gylfe, 2004). Ca 2+ spiking is sufficiently pronounced to activate a hyperpolarizing K + current that can arrest action potential firing (Ämmälä et al, 1993b;Dryselius et al, 1999) and provide a negative feedback on the slow [Ca 2+ ] i oscillations (Bertram et al, 2007a;Bertram et al, 2007b) independent of the Ca 2+ effects on metabolism discussed above ( Figure 2D). …”

“…The situation is further complicated by the fact that Ca 2+ stimulates metabolism by activating mitochondrial dehydrogenases (McCormack et al, 1990;Civelek et al, 1996;Pitter et al, 2002) and that Ca 2+ may regulate glycolytic enzymes (Jung et al, 2000). Metabolic oscillations may indeed reflect intrinsic oscillatory mechanisms in glucose metabolism, but the oscillations are modified both by stimulatory and inhibitory feedback effects of Ca 2+ (Luciani et al, 2006;Bertram et al, 2007b (Henquin, 2000) or after knocking out functional K ATP channels (Nenquin et al, 2004;Szollosi et al, 2007). This K ATP channel-independent process is mostly considered as an amplification mechanism, which remains functionally silent unless [Ca 2+ ] i is elevated.…”

Reactive oxygen and nitrogen species disturb Ca2+oscillations in insulin-secreting MIN6 β-cells

“…The period of the induced oscillations was typically 20-30 sec, similar to published results for MIN6 cells 23,30,31 and so-called fast Ca 2C oscillations observed in mouse islets. 32,33 To obtain insight into this behavior, we used a mathematical model of oscillatory behavior in b-cells. 25 We assumed that, compared to pancreatic b cells in islets of Langerhans, MIN6 cells have larger K C currents, 31 which prevent large-amplitude oscillations.…”