The metabolism of cyclic AMP and glucose in isolated islets from Acomys cahirinus

Grill, Valdemar; Cerasi, Erol

doi:10.1007/bf00423150

Cited by 9 publications

(7 citation statements)

References 19 publications

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“…Work from this laboratory [23] and elsewhere [4,[24][25][26] presented evidence to suggest that the stimulation of B cell cyclic AMP levels by glucose is particularly important for the expression of normal first phase insulin release. By the present direct measurements of islet cyclic AMP we were able to confirm earlier observations using prelabelling of islets with 3H-adenine [20], that the adenylate cyclase system of the spiny mouse is essentially glucoseinsensitive, in keeping with the blunted first phase insulin response to the sugar. Although cyclic AMP levels could be raised by the phosphodiesterase inhibitor IBMX and the adenylate cyclase stimulator forskolin in Acomys islets to the same extent as in rat islets, complete insensitivity of the enzyme to glucose was retained in either case.…”

Section: Discussionsupporting

confidence: 86%

“…More important, the dynamics of insulin release are strikingly reminiscent of those seen in glucose intolerant man [15,17,20], in that first phase response to glucose is grossly reduced, while second phase response is less impaired [17]. We have previously shown that if Acomys islets are primed with glucose to generate time-dependent potentiation, the kinetics of the insulin response to a subsequent glucose stimulus are markedly improved, a near-normal first phase release being elicited [17].…”

Section: Discussionmentioning

confidence: 92%

“…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.…”

mentioning

confidence: 98%

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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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 98%

See 1 more Smart Citation

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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“…The mice showed a low response to various secretagogues in the initial and late phases of insulin release, including glucose, arginine, glucagon, and cyclic AMP both in vivo and in vitro Junod et al 1969;Rabinovitch et al 1975). This response was attributed to several factors such as low islet adenylate cyclase activity, low cAMP response of ␤-cells after a glucose load, low amount of vincristine precipitable material in ␤-cell microtubuli through which insulin granules are extruded, and scarcity of autonomic islet innervation (Grill and Cerasi 1979;Gutzeit et al 1974;Malaisse-Lagae et al 1975;Orci et al 1970). These findings were first interpreted as resulting from a genetic mutation in the animals maintained in captivity, but it is more likely that such responses of the islets may be a native characteristic of animals living in a desert environment, aimed at the protection of the pancreas against overstimulation.…”

Section: Characteristics Of Spiny Mice In the Geneva Colonymentioning

confidence: 89%

Nutritionally Induced Diabetes in Desert Rodents as Models of Type 2 Diabetes: Acomys cahirinus (Spiny Mice) and Psammomys obesus (Desert Gerbil)

Shafrir

Ziv²,

Kalman³

2006

ILAR Journal

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The dietary effects of hyperglycemia increasingly result in type 2 diabetes in humans. Two species, the spiny mice (Acomys cahirinus) and the desert gerbil (Psammomys obesus), which have different metabolic responses to such effects, are discussed. Spiny mice exemplify a pathway that leads to diabetes without marked insulin resistance due to low supply of insulin on abundant nutrition, possibly characteristic of a desert animal. They respond with obesity and glucose intolerance, beta-cell hyperplasia, and hypertrophy on a standard rodent diet supplemented with fat-rich seeds. The accompanying hyperglycemia and hyperinsulinemia are mild and intermittent but after a few months, the enlarged pancreatic islets suddenly collapse, resulting in loss of insulin and ketosis. Glucose and other secretagogues produce only limited insulin release in vivo and in vitro, pointing to the inherent disability of the beta-cells to respond with proper insulin secretion despite their ample insulin content. On a 50% sucrose diet there is marked lipogenesis with hyperlipidemia without obesity or diabetes, although beta-cell hypertrophy is evident. P.obesus is characterized by muscle insulin resistance and the inability of insulin to activate the insulin signaling on a high-energy (HE) diet. Insulin resistance imposes a vicious cycle of Hyperglycemia and compensatory hyperinsulinemia, leading to beta-cell failure and increased secretion of proinsulin. Ultrastructural studies reveal gradual disappearance of beta-cell glucokinase, GLUT 2 transporter, and insulin, followed by apoptosis of beta-cells. Studies using the non-insulin-resistant HE diet-fed animals maintained as a control group are discussed. The insulin resistance that is evident to date in the normoglycemic state on a low-energy diet indicates sparing of glucose fuel in muscles of a desert-adapted animal for the benefit of glucose obligatory tissues. Also discussed are the effect of Psammomys age on the disabetogenicity of the HE diet; the impaired function of several components of the insulin signal transduction pathway in muscles, which reduces the availability of GLUT4 transporter; the testing of several antidiabetic modalities for the prevention of nutritional diabetes in Psammomys; and various complications related to the diabetic condition.

