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

Abstract

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.

Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 β-cells

“…To determine the possibly distinct roles of Rac1 in the two phases, we measured insulin secretion from the dominant-negative Rac1-transfected cells during two consecutive static stimulating periods [initial 15 min as the early secretion event and followed by a 20-min incubation reflecting the late (sustained) secretion event], an approach used previously to study the early and late-phase insulin secretion responses to glucose in isolated islets (44). The potentiating effect of forskolin on glucosestimulated insulin secretion was greater (by 165%) during the late period than the early phase (by 101%) in the control cells (Fig.…”

Overnutrition in spiny mice (Acomys cahirinus): ?-cell expansion leading to rupture and overt diabetes on fat-rich diet and protective energy-wasting elevation in thyroid hormone on sucrose-rich diet

“…These observations were interpreted as a compensation for the impaired insulin secretion in spiny mice14. In later experiments, low insulin response could be potentiated by priming with high glucose concentration15, 16. The possibility to amplify insulin secretion from isolated islets indicates that the secretion defect is functional rather than inherent.…”

Fast and cAMP-Sensitive Mode of Ca2+-Dependent Exocytosis in Pancreatic β-Cells

“…Adenylate cyclase thus contributes to glucose-sensing mechanisms (aspect A) in the regulation of insulin exocytosis by cAMP. Indeed, islets of the spiny mouse, which do not exhibit the first phase of glucose-induced insulin secretion, contain an adenylate cyclase that is insensitive to glucose concentration (18). Furthermore, certain diabetic animals have been shown to exhibit reduced cAMP responses to glucose (19,20).…”