Regulation of pancreatic β-cell electrical activity and insulin release by physiological amino acid concentrations

Bolea, Sonia; Pertusa, José A. G.; Martı́n, Franz; Sánchez-Andrés, Juan Vicente; Soria, Bernat

doi:10.1007/s004240050334

Cited by 43 publications

(36 citation statements)

References 14 publications

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“…Therefore, in this study, differences in glucagon responses cannot be explained by different insulin responses. Based on the amino-acid composition of the mixtures and previous data (Rocha et al, 1972;Hermans et al, 1987;Bolea et al, 1997;Smith et al, 1997;van Loon et al, 2000;Calbet and MacLean, 2002), we expected egg protein hydrolysate to induce the highest peak concentrations for insulin and glucagon, gluten protein hydrolysate to induce the lowest peak concentrations for insulin, and whey protein hydrolysate to induce the lowest peak concentrations for glucagon. Instead the only significant difference between the drinks was a lower glucagon response after the gluten hydrolysate as compared to egg protein hydrolysate.…”

Section: Discussionmentioning

confidence: 82%

The effect of different protein hydrolysate/carbohydrate mixtures on postprandial glucagon and insulin responses in healthy subjects

Claessens

Calame²,

Siemensma³

et al. 2007

Eur J Clin Nutr

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Objectives: To study the effect of four protein hydrolysates from vegetable (pea, gluten, rice and soy) and two protein hydrolysates from animal origin (whey and egg) on glucagon and insulin responses. Subjects/Methods: Eight healthy normal-weight male subjects participated in this study. The study employed a repeatedmeasures design with Latin square randomization and single-blind trials. Protein hydrolysates used in this study (pea, rice, soy, gluten, whey and egg protein hydrolysate) consisted of 0.2 g hydrolysate per kg body weight (bw) and 0.2 g maltodextrin per kg bw and were compared to maltodextrin alone. Postprandial plasma glucose, glucagon, insulin and amino acids were determined over 2 h. Results: All protein hydrolysates induced an enhanced insulin secretion compared to maltodextrin alone and a correspondingly low plasma glucose response. A significant difference was observed in area under the curve (AUC) for plasma glucagon between protein hydrolysates and the maltodextrin control drink (Po0.05). Gluten protein hydrolysate induced the lowest glucagon response. Conclusions: High amino-acid-induced glucagon response does not necessarily go together with low insulin response. Protein hydrolysate source affects AUC for glucagon more profoundly than for insulin, although the protein load used in this study seemed to be at lower level for significant physiological effects.

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Section: Discussionmentioning

confidence: 82%

The effect of different protein hydrolysate/carbohydrate mixtures on postprandial glucagon and insulin responses in healthy subjects

Claessens

Calame²,

Siemensma³

et al. 2007

Eur J Clin Nutr

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“…A thorough inspection of Fig. 5 in Bolea et al (36) reveals that in islet B-cells, a fixed frequency of electrical spikes is associated with greater insulin release when amino acids are present than when they are absent. Hence, it is conceivable that the amino acid sensor acts on a pathway beyond Ca 2+ influx.…”

Section: Discussionmentioning

confidence: 99%

Effects of Glucose and Amino Acids on Free ADP in βHC9 Insulin-Secreting Cells

2001

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Stimulation of insulin release by glucose is widely thought to be coupled to a decrease in the activity of ATP-sensitive K + channels (K ATP channels) that is caused by a decreased concentration of free ADP. To date, most other investigators have reported only on total cellular ADP concentrations, even though only a small fraction of all ADP is free and only the free ADP affects K ATP channels. We tested the hypothesis that amino acids elicit insulin release via a decrease in the activity of K ATP channels owing to a decrease in the level of free ADP. We estimated the concentration of free ADP in ␤HC9 hyperplastic insulin-secreting cells based on the cell diameter and on luminometric measurements of ATP, phosphocreatine, and total creatine. The concentration of free ADP fell exponentially as the concentration of glucose increased. A physiological mixture of amino acids greatly stimulated insulin release at 0-30 mmol/l glucose but affected the concentration of free ADP only to a minor degree and significantly so only at ≤2 mmol/l glucose. In the presence of 2-deoxyglucose and NaN 3 , amino acids were unable to stimulate insulin release. When K ATP channels were held open with diazoxide (and the plasma membrane partially depolarized with high extracellular KCl), amino acids still stimulated insulin release. We conclude that amino acid-induced insulin release depends on two components: a yet-unknown amino acid sensor and K ATP channels, which serve to attenuate hormone release when cellular energy stores are low. We propose that glucoseinduced insulin release may be regulated similarly by two components: glucokinase and K ATP channels. Diabetes 50:291-300, 2001A ccording to the most widely accepted hypothesis, glucose induces insulin release as follows. Glucose rapidly equilibrates across the plasma membrane and is phosphorylated with the help of glucokinase, which determines flux through glycolysis (1). Pyruvate from glycolysis enters the citric acid cycle and determines ATP production from oxidative phosphorylation. As a result, the concentrations of ATP and free ADP reflect the concentration of blood glucose. The plasma membrane contains ATP-sensitive K + channels (K ATP channels). ATP inhibits the channels, and ADP relieves this inhibition (2). In the absence of glucose, K ATP channels are quite active and dictate the membrane potential. In the presence of glucose, initially, the balance between K + flux through K ATP channels and ionic fluxes through yet unknown "leak conductances" determines the membrane potential (2). Once the membrane potential is more positive than about -40 mV, Ca 2+ channels open intermittently, allowing the influx of extracellular Ca 2+ (2). As intracellular Ca 2+ rises, the exocytotic machinery is activated, which moves secretory granules containing insulin to the plasma membrane surface. In partial support of the above hypothesis, patients with a mutant glucokinase of abnormal affinity to glucose have an abnormal set point for glucose homeostasis (3-5), and other patients with K ATP c...