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“…To elucidate the metabolic defect(s) of the/3 cells, suitable animal models for Type 2 diabetes are needed. The spiny mouse (Acomys cahirinus) is a semi-desert rodent which has been studied extensively as a model for Type 2 diabetes in man [8][9][10][11][12][13][14][15][16]. Bred in captivity, these animals demonstrate various degrees of glucose intolerance, become obese with age and develop hyperglycaemia.…”

Section: Discussionmentioning

confidence: 99%

Correction of diabetic pattern of insulin release from islets of the spiny mouse (Acomys cahirinus) by glucose priming in vitro

1985

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Summary.Insulin release kinetics were studied in perifused islets of Langerhans, isolated from mildly hyperglycaemic and from normoglycaemic spiny mice (Acomys cahirinus), a rodent predisposed to develop spontaneously non-ketotic diabetes. In both groups, insulin response to glucose (16.7 mmol/1) was delayed in comparison with that of rat islets, the release kinetics being analogous to that of human Type 2 (non-insulin-dependent) diabetes. Thirty min priming of the isolated Acomys islets with glucose (16.7 retool/l) resulted in potentiation of the insulin release to a second stimulation. The degree of potentiation decreased exponentially with the time interval between stimulations, showing a tl/2 of 18 min. Induction of potentiation by glucose was time-dependent, giving a maximal effect after 20 min of priming. In addition to overall amplification of the insulin response, printing with glucose accelerated markedly the initial release rates, correcting the dynamics of the response. We conclude that: (1) decreased and delayed insulin secretion is found in Acomys cahirinus before the development of hyperglycaemia; (2) induction of time-dependent potentiation in the islet by priming with glucose corrects the diabetic-type dynamics of insulin release; (3) therefore the deficient insulin release of Acomys is of a functional nature, the mechanism of potentiation bypassing the defect; (4) since insulin release in Acomys resembles that in prediabetic and diabetic man, similar conclusions might apply to the islet dysfunction in Type 2 diabetes.Key words: Insulin secretion, time-dependent potentiation, non-insulin dependent-diabetes, Acomys cahirinus.Glucose intolerance and hyperglycaemia in Type 2 diabetes are the result of an inappropriate pancreatic response to changes in the blood glucose level, accompanied by some decrease in peripheral response to insulin [1]. The inappropriate pancreatic response is characterized by reduction in the sensitivity of fl cells to glucose and delay or absence of the acute insulin response [2][3][4][5][6][7]. To elucidate the metabolic defect(s) of the/3 cells, suitable animal models for Type 2 diabetes are needed. The spiny mouse (Acomys cahirinus) is a semi-desert rodent which has been studied extensively as a model for Type 2 diabetes in man [8][9][10][11][12][13][14][15][16]. Bred in captivity, these animals demonstrate various degrees of glucose intolerance, become obese with age and develop hyperglycaemia. At all stages of glucose intolerance, whether obese or lean, bred in captivity or newly captured, the spiny mouse exhibits decreased insulin response to glucose stimulation, both in vivo and in vitro [10][11][12][13][14]16].Studies in recent years demonstrated that apart from initiating immediate insulin release, glucose generates a time-dependent state of potentiation in the islets of Langerhans, which leads to the amplification of insulin secretion upon subsequent stimulation [17][18][19][20][21][22]. The present study examines the effect of such glucose priming on insulin relea...

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The metabolism of cyclic AMP and glucose in isolated islets from Acomys cahirinus

Cited by 9 publications

References 19 publications

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

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

Nutritionally Induced Diabetes in Desert Rodents as Models of Type 2 Diabetes: Acomys cahirinus (Spiny Mice) and Psammomys obesus (Desert Gerbil)

Correction of diabetic pattern of insulin release from islets of the spiny mouse (Acomys cahirinus) by glucose priming in vitro

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