Role Of Endogenous Glucagon-like Peptide-1 Research Articles

Septal Glucagon-Like Peptide 1 Receptor Expression Determines Suppression of Cocaine-Induced Behavior.

Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction. However, the role of endogenous GLP-1 in the attenuation of reward-oriented behavior, and the essential domains of the mesolimbic system mediating these beneficial effects, are largely unknown. We hypothesized that the central regions of highest Glp-1r gene activity are essential in mediating responses to drugs of abuse. Here, we show that Glp-1r-deficient (Glp-1r(-/-)) mice have greatly augmented cocaine-induced locomotor responses and enhanced conditional place preference compared with wild-type (Glp-1r(+/+)) controls. Employing mRNA in situ hybridization we located peak Glp-1r mRNA expression in GABAergic neurons of the dorsal lateral septum, an anatomical site with a crucial function in reward perception. Whole-cell patch-clamp recordings of dorsal lateral septum neurons revealed that genetic Glp-1r ablation leads to increased excitability of these cells. Viral vector-mediated Glp-1r gene delivery to the dorsal lateral septum of Glp-1r(-/-) animals reduced cocaine-induced locomotion and conditional place preference to wild-type levels. This site-specific genetic complementation did not affect the anxiogenic phenotype observed in Glp-1r(-/-) controls. These data reveal a novel role of GLP-1R in dorsal lateral septum function driving behavioral responses to cocaine.

Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: Projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetic patients and shown to reduce food intake and body weight. The anorexigenic effects of GLP-1 and GLP-1 receptor agonists are thought to be mediated primarily via the hypothalamic paraventricular nucleus (PVN). GLP-1, an intestinal hormone, is also localized in the nucleus tractus solitarius (NTS) of the brain stem. However, the role of endogenous GLP-1, particularly that in the NTS neurons, in feeding regulation remains to be established. The present study examined whether the NTS GLP-1 neurons project to PVN and whether the endogenous GLP-1 acts on PVN to restrict feeding. Intra-PVN injection of GLP-1 receptor antagonist exendin (9–39) increased food intake. Injection of retrograde tracer into PVN combined with immunohistochemistry for GLP-1 in NTS revealed direct projection of NTS GLP-1 neurons to PVN. Moreover, GLP-1 evoked Ca2+ signaling in single neurons isolated from PVN. The majority of GLP-1-responsive neurons were immunoreactive predominantly to corticotropin-releasing hormone (CRH) and nesfatin-1, and less frequently to oxytocin. These results indicate that endogenous GLP-1 targets PVN to restrict feeding behavior, in which the projection from NTS GLP-1 neurons and activation of CRH and nesfatin-1 neurons might be implicated. This study reveals a neuronal basis for the anorexigenic effect of endogenous GLP-1 in the brain.

Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion

Objective. To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. Material and methods. In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma concentrations of insulin, glucagon and glucose were measured during infusion of saline or the GLP-1 receptor antagonist exendin(9-39)amide (Ex(9-39)) at 300 pmol·kg−1·min−1. Results. Ex(9-39) infusion had no effect on the total gastric emptying curve, but changed the intra-gastric distribution of the meal. During infusion of Ex(9-39), more content stayed in the upper stomach (79.1 ± 2.5% of total during Ex(9-39) compared to 66.6 ± 5.7% during saline at 5 min). During Ex(9-39) infusion, higher concentrations of plasma glucagon were measured both before (after 40 min of Ex(9-39) infusion the glucagon level was 15.1 ± 0.7 pmol·L−1 compared to 5.4 ± 1.4 during saline) and after the meal, and postprandial GLP-1 levels increased. Basal insulin and glucose levels were not affected by Ex(9-39), but the postprandial rise of insulin and glucose enhanced during Ex(9-39). Conclusions. Endogenous GLP-1 is involved in the regulation of gastric motility in relation to meal intake and also in the regulation of postprandial insulin and glucose levels. Furthermore, endogenous GLP-1 seems to tonically restrain glucagon secretion.

The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus

Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of ‘incretins,’ particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.

Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy.

A reduction in beta-cell mass is an important causative factor in type 1 and type 2 diabetes. Glucagon-like peptide-1 (GLP-1) and the long-acting agonist exendin 4 (Ex-4) expand beta-cell mass by stimulating neogenesis and proliferation. In the partial pancreatectomy (Ppx) model, exogenous Ex-4 promotes islet regeneration, leading to sustained improvement in glucose tolerance. In this study, we investigate the potential role of endogenous GLP-1 in islet growth. We examined beta-cell mass regeneration after 70% Ppx in mice receiving the GLP-1 antagonist Ex9-39 and in GLP-1R(-/-) mice. In Ex9-39-treated sham-operated mice, persistent fasting hyperglycemia was observed, but beta-cell mass was not diminished. In pancreatectomized mice, persistent glucose intolerance was noted, but this was not further exacerbated by Ex9-39. Accordingly, beta-cell mass recovery of Ppx mice was not impaired by Ex9-39. In contrast, GLP-1R(-/-) CD1 mice showed worse glucose intolerance after Ppx compared with wild-type CD1 Ppx mice, and this correlated with a significant defect in beta-cell mass regeneration. The recovery of beta-cell mass differed markedly in the BALB/c and CD1 control mice, indicating a significant role of genetic background in the regulation of beta-cell mass. These studies point to a role for endogenous GLP-1 in beta-cell regeneration after Ppx in mice.