The expression of GLP‐1 receptor mRNA and protein allows the effect of GLP‐1 on glucose metabolism in the human hypothalamus and brainstem

Álvarez, Elvira; Martinez, Margareta; Roncero, Isabel; Chowen, Julie A.; García-Cuartero, Beatriz; Gispert, Juan Domingo; Sanz, Carmen; Vázquez, Patricia; Maldonado, Antonio; Cáceres, Javier de; Desco, Manuel; Pozo, Miguel A.; Blázquez, Enrique

doi:10.1111/j.1471-4159.2004.02914.x

Cited by 250 publications

(176 citation statements)

References 43 publications

Supporting

Mentioning

162

Contrasting

Unclassified

Order By: Relevance

Section: Evidence From Human Studies Supporting Cns Regulation Of Metmentioning

confidence: 99%

“…There was no effect on peripheral glucose uptake. Because GLP-1 receptors have been shown in various human brain regions (84,85), these studies suggest that central GLP-1 signaling may regulate EGP in humans.Several brain imaging studies have implied that the brain serves as a metabolic sensor impacting whole body energy homeostasis in humans. Functional MRI scans detecting blood oxygen level-dependent signals showed hypothalamic signaling changes in response to glucose infusions (86 -88).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (K ATP ) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.The estimated global prevalence of Type 2 diabetes (T2DM) 2 is 347 million (1). Because glycemic control is achieved in only ϳ40% of patients, additional therapeutic strategies are needed (2). Increased endogenous glucose production (EGP) is the main source of fasting hyperglycemia (3, 4), contributing ϳ80% of diurnal hyperglycemia in T2DM (5). Apart from insulin, there is no treatment targeting basal EGP. Better understanding its regulation would have important therapeutic implications. We will examine the evidence for central sensing of nutritional and hormonal signals in animal models and humans, focusing on CNS regulation of glucose metabolism. Evidence for CNS Nutrient and Hormone Sensing in AnimalsUnlike other organs, the brain is an obligate consumer of glucose (6). Central regulation of EGP would therefore be teleologically advantageous. Since the first demonstration by Claude Bernard (7) that lesions in the floor of the fourth ventricle altered blood glucose levels, the ability of central glucose sensing to regulate peripheral glucose homeostasis has been extensively examined in animal models. There are glucosesensing neurons in many areas of the brain (8), particularly the hypothalamus (9). Specifically, the ventromedial hypothalamus (VMH) and arcuate nucleus (10) integrate hormonal and nutrient signals impacting peripheral metabolism (Fig. 1). Central signals appear to activate hypothalamic ATP-sensitive potassium (K ATP ) channels (9,11,12) composed of an inward rectifier potassium ion channel Kir6.2 subunit and a sulfonylurea receptor (SUR) subunit. Pharmacologic compounds including diazoxide activate and thereby close hypothalamic K ATP channels, whereas sulfonylureas inhibit and thereby open them, ultimately modulating EGP (12).Glucose-Elegant studies in rats showed that direct infusion of D-glucose into the VMH inhibited counterregulatory hormonal responses to systemic hypoglycemia during a hypoglycemic clamp, indicating that VMH glucose sensing is needed for the systemic response to peripheral hypoglycemia (13). VMH infusion of L-lactate, a byproduct of glucose metabolism and an alternate fuel source for neurons in conditions of glucose deficiency, produced similar suppression of the counterregulatory hormonal response to systemic...

show abstract

Section: Evidence From Human Studies Supporting Cns Regulation Of Metmentioning

confidence: 99%

mentioning

confidence: 99%

Evidence for Central Regulation of Glucose Metabolism

Carey

Kehlenbrink

Hawkins

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In this sense, we cannot discard other short-term effects, i.e. the interactions of GK and GKRP present in the hypothalamus of rat and human brain (Alvarez et al 2002(Alvarez et al , 2005 or GK-PFK2 interaction as occurs in liver and b-cells (Massa et al 2004, Baltrusch & Tiedge 2006.…”

Section: Effect Of Ins and Other Peptides On Gk Activities In Hypothamentioning

confidence: 99%

“…7). Discussion GK has been characterized in the brains of human (Alvarez et al 2005) and experimental animals (Jetton et al 1994, Navarro et al 1996, Roncero et al 2000; the isoform present in the central nervous system being similar to that found in pancreatic b-cells (Roncero et al 2000), where it seems to contribute as a glucose sensor involved in the control offood intake (Alvarez et al 1996). These findings open the door to study the effects of glucose and anorexigenic and orexigenic peptides as substances that may potentially modulate the expression of the GK gene and/or the activity of this enzyme in brain.…”

Section: Effect Of Ins and Other Peptides On Gk Activities In Hypothamentioning

confidence: 99%

Effects of glucose and insulin on glucokinase activity in rat hypothalamus

Sanz¹,

Roncero²,

Vázquez³

et al. 2007

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

In an attempt to study the role of glucokinase (GK) and the effects of glucose and peptides on GK gene expression and on the activity of this enzyme in the hypothalamus, we used two kinds of biological models: hypothalamic GT1-7 cells and rat hypothalamic slices. The expression of the GK gene in GT1-7 cells was reduced by insulin (INS) and was not modified by different glucose concentrations, while GK enzyme activities were significantly reduced by the different peptides. Interestingly, a distinctive pattern of GK activities between the ventromedial hypothalamus (VMH) and lateral hypothalamus (LH) were found, with higher enzyme activities in the VMH as the glucose concentrations rose, while LH enzyme activities decreased at 2 . 8 and 20 mM glucose, the latter effect being prevented by incubation with INS. These effects were produced only by D-glucose and the modifications found were due to GK, but not to other hexokinases. In addition, GK activities in the VMH and the LH were reduced by glucagonlike peptide 1, leptin, orexin B, INS, and neuropeptide Y (NPY), but this effect was only statistically significant for NPY in LH. Our results indicate that the effects of both glucose and peptides occur on GK enzyme activities rather than on GK gene transcription. Moreover, the effects of glucose and INS on GK activity suggest that in the brain GK behaves in a manner opposite to that in the liver, which might facilitate its role in glucose sensing. Finally, hypothalamic slices seem to offer a good physiological model to discriminate the effects between different areas.

show abstract

“…There is an extensive literature on the insulinotropic effects of the incretins and their ability to promote ␤-cell proliferation and survival (1)(2)(3)(4)(5)(6). Receptors for both GIP (GIPR) and GLP-1 have been shown to be expressed in tissues other than the pancreas, including adipose tissue (7)(8)(9), gastrointestinal tract (10,11), and the brain (12,13). As a result of the recent introduction of the GLP-1 agonist Exenatide and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase IV as therapeutics for type 2 diabetes (14), considerable interest has developed in the non-␤-cell effects of the incretins.…”

mentioning

confidence: 99%