Insulin-secretional effect of exogenic amino acids in rabbits (original) (raw)
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In vitro stimulation of insulin release by non-metabolizable, transport-specific amino acids
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1971
The insulin-releasing ability and uptake characteristics of non-metabolizable, transport-specific amino acids were studied in an in vitro system, using microdissected pancreatic islets with more than 9 ° O//o/~-cells. Among the four stereoisomers of 2-aminobicyclo(2,2,i)heptane-2-carboxylic acid (BCH), only the b(-) form stimulated insulin release. This isomer is known as a specific substrate for transport system L in other cells. It was rapidly taken up by the islet cells and stimulated insulin release both in the presence and in the absence of glucose. 4-Amino-I-guanylpiperidine-4-carboxylic acid (GPA), a substrate for cationic transport systems, stimulated insulin release in the presence but not in the absence of glucose. In this respect GPA is similar to arginine. Like arginine, GPA also accumulated in the islet cells to yield distribution ratios well above unity. The results are consonant with the previous hypothesis that amino acids stimulate insulin release by binding to specific transport molecules. Abbreviations: BCH, 2-aminobicyclo(2,2,I)heptane-2-carboxylic acid; GPA, 4-aminoi-guanylpiperidine-4-carboxylic acid.
Amino acid metabolism, insulin secretion and diabetes
Biochemical Society Transactions, 2007
In addition to the primary stimulus of glucose, specific amino acids may acutely and chronically regulate insulin secretion from pancreatic β-cells in vivo and in vitro. Mitochondrial metabolism is crucial for the coupling of glucose, alanine, glutamine and glutamate recognition with exocytosis of insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP (the main coupling messenger in insulin secretion) and other factors that serve as sensors for the control of the exocytotic process. The main factors that mediate the key amplifying pathway over the Ca 2+ signal in nutrient-stimulated insulin secretion are nucleotides (ATP, GTP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. In addition, after chronic exposure, specific amino acids may influence gene expression in the β-cell, which have an impact on insulin secretion and cellular integrity. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
Archives of Biochemistry and Biophysics, 1984
I. The metabolic situation found in pancreatic islets exposed to both L-glutamine and 2-ketoisocaproate was investigated in order to assess its relevance to the synergistic effects of these nutrients upon insulin release. 2. In islet homogenates, several 2-keto acids could be used as partners for the transamination of L-glutamate to 2-ketoglutarate. The rate of transamination did not correlate positively with the capacity of each 2-keto acid to stimulate insulin release in the presence of L-glutamine. 3. L-Glutamine enhanced the production of L-leucine from 2-ketoisocaproate and inhibited the conversion of the 2-keto acid to acetoacetate and CO2. L-Glutamine also inhibited the oxidation of pyruvate. 4. In the presence of 2-ketoisocaproate, the rate of generation of 2-ketoglutarate from exogenous L-glutamine was increased, but the oxidative deamination of glutamate was suppressed. 5. L-Valine antagonized the effect of 2-ketoisoeaproate to augment 14C02 output from islets prelabelled with L-[U-~4C]glutamine. 6. L-Glutamine did not increase the islet content of reduced pyridine nudeotides beyond the high level reached in the sole presence of 2-ketoisocaproate. 7. If allowance was made for the influence of exogenous nutrients upon the oxidation of endogenous nutrients, the insulin output evoked by L-glutamine and/or 2-keto acids tightly depended on the increment in oxidation rate attributable to these nutrients. 8. The metabolic and secretory responses to L-glutamine and 2-ketoisoeaproate were best explained by a stimulation of transamination reactions between 2-ketoisocaproate and glutamate derived from exogenous glutamine. * This paper is the sixth in a series. Materials and Methods All experiments were performed with islets removed from fed albino rats. For the measurement of transaminase activity, groups of 400 islets each were sonicated (2 X 5 s) in 0.7 ml of a Tris-acetate buffer (10 mM, pH 8.6). The reaction mixture (100 #1) contained (final concentrations) 50 mM Tris-acetate (.pH 8.6), 2 mM L-[U-14C]-.glutamate, 50/.tM, pyridoxal phosphate, 1.4 mM mercaptoethanol, 10 mM of an unlabeUed 2-keto acid and 30 ~1 islet homogenate. After 20 rain incubation at 30°C, the reaction was stopped by diluting the reaction mixture 15-fold with cold H20 (0-4°C)and immediately passing it through an ion-exchange resin
Clinical Science, 2009
Acute insulin-releasing actions of amino acids have been studied in detail, but comparatively little is known about the β-cell effects of long-term exposure to amino acids. The present study examined the effects of prolonged exposure of β-cells to the metabolizable amino acid L-alanine. Basal insulin release or cellular insulin content were not significantly altered by alanine culture, but acute alanine-induced insulin secretion was suppressed by 74 % (P < 0.001). Acute stimulation of insulin secretion with glucose, KCl or KIC (2-oxoisocaproic acid) following alanine culture was not affected. Acute alanine exposure evoked strong cellular depolarization after control culture, whereas AUC (area under the curve) analysis revealed significant (P < 0.01) suppression of this action after culture with alanine. Compared with control cells, prior exposure to alanine also markedly decreased (P < 0.01) the acute elevation of [Ca 2+ ] i (intracellular [Ca 2+ ]) induced by acute alanine exposure. These diminished stimulatory responses were partially restored after 18 h of culture in the absence of alanine, indicating reversible amino-acid-induced desensitization. 13 C NMR spectra revealed that alanine culture increased glutamate labelling at position C4 (by 60 %; P < 0.01), as a result of an increase in the singlet peak, indicating increased flux through pyruvate dehydrogenase. Consistent with this, protein expression of the pyruvate dehydrogenase kinases PDK2 and PDK4 was significantly reduced. This was accompanied by a decrease in cellular ATP (P < 0.05), consistent with diminished insulin-releasing actions of this amino acid. Collectively, these results illustrate the phenomenon of β-cell desensitization by amino acids, indicating that prolonged exposure to alanine can induce reversible alterations to metabolic flux, Ca 2+ handling and insulin secretion.
