Control of pulsatile insulin secretion in man

Abstract

Plasma insulin and glucose concentrations were examined in man in a basal state from central venous samples taken at 1-min intervals for up to 2.5 h. Normal subjects have insulin oscillations of mean period 14 min (significant autocorrelation, p less than 0.0001) with changes in concentration of 40% over 7 min. The pulsation frequency was stable through cholinergic, endorphin, alpha-adrenergic or beta-adrenergic blockade, or small perturbations with glucose or insulin. Stimulation of insulin secretion by intravenous glucose, tolbutamide or sodium salicylate increased the amplitude of the insulin oscillations while the frequency remained stable. Patients with a truncal vagotomy or after Whipple's operation had longer-term oscillations of 33 and 37 min periodicity (autocorrelation: p less than 0.0001), with insulin-associated glucose swings four times larger than those of normal subjects. Type 2 (non-insulin-dependent) diabetic patients had a similarly increased insulin-associated glucose swing of six times that seen in normal subjects. The hypothesis is proposed that the 14-min cycle of insulin production is controlled by a 'pacemaker' which assists glucose homeostasis. The longer 33-37-min oscillations, seen in those with denervation, may arise from a limit-cycle of the feedback loop between insulin from the B cells and glucose from the liver. The vagus may provide hierarchical control of insulin release.

The in vivo regulation of pulsatile insulin secretion

“…The presence of preserved pulsatile insulin secretion after pancreas transplantation, albeit at increased frequency, further indicates the presence of an intra-pancreatic coordinating mechanism [75]. In vivo, cholinergic, alphaadrenergic and beta-adrenergic blocking agents did not perturb the detected periodicity in humans [131] or in monkeys [76], thus failing to support significance of these receptors on controlling pulsatile insulin release in vivo.…”

“…In addition, the overall insulin secretion could be regulated by nerve blockers [76,131] and neurotransmitters such as galanine [134], epinephrine [135,136], GABA [137] dopamine [138], as well as nitric oxide [139], and because overall insulin release is pulsatile, the impact of these agents is probably involved in the regulation of pulses, although they have not been studied. In addition, sensory nerve blocking markedly increases insulin release [140], suggesting an inhibitory role of sensory nerves, and this could explain the loss of auto-feedback inhibition of insulin on insulin release in humans with pancreas transplant [141].…”

“…In humans, an amplification of peripheral insulin oscillations with no change in frequency has been reported [131]. In a canine model, tolbutamide infusion results in a massive amplification of secretory burst mass with no effects on frequency or basal secretion and with no deterioration of the pulsatile pattern [32].…”

Determination of the glycaemic index of foods: interlaboratory study

“…Blood glucose concentrations oscillate on a minute-by-minute basis (Abdallah et al, 1997), driven, at least in part, by the pulsatile nature of insulin secretion (Matthews et al, 1983). Presumably, the oscillations of plasma glucose in different tissues in the body are not in phase with each other, because it takes different lengths of time for the pulses of insulin from the pancreas to reach them.…”

Oscillatory control of insulin secretion

“…in plasma glucose and reflect a pacemaker function of the pancreas (Lang et al, 1981;Matthews et al, 1983a). Studies in normal subjects with suppressed endogenous insulin secretion and diabetic patients have indicated that less insulin is required to maintain normoglycaemia if the hormone is infused in an oscillatory manner compared to a constant rate (Matthews et al, 1983b;Bratusch-Marrain et al, 1986;Matthews et al, 1987;Paolisso et al, 1988a;Paolisso et al, 1988b).…”