Time-dependent potentiation of insulin release induced by alpha-ketoisocaproate and leucine in rats: possible involvement of phosphoinositide hydrolysis

Zawalich, Walter S.

doi:10.1007/bf00271588

Cited by 27 publications

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“…At least five experiments were conducted under each condition. activate one of the several isozymes of PLC identified in islets (13,15,19,38). Thus, MP shares this property with such diverse agonists as carbachol, acetylcholine, cholecystokinin, leucine, monomethylsuccinate, glucose, ␣-ketoisocaproate, and tolbutamide.…”

Section: Mp Induces Time-dependent Potentiation Of Insulinmentioning

confidence: 99%

“…Because these latter stimulants for insulin secretion share in common many of the same stimulatory features of glucose on the beta cell, the concept that mitochondrial-derived signals mediate, at least in part, the stimulatory actions of the hexose has been proposed (11, 12). For example, both glucose and ␣-ketoisocaproate stimulate similar changes in insulin secretion and the calcium-dependent hydrolysis of islet phosphoinositide (PI) 1 pools and sensitize the beta cells to subsequent restimulation, a phenomenon also referred to as priming or time-dependent potentiation (TDP) (13)(14)(15).Standing at odds with this unifying concept, implicating the importance of mitochondrial signals in the regulation of secretion regardless of the nutrient molecule used, are studies with pyruvate. Although it seems to be well metabolized, pyruvate alone has no insulinotropic effect, although in combination with stimulatory glucose, a small stimulatory action has been described (16).…”

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Influence of Pyruvic Acid Methyl Ester on Rat Pancreatic Islets

Zawalich

1997

Journal of Biological Chemistry

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The methyl ester of pyruvic acid (methyl pyruvate) stimulated a dose-dependent increase in insulin secretion from isolated perifused rat islets. The threshold level for release was about 10 mM, and at 20 mM the addition of MP to perifused islets resulted in a large first phase of secretion followed by an insulin-secretory response that was sustained for at least 40 min. When compared to the effects of 20 mM glucose, peak firstphase release rates in response to 20 mM methyl pyruvate were comparable, but the second phase of release was only about 10 -15% of that observed with an equimolar level of the hexose. The stimulatory effects of 20 mM methyl pyruvate on secretion were abolished by the K 1؉ -ATP channel blocker diazoxide (200 M) and by the calcium channel antagonist nitrendipine (500 nM). The glucokinase inhibitor mannoheptulose (20 mM) had no adverse effect on the secretory response to 20 mM methyl pyruvate, whereas 10 M forskolin amplified the insulinotropic action of MP. Sodium pyruvate alone or in combination with 10 M forskolin had no insulinotropic effect. In additional experiments islet phosphoinositide pools were labeled with myo-2-[ 3 H]inositol, and the subsequent accumulation of labeled inositol phosphates was used to monitor the activation of phospholipase C. Methyl pyruvate stimulated a dose-dependent increase in inositol phosphate levels when measured after a 30-min incubation period with a maximal increase of about 300% at 20 mM methyl pyruvate. The increase in phosphoinositide hydrolysis caused by methyl pyruvate (20 mM) was, like insulin secretion, reduced by both diazoxide and nitrendipine but was immune to inhibition by mannoheptulose. Pyruvate (20 mM) had no effect on inositol phosphate accumulation. Prior short-term exposure to methyl pyruvate sensitized islets to subsequent stimulation with 15 mM glucose. Sodium pyruvate did not sensitize islets. These findings support the concept that the mitochondrial metabolism of nutrient molecules is an event sufficient to acutely augment insulin release from the beta cell, to increase phospholipase C-mediated phosphoinositide hydrolysis, and to induce time-dependent potentiation of insulin secretion.The regulation of fuel-induced insulin secretion from pancreatic beta cells depends upon the intermediary metabolism of these compounds via several established metabolic pathways (1). In addition to glucose, mannose, glyceraldehyde, and dihydroxyacetone, which are metabolized initially by cytosolic glycolytic enzymes (2-5), a variety of insulinotropic nutrient molecules are metabolized solely within the mitochondria. These include among others leucine, monomethylsuccinate, and ␣-ketoisocaproate (6 -10). Because these latter stimulants for insulin secretion share in common many of the same stimulatory features of glucose on the beta cell, the concept that mitochondrial-derived signals mediate, at least in part, the stimulatory actions of the hexose has been proposed (11, 12). For example, both glucose and ␣-ketoisocaproate stimulate similar changes in i...

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Section: Mp Induces Time-dependent Potentiation Of Insulinmentioning

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Influence of Pyruvic Acid Methyl Ester on Rat Pancreatic Islets

Zawalich

1997

Journal of Biological Chemistry

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“…We have recently proposed that the late response is the expression of the effect of a time-dependent regulatory loop on insulin release [2] and have demonstrated that this loop is functionally intact in islets from the spiny mouse [17], as it seems to be in glucose intolerant people [16]. The activation of protein kinase C by diacylglycerol has been proposed to be important for late phase insulin release and time-dependent potentiation [3,4,29]. In the case of Acomys islets, the previous activation of diacylglyceroldependent protein kinase C by glucose priming could, therefore, be the factor that improves the insulin response, bypassing the defective signal for first phase release.…”

Section: Discussionmentioning

confidence: 99%

Reduced early and late phase insulin response to glucose in isolated spiny mouse (Acomys cahirinus) islets: a defective link between glycolysis and adenylate cyclase

