Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Preitner, Frédéric; Ibberson, Mark; Franklin, Isobel; Binnert, Christophe; Pende, Mario; Gjinovci, Asllan; Hansotia, Tanya; Drucker, Daniel J.; Wollheim, Claes B.; Burcelin, Rémy; Thorens, Bernard

doi:10.1172/jci20518

Cited by 116 publications

(110 citation statements)

References 52 publications

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“…As regard with the incretin effects of GIP, although, we did not perform oral glucose tolerance test to assess insulin response in this condition, studies performed on the same GIPR KO model that we used revealed that these animals are hypoinsulinemic in response to oral glucose challenge with a 40% reduction in plasma insulin level [17]. Insulin-deficient mice present a growth retardation that occurred predominantly in the fetal life with a decrease in bone formation [40].…”

Section: Discussionmentioning

confidence: 99%

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Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Gaudin-Audrain¹,

Irwin²,

Mansur³

et al. 2013

Bone

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A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

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Section: Discussionmentioning

confