Time-dependent inhibition of insulin release: glucose-arginine interactions in the perfused rat pancreas

Нешер, Ронит; Waldman, Lewis K.; Cerasi, Erol

doi:10.1007/bf00281123

Cited by 16 publications

(20 citation statements)

References 9 publications

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“…Moreover, this finding is likely not unique for arginine since a similar hyperresponse has also been demonstrated in the NSZ model for leucine (I17), isoproterenol (3), and 3-isobutyl-I-methylxanthine (6) as well as for arginine (6,17). However, the potentiation ofthis response by the high glucose perfusate in each group can only be estimated from the results in this study, for the magnitude of the insulin levels attained to the second arginine challenge as well as to the 16.7 glucose alone was likely suppressed by the initial arginine exposure (18).…”

Section: Discussionmentioning

confidence: 50%

Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions.

Leahy¹,

Cooper²,

Deal³

et al. 1986

J. Clin. Invest.

301

200

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We have proposed that chronic hyperglycemia alters the ability of glucose to modulate insulin secretion, and have now examined the effects of different levels of hyperglycemia on B cell function in normal rats using chronic glucose infusions. Rats weighing 220-300 g were infused with 0.45% NaCl or 20, 30, 35, or 50% glucose at 2 ml/h for 48 h, which raised the plasma glucose by 18 mg/dl in the 30% rats, 37 mg/dl in the 35% rats, and 224 mg/dl in the 50% group. Insulin secretion was then examined using the in vitro isolated perfused pancreas. Glucose-induced insulin secretion remained intact in the normoglycemic 20% glucose rats and it was potentiated in the mildly hyperglycemic 30% glucose rats. However, with even greater hyperglycemia in the 35% glucose group the insulin response to a high glucose perfusate was severely blunted, and it was totally lost in the most hyperglycemic 50% glucose rats. In a second protocol that examined glucose potentiation of arginine-stimulated insulin release, a similar impairment in the ability of glucose to modulate the insulin response to arginine was found with increasing levels of chronic hyperglycemia. On the other hand, the ability of a high glucose concentration to inhibit arginine-stimulated glucagon release was preserved in all glucose-infused rats, but the glucagon levels attained in response to the arginine at 2.8 mM glucose were much less in the 50% glucose rats than in all the other groups. These data clearly show that after 48 h of marked hyperglycemia, glucose influence upon insulin secretion in the rat is severely impaired. This model provides a relatively easy and reproducible method to study the effects of long-term hyperglycemia on B cell function.

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Section: Discussionmentioning

confidence: 50%

Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions.

Leahy¹,

Cooper²,

Deal³

et al. 1986

J. Clin. Invest.

301

200

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“…Several non-metabolizable secretagogues exert synergistic effects with glucose on insulin secretion, which is particularly marked during first phase response [1][2][3]10]. Thus, arginine (5 retool/l) increased the early insulin response of rat islets to 8.3 mmol/l glucose by 30% and to 16.7 mmol/1 by 60%; the amino acid was ineffective, however, in augmenting the early or late insulin response in Acomys islets at either glucose concentration (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Upon stimulation with glucose, normal islets exhibit biphasic dynamics of insulin release, representing the net expression of the interaction between several regulatory events, including time-dependent inhibitory and potentiating signals [1][2][3][4][5][6][7][8][9][10]. Limited information exists regarding the nature of these regulatory signals.…”

mentioning

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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“…The divergent consequences of nutrient and non-nutrient stimulation on the subsequent response pattern have been shown early on [30,31]. It can be assumed that cell culture conditions or, in freshly isolated islets, the metabolic condition of the animal, may leave their mark not just for a few minutes.…”

Section: Discussionmentioning

confidence: 99%

Different responses of mouse islets and MIN6 pseudo-islets to metabolic stimulation: a note of caution

et al. 2015

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MIN6 cells and MIN6 pseudo-islets are popular surrogates for the use of primary beta cells and islets. Even though it is generally agreed that the stimulus-secretion coupling may deviate from that of beta cells or islets, direct comparisons are rare. The present side-by-side comparison of insulin secretion, cytosolic Ca(2+) concentration ([Ca(2+)] i ) and oxygen consumption rate (OCR) points out where similarities and differences exist between MIN6 cells and normal mouse beta cells. In mouse islets and MIN6 pseudo-islets depolarization by 40 mM KCl was a more robust insulinotropic stimulus than 30 mM glucose. In MIN6 pseudo-islets, but not in mouse islets, the response to 30 mM glucose was much lower than to 40 mM KCl and could be suppressed by a preceding stimulation with 40 mM KCl. In MIN6 pseudo-islets, glucose was less effective to raise [Ca(2+)] i than in primary islets. In marked contrast to islets, the OCR response of MIN6 pseudo-islets to 30 mM glucose was smaller than to 40 mM KCl and was further diminished by a preceding stimulation with 40 mM KCl. The same pattern was observed when MIN6 pseudo-islets were cultured in 5 mM glucose. As with insulin secretion memory effects on the OCR remained after wash-out of a stimulus. The differences between MIN6 cells and primary beta cells were generally larger in the responses to glucose than to depolarization by KCl. Thus, the use of MIN6 cells in investigations on metabolic signalling requires particular caution.

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Time-dependent inhibition of insulin release: glucose-arginine interactions in the perfused rat pancreas

Cited by 16 publications

References 9 publications

Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions.

Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions.

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

Different responses of mouse islets and MIN6 pseudo-islets to metabolic stimulation: a note of caution

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