1989

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Summary. The spiny mouse (Acomys cahirinus) exhibits low insulin responsiveness to glucose with a nearly absent early phase release. The alternative fuel-secretagogue glyceraldehyde (10 retool/l) produced a maximal early insulin response in rat islets but failed to affect early response in Acomys; however, it potentiated the late insulin response in both species alike. Glucagon (1.5 ~mol/1) potentiated the early insulin response to intermediate (8.3 retool/l) glucose in rat and Aeomys islets by two-and four-fold, respectively. Glucose doubled cyclic AMP levels in rat islets but no significant response was noted in Aeomys islets. Isobutylmethylxanthine (0.1 retool/l) and forskolin (25 ~mol/1) caused a significant rise in islet cyclic AMP levels in both types of islets; however, neither agent restored the glucose stimulation of cyclic AMP in spiny mouse islets. Forskolin and isobutylmethylxanthine potentiated early and late phase insulin release in both species; however, neither augmented the early response in the Acomys to the degree observed in rat islets. Thus: (1) The early stages of glucose intolerance in man are characterized by severe reduction in early phase insulin response to glucose, and a delayed and often reduced late phase response. The nature of the metabolic defect(s) responsible for the poor responsiveness of the B cell is unknown. The spiny mouse, Aeomys cahirinus, exhibits such diabetic-like kinetics of insulin response to glucose in vivo and in vitro [11][12][13][14][15], and often develops glucose intolerance when raised in captivity. The spiny mouse is, therefore, a convenient animal model for mild Type 2 (non-insulin-dependent) diabetes. Using islets from this animal, it could thus be shown that the early phase of insulin release is more reduced than the late response [12,14,15], and that a first phase insulin response can be partially restored by priming the islets with glucose for 20-60 min, a finding that is pertinent also for glucose intolerant man [16,17].Cumulative evidence suggests that a normal first phase insulin response necessitates activation of B cell adenylate cyclase by glucose stimulation, resulting in a normal cyclic AMP response [1,4,18,19]. The cyclic AMP response of Acomys islets to glucose was found deficient [20]. In the present study we examined further the responsiveness of Acomys islets to a variety of secretagogues in an attempt to define the nature of the deficient signal that causes a low insulin response to glucose, with emphasis on agents that elevate the islet cyclic AMP concentration. The spiny mouse belongs to rodent species unrelated to any common laboratory animal. In previous studies we examined the overall rates of insulin response as well as its dynamics in this species and compared it to those seen in the rat and the mouse [11][12][13][14][15]17]. In the present study emphasis is given to the kinetics of insulin release rather than to its absolute magnitude when comparing results obtained in Acomys and in the control rat islets.

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“…A variety of structurally distinct agonists, including glucose, -ketoisocaproate, monomethyl succinate and carbachol, activate phospholipase C (PLC) in islets (Axen et al 1983, Best & Malaisse 1983, Best 1986, Zawalich 1988b, MacDonald et al 1989, Zawalich et al 1989, Vadakekalam et al 1996. We next explored the potential influence of caloric restriction on PLC activation, monitored by IP accumulation in response to agonist addition.…”

Section: Ip Accumulation In Islets From Fed and Fasted Donorsmentioning

confidence: 99%

Glucose-induced insulin secretion from islets of fasted rats: modulation by alternate fuel and neurohumoral agonists

Zawalich

Zawalich²

2000

Journal of Endocrinology

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Islets from fed and 24-h-fasted rats were studied immediately after collagenase isolation. (1) After a 24-h fast, the insulin secretory responses to 8 mM glucose measured during perifusion were reduced by more than 90% from islets of fasted donors. (2) Increasing glucose to 11 or 27·5 mM resulted in enhanced insulin secretion from islets of fasted animals. (3) Fasting did not reduce islet insulin content. (4) Responses to 8 or 27·5 mM glucose were not affected if fatty acid-free albumin was used during the perifusion. (5) Inclusion of -ketoisocaproate (5 mM), monomethyl succinate (10 mM) or carbachol (10 µM) significantly amplified insulin release from fasted islets in the simultaneous presence of 8 mM glucose. (6) Phospholipase C activation by glucose, carbachol or their combination was not adversely affected by fasting. (7) The response to the protein kinase C activator, phorbol 12-myristate 13-acetate (500 nM), was reduced by about 60% after fasting. (8) Extending the fast to 48 h resulted in a severe decline in response to 11 mM glucose; however, the further addition of 10 µM carbachol still enhanced release from these islets. The results confirm that caloric restriction impairs islet sensitivity to glucose stimulation and that protein kinase C may be involved in the reduction of glucose-induced insulin release from these islets. The activation of phospholipase C by cholinergic stimulation may contribute to the maintenance of insulin secretion from calorically restricted animals. These results also demonstrate that free fatty acids are not essential for glucose to evoke secretion from isolated islets of fasted donors.

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Time-dependent potentiation of insulin release induced by alpha-ketoisocaproate and leucine in rats: possible involvement of phosphoinositide hydrolysis

Cited by 27 publications

References 27 publications

Influence of Pyruvic Acid Methyl Ester on Rat Pancreatic Islets

Influence of Pyruvic Acid Methyl Ester on Rat Pancreatic Islets

Reduced early and late phase insulin response to glucose in isolated spiny mouse (Acomys cahirinus) islets: a defective link between glycolysis and adenylate cyclase

Glucose-induced insulin secretion from islets of fasted rats: modulation by alternate fuel and neurohumoral agonists

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