Superior Efficacy of PulsatileVersusContinuous Hormone Exposure on Hepatic Glucose Productionin Vitro*

Abstract

To elucidate the potency of continuous vs. intermittent exposure to hormonal stimuli, hepatic glucose production of isolated perfused rat livers was monitored in response to glucagon and insulin infusion. Using a nonrecirculating perfusion system, continuous exposure to glucagon (35 pM) induced a rise in hepatic glucose production from basal 0.33 +/- 0.03 mmol/(96 min X 100 g BW) to 0.65 +/- 0.02 mmol/(96 min X 100 g BW), while intermittent exposure (3 min on/off intervals; total dose 50%) to the same glucagon concentration elicited an almost identical rise in hepatic glucose production to 0.59 +/- 0.12 mmol/(96 in X 100 g BW). Insulin (100 mU/liter) given continuously and intermittently (3 min on/off intervals) inhibited glucagon-stimulated (70 pM) hepatic glucose production to the same extent, i.e. by 37.4% and 41.1%, respectively. Doubling the off period to 6 min and thereby reducing the total hormone dose to 33% did not diminish insulin's suppressive effect on glucagon-stimulated hepatic glucose release (34.6%). When the latter infusion protocol was applied with insulin at 300 mU/liter, hepatic glucose production during the first 40 min of glucagon infusion was more restrained (P less than 0.01) than during continuous delivery of 100 mU/liter, although the same amount of insulin was infused per period of time. In parallel, glucagon-stimulated cAMP release was similarly suppressed by insulin in all experiments. From this we conclude that the effect on hepatic glucose production of pulsatile administration of glucagon as well as of insulin, depending on the applied time interval of hormone exposure, is equipotent or even superior to the respective hormones' continuous infusion even if the hormone load is significantly reduced.

Individual Mice Can Be Distinguished by the Period of Their Islet Calcium Oscillations

“…n humans and animals, insulin secretion is pulsatile, and this pulsatility is advantageous for insulin action on its target tissues (1)(2)(3). Furthermore, pulsatile insulin secretion is disrupted in type 2 diabetes, with reduction in the amplitude and possibly frequency of the insulin pulses in diabetic patients (4 -6) and their close relatives (7,8).…”

The conscious Göttingen minipig as a model for studying rapid pulsatile insulin secretion in vivo

“…In addition, insulin action is markedly impaired in diabetes and prediabetes [44]. The impaired pulsatile insulin release has been linked to impaired insulin action [4,5,6,7] but the causes and implications need to be fully established. Mechanistic studies in animal models are an important tool for evaluating this relation in vivo.…”

“…This problem can, to some extent, be circumvented by studying first degree relatives of diabetic patients who are at risk of the disease but are still not affected by the effects of hyperglycaemia [9]. However, animal models are a valuable research tool for examining the relation between beta-cell mass, function and morphology on the one hand and insulin It is well documented that insulin concentrations show large amplitude oscillations in the peripheral circulation with a periodicity of 5 to 15 min [1,2,3], and it has been shown that these oscillations are of importance for insulin action in liver [4], muscle [5,6] and adipose tissues [7]. Since Type II (non-insulin-depenresistance on the other, because carefully controlled studies can involve surgical [10,11,12] or toxicological [10,13,14,15,16,17] induction of diabetes and long-term maintenance on experimental diets can induce insulin resistance and lipotoxicity [18,19,20,21].…”

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

“…4 Importantly, secretory pulses are more effective than constant insulin levels in lowering plasma glucose levels. 3,5,6 In particular, hepatic signaling is highly sensitive to whether insulin is released in pulses, 7 leading to the suggestion that insulin resistance in the liver is secondary to disturbed pulsatile insulin release. 8 Thus, a deeper understanding of oscillatory b-cell activity and its disturbance has clinical relevance.…”