Diabetologia, 2006
Aims/hypothesis The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids. Materials and methods Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg −1 min −1) and eu-, hypo-and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low-or high-dose alanine, or saline. Results With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181±16 ng l −1 min −1) and high-dose alanine (238±20 ng l −1 min −1) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112±5 ng l −1 min −1). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu-or hyperglycaemia. Conclusions/interpretation In type 1 diabetes, the usually deficient responses of glucagon to hypoglycaemia may improve after increasing the concentration of plasma amino acids. Amino acid-enhanced secretion of glucagon in response to hypoglycaemia remains under physiological control since it is regulated primarily by the ambient plasma glucose concentration. These findings might be relevant to improving counter-regulatory defences against insulininduced hypoglycaemia in type 1 diabetes.
General and Comparative Endocrinology, 1982
The potential for a direct effect of selective amino acids on avian pancreatic polypeptide (APP) and insulin secretion was investigated using a system of perifused microfragments of chicken pancreas. Leucine, isoleucine, phenylalanine, and valine produced a sustained increase in APP release when each was evaluated at 5-mM concentrations; 15 mM arginine also produced a sustained increase in APP secretion. The secretory response differed among the amino acids such that 5 mir4 leucine and isoleucine produced a transitory increase in insulin secretion while lysine, phenylalanine, and arginine produced a sustained increase in insulin secretion. In general, APP secretion exhibited a greater maximal response and a lower threshold for stimulation by various amino acids in vitro than did insulin. The significance of this effect is somewhat unclear due to the failure of intravenous arginine or leucine to alter circulating levels of APP in vivo. In conclusion, amino acids directly increase APP secretion from the chicken pancreas in vitro; although they are relatively unresponsive to glucose, perifused chicken B cells respond to amino acids as do B cells from mammalian species.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1972
The transport of L-leucine and D-leucine was studied in microdissected pancreatic islets of obese-hyperglycemic mice. These islets consist to more than 9 ° % of r-cells and are known to release insulin in response to L-leucine but not in response to D-leucine. Both L-leucine and D-leucine were distributed in a space that was larger than that occupied by sucrose, suggesting that both leucine isomers penetrated into the r-cells. The uptake of either isomer was inhibited by L-isoleucine, L-tryptophan, t-phenylalanine and glycine. L-Leucine inhibited the uptake of D-leucine, and D-leucine inhibited the uptake of L-leucine. There was no detectable difference between L-leucine and D-leucine with respect to the concentration dependence of uptake as measured in relation to sucrose. A significantly greater uptake of L-leucine than of D-leucine may be due to the fact that L-leucine was incorporated into islet protein. It appears that D-leucine and L-leucine are largely transported by the same system in pancreatic fl-cells. Consequently, it may be necessary to somewhat qualify the current hypothesis suggesting that the site signalling insulin release in response to L-leucine is identical with the receptor site of transport system L. Abbreviations: BCH, 2-amino-bicyelo(2,2,l)heptane-2-carboxylic acid; GPA, 4-amino-I-guanylpiperidine-4-carboxylic acid.
Metabolism-clinical and Experimental, 1982
In the absence of another exogenous nutrient, L-glutamine does not stimulate insulin release from rat pancreatic islets or isolated perfused pancreases. L-glutamine. however. augments insulin release evoked by L-leucine. These two amino acids could interact by providing both the substrate (L-glutamate) and an activator IL-leucine) for the reaction catalyzed by glutamate dehydrogenase. Under suitable experimental conditions, as little as 0.5 mM L-glutamine is sufficient to enhance leucine-stimulated insulin release. When the pancreases or islets are first exposed to L-glutamine and then stimulated with L-leucine, the rate of secretion is much higher than that evoked by L-leucine in tissue not first exposed to L-glutamine. The memory of a prior exposure to L-glutamine persists for at least 25 min after removal of the latter amino acid from the extracellular fluid. This memory phenomenon is not dependent on the presence of Ca*+ in the extracellular fluid during the first exposure to L-glutamine, but is suppressed when such a prior exposure is performed in the absence of extracellular Kf. The memory phenomenon could be due, in part at least, to inhibition by L-glutamine of K' conductance in the B-cell plasma membrane. Moreover, the amount of L-glutamate which accumulates in islets exposed to L-glutamine is sufficient to maintain, for a much longer period than with other nutrient secretagogues, a sustained increase in catabolic fluxes after removal of the amino acid from the extracellular fluid.
Amino acid metabolism, β-cell function, and diabetes
2006
Specific amino acids are known to acutely and chronically regulate insulin secretion from pancreatic -cells in vivo and in vitro. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to exocytosis of insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling messenger in insulin secretion, and other coupling factors, which serve as sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the key amplifying pathway over the Ca 2؉ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (ATP, GTP, cAMP, and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and glutamate. This scenario further highlights the importance of the key enzymes or transporters, e.g., glutamate dehydrogenase, the aspartate and alanine aminotransferases, and the malate-aspartate shuttle in the control of insulin secretion. In addition, after chronic exposure, amino acids may influence gene expression in the -cell, which subsequently alters levels of insulin secretion. Therefore, amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion. Diabetes 55 (Suppl. 2):