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, 158 (7), 2124-2133

Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats

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Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats

Lene Jessen et al. Endocrinology.

Abstract

The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 receptors (GLP-1rs) expressed in brain regions involved in metabolic regulation. GLP-1 in the central nervous system (CNS) induces satiety, visceral illness, and stress responses. However, recent evidence suggests CNS GLP-1 is also involved in glucose regulation. To test the hypothesis that central GLP-1 regulates islet hormone secretion, conscious rats were given intracerebroventricular (ICV) GLP-1, GLP-1r antagonist exendin-[9-39] (Ex-9), or saline during fasting or hyperglycemia from intravenous glucose. Administration of CNS GLP-1 increased fasting glucose, glucagon, corticosterone, and epinephrine and blunted insulin secretion in response to hyperglycemia. Paradoxically, GLP-1r blockade with ICV Ex-9 also reduced glucose-stimulated insulin secretion, and administration of ICV Ex-9 to freely feeding rats caused mild glucose intolerance. Thus, direct administration of CNS GLP-1 affected islet hormone secretion counter to what is seen with peripherally administered GLP-1, an effect likely due to stimulation of sympathetic nervous system activity. In contrast, blockade of brain GLP-1r supports a role for CNS GLP-1 on glucose-stimulated insulin secretion and glucose control after a meal. These findings suggest a model in which activation of CNS GLP-1r by endogenous peptide promotes glucose tolerance, an effect that can be overridden by stress responses stimulated by exogenous GLP-1.

Figures

Figure 1.
Figure 1.
Blood glucose values in rats receiving infusions with (a, top) ICV saline, (a, middle) GLP-1, and (a, bottom) Ex-9 during fasting and intravenously induced hyperglycemia. Comparisons of fasting glucose (b) before (t = −70 to −60 minutes) and (c) after a 60-minute (t = −15 to 0 minutes) infusion of saline, GLP-1, or Ex-9. (d) Glucose infusion rates to maintain hyperglycemia (t = 0 to 60 minutes) in rats receiving ICV infusions. Ten rats per group; data are mean ± standard error of the mean. *P < 0.05.
Figure 2.
Figure 2.
(a) Plasma insulin before and after intravenous hyperglycemia (t = 0 to 60 min) in rats given ICV saline (black), GLP-1 (gray), or Ex-9 (white). (b) Mean insulin levels (average increment from baseline) for the same groups over 60 minutes of hyperglycemia. (c) Plasma glucagon before and after the glucose clamp in rats given ICV saline (black), GLP-1 (gray), or Ex-9 (white). (d) Mean change in fasting glucagon levels during 60 minutes (t = −60 to 0 minutes) infusion of saline (black), GLP-1 (gray), or Ex-9 (white). Ten rats per group; data are mean ± standard error of the mean. *P < 0.05.
Figure 3.
Figure 3.
(a) Plasma corticosterone in rats given ICV saline (black), GLP-1 (gray), or Ex-9 (white) before and after a hyperglycemic clamp (experiment 1). (b) Plasma corticosterone and epinephrine in fasted rats receiving ICV GLP-1 (gray) or saline (black) (experiment 2). Eight to 10 rats were included in each group; data are mean ± standard error of the mean. *P < 0.05.
Figure 4.
Figure 4.
(a) Representative sections of adrenal cortex, paraventricular nucleus (PVN), and nucleus of the solitary tract (NTS) from rats treated with 120 minutes of ICV saline or GLP-1 and stained for Fos-immunoreactivity (experiment 2). (b) Numbers of cells staining for Fos in the adrenal medulla, PVN, or NTS. Ten rats per group; data are mean ± standard error of the mean. *P < 0.05.
Figure 5.
Figure 5.
(a) Blood glucose before and after mixed meal ingestion in rats infused with ICV saline (black) or Ex-9 (white). (b) Individual values for glucose area under the curve (AUC) and (c) mean values for the two groups: saline (black) and Ex-9 (white). (d) Mean postprandial insulin concentrations during the meal study; (e) change in fasting plasma glucagon during ICV infusion of saline or Ex-9; plasma concentrations of d-xylose before and after the meal test. Eleven rats were included in each group; data are mean ± standard error of the mean. *P < 0.05.

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