Are Metabolic Oscillations Responsible for Normal Oscillatory Insulin Secretion?

Abstract

Normal insulin secretion is oscillatory in vivo and in vitro, with a period of approximately 5-10 min. The mechanism of generating these oscillations is not yet established, but a metabolic basis seems most likely for glucose-stimulated secretion. The rationale is that 1) spontaneous oscillatory operation of glycolysis is a well-established phenomenon; 2) oscillatory behavior of glycolysis involves oscillations in the ATP/ADP ratio, which can cause alternating opening and closing of ATP-sensitive K+ channels, leading to the observed oscillations in membrane potential and Ca2+ influx in pancreatic beta-cells, and may also have downstream effects on exocytosis; 3) spontaneous Ca2+ oscillations are an unlikely basis in this case, since intracellular stores are not of primary importance in the stimulus-secretion coupling, and furthermore, insulin oscillations occur under conditions when intracellular Ca2+ levels are not changing; 4) a neural basis cannot account for insulin oscillations from perifused islets and clonal beta-cells or from transplanted islets or pancreas in vivo; 5) observed oscillations in metabolite levels and fluxes further support a metabolic basis, as does the presence in beta-cells of the oscillatory isoform of phosphofructokinase (PFK-M). The fact that normal oscillatory secretion is impaired in patients with NIDDM and in their near relatives suggests that such derangement may be involved in the development of the disease; furthermore, this probably reflects an early defect in the regulation and operation of the fuel metabolizing/sensing pathways of the pancreatic beta-cell.

Oscillatory control of insulin secretion

“…According to one hypothesis oscillations are an inherent property of metabolism (Tornheim, 1997). Another possibility involves feedback effects of Ca 2+ on metabolism (Detimary et al, 1998;Magnus and Keizer, 1998a;Magnus and Keizer, 1998b;Jung et al, 2000;Krippeit-Drews et al, 2000;Kindmark et al, 2001;Luciani et al, 2006;Bertram et al, 2007a).…”

“…According to the former alternative the metabolic oscillations originate in glycolysis due to allosteric feedback activation of the "oscillatory" isoform of phosphofructokinase (PFK-M) in β-cells (Tornheim, 1997). However, oscillations in [Ca 2+ ] i remained normal after 95-98% suppression of PFK-M activity in mouse islets (Richard et al, 2007).…”

The in vivo regulation of pulsatile insulin secretion

“…Furthermore, the relation between the in vivo observed secretory bursts and the in vitro observed pulsatile release from the isolated pancreas [9,10,101] and the isolated peri-perfused islets [102,103], as well as episodic beta-cell depolarization [104±106], beta-cell glycolysis [105,107], and beta-cell increase in calcium remains to be established [104, 105, 108±111]. The coupling of cyclic metabolism to pulsatile in vitro release has been addressed in an excellent review by Tornheim [112]. Mathematical models have been used to better understand the mechanisms underlying coordinate pulsatile release [113,114].…”

“…The neuronal control of in vivo pulsatile insulin secretion Observation of in vivo pulses implies that most betacells secrete in pulses and at the same time. In vitro studies on individual beta-cells show that they secrete in pulses [109], and that the pulsatile release pattern is probably linked to cyclic glycolysis [107], with cyclic generation of lactate [107], cyclic oxygen consumption [105], resulting in beta-cell depolarization through ATP-dependent potassium channels, causing influx of calcium, and subsequently (ATPdependent) exocytosis as reviewed in [112] and [123]. Thus the necessary mechanisms for the pulsatile release is within the individual beta-cells [112,124], and the ability to act as pacemaker resides within the beta-cell [115].…”

“…exocytotic process. The cyclic glycolysis involves a positive feedback stimulation of phosphofructokinase by its product, fructose-1,6-biphosphate [112]. It seems plausible that similar mechanisms could be involved in vivo, as indicated from impaired pulsatile secretion in phosphofructokinase defects [144], implying that effects on secretory burst mass, but not frequency, are to expected.…”