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“…For this study, we have defined physiological concentrations of leucine and glutamine as 0.4 mM and 0.2 mM, respectively, based on reported plasma concentrations of leucine and glutamine (0.119 mM and 0.338 mM, respectively) in fed mice (18).…”

Section: Methodsmentioning

confidence: 99%

The Role of AMPK and mTOR in Nutrient Sensing in Pancreatic β-Cells

Gleason

Witters

et al. 2007

Journal of Biological Chemistry

165

135

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The AMP-activated protein kinase (AMPK) is a central regulator of the energy status of the cell, based on its unique ability to respond directly to fluctuations in the ratio of AMP:ATP. Because glucose and amino acids stimulate insulin release from pancreatic ␤-cells by the regulation of metabolic intermediates, AMPK represents an attractive candidate for control of ␤-cell function. Here, we show that inhibition of AMPK in ␤-cells by high glucose inversely correlates with activation of the mammalian Target of Rapamycin (mTOR) pathway, another cellular sensor for nutritional conditions. Forced activation of AMPK by AICAR, phenformin, or oligomycin significantly blocked phosphorylation of p70S6K, a downstream target of mTOR, in response to the combination of glucose and amino acids. Amino acids also suppressed the activity of AMPK, and this at a minimum required the presence of leucine and glutamine. It is unlikely that the ability of AMPK to sense both glucose and amino acids plays a role in regulation of insulin secretion, as inhibition of AMPK by amino acids did not influence insulin secretion. Moreover, activation of AMPK by AICAR or phenformin did not antagonize glucose-stimulated insulin secretion, and insulin secretion was also unaffected in response to suppression of AMPK activity by expression of a dominant negative AMPK construct (K45R). Taken together, these results suggest that the inhibition of AMPK activity by glucose and amino acids might be an important component of the mechanism for nutrient-stimulated mTOR activity but not insulin secretion in the ␤-cell.The ␤-cell is unique compared with other mammalian cell types in that its primary function to synthesize and secrete insulin is tightly coupled to its metabolic rate. Glucose is the most potent nutrient in stimulating insulin release. Upon entry into the ␤-cell, glucose is rapidly metabolized, resulting in the generation of mitochondria-derived metabolic intermediates including ATP. This increase in ATP leads to closure of ATPsensitive K ϩ (K ATP )-channels, depolarization of the plasma membrane and opening of voltage-gated L-type Ca 2ϩ channels. The subsequent increase in intracellular Ca 2ϩ concentration [Ca 2ϩ ] i triggers insulin exocytosis (1). The ␤-cell also utilizes certain key amino acids that, via mitochondrial metabolism, can further generate coupling factors that elicit an insulin secretory response (2, 3). In addition to their role as insulin secretagogues, glucose and other nutrients stimulate protein translation and ␤-cell growth and proliferation (4, 5). While much is known regarding how the ␤-cell couples glucose metabolism to insulin secretion, the mechanisms by which ␤-cells sense metabolism of other fuels, such as amino acids, and augment glucose-stimulated insulin release are less clear. Further, it is unclear how the ␤-cell coordinates nutrient abundance with enhanced protein translation and cell growth. This aspect of ␤-cell function is particularly important under conditions of increased insulin demand, such as obesity a...

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Regulation of pancreatic β-cell electrical activity and insulin release by physiological amino acid concentrations

Cited by 43 publications

References 14 publications

The effect of different protein hydrolysate/carbohydrate mixtures on postprandial glucagon and insulin responses in healthy subjects

The effect of different protein hydrolysate/carbohydrate mixtures on postprandial glucagon and insulin responses in healthy subjects

Effects of Glucose and Amino Acids on Free ADP in βHC9 Insulin-Secreting Cells

The Role of AMPK and mTOR in Nutrient Sensing in Pancreatic β-Cells

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