Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides

Aziz, Alfred; Anderson, G. Harvey; Giacca, Adria; Cho, France

doi:10.1152/ajpregu.00850.2004

Cited by 11 publications

(7 citation statements)

References 40 publications

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“…A similar hyperglycemic effect was observed following an acute Ex-4 injection in fasted nondiabetic rats. One mechanism for this could be a Ex-4-induced sympathoadrenal activation (2,28). Consistent with this hypothesis, Ex-4 was shown to activate neurons in brain sites involved in autonomic and adrenal medulla controls (55).…”

Section: Discussionmentioning

confidence: 78%

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

Baraboi

St-Pierre

Shooner

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 g/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 g/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 g/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 g/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.

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Section: Discussionmentioning

confidence: 78%

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

Baraboi

St-Pierre

Shooner

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In GK rats, after the transient decrease, glucose actually increased and remained at a high level until 2 h. Likewise, several other groups have observed that acute administration of exendin-4 causes hyperglycemia in multiple strains of rats (Aziz et al, 2005;Pé rez-Tilve et al, 2010). Extensive studies showed that acute administration of exendin-4 only lowered the glycemic response to glucose challenge in the early phase as a result of augmented early insulin secretion, and then induced hyperglycemia dose-dependently 15 to 30 min after drug administration without further increased insulin response (Pé rez-Tilve et al, 2010).…”

Section: Pk/pd Modeling Of Exendin-4 In Goto-kakizaki Ratsmentioning

confidence: 76%

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Gao

Jusko²

2010

J Pharmacol Exp Ther

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The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki rats after single doses at 0.5, 1, 5, or 10 g/kg by intravenous administration and 5 g/kg by subcutaneous administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition model was used to characterize the PK of exendin-4. Glucose turnover was described by an indirect response model, with insulin stimulating glucose disposition. Insulin turnover was characterized by an indirect response model with a precursor compartment. After intravenous doses, exendin-4 rapidly disappeared from the circulation, whereas it exhibited rapid absorption (T max ϭ 15-20 min) and incomplete bioavailability (F ϭ 0.51) after the subcutaneous dose. Exendin-4 increased insulin release at 2 to 5 min with capacity S max ϭ 6.91 and sensitivity SC 50 ϭ 1.29 nM, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined because of enhanced insulin secretion, and then gradually increased because of the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor S RC ϭ 0.112 1/nM. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.

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“…However, the elevation of plasma glucose induced by Ex-4 was prevented by AP ϩ SFO lesion. Hyperglycemia following Ex-4 injection in fasted nondiabetic rats has been reported (3,34). The mechanism underlying this phenomenon would seem to involve the sympathoadrenal system.…”

Section: Discussionmentioning

confidence: 99%

Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist

Baraboi

Smith

Ferguson

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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The mechanism and route whereby glucagon-like peptide 1 (GLP-1) receptor agonists, such as GLP-1 and exendin-4 (Ex-4), access the central nervous system (CNS) to exert their metabolic effects have yet to be clarified. The primary objective of the present study was to investigate the potential role of two circumventricular organs (CVOs), the area postrema (AP) and the subfornical organ (SFO), in mediating the metabolic and CNS-stimulating effects of Ex-4. We demonstrated that electrolytic ablation of the AP, SFO, or AP + SFO does not acutely prevent the anorectic effects of Ex-4. AP + SFO lesion chronically decreased food intake and body weight and also modulated the effect of Ex-4 on the neuronal activation of brain structures involved in the hypothalamic-pituitary-adrenal axis and glucose metabolism. The results of the study also showed that CVO lesions blunted Ex-4-induced expression of c-fos mRNA (a widely used neuronal activity marker) in 1) limbic structures (bed nucleus of the stria terminalis and central amygdala), 2) hypothalamus (paraventricular hypothalamic nucleus, supraoptic nucleus, and arcuate nucleus), and 3) hindbrain (lateral and lateral-external parabrachial nucleus, medial nucleus of the solitary tract, and ventrolateral medulla). In conclusion, although the present results do not support a role for the CVOs in the anorectic effect induced by a single injection of Ex-4, they suggest that the CVOs play important roles in mediating the actions of Ex-4 in the activation of CNS structures involved in homeostatic control.

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Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides

Cited by 11 publications

References 40 publications

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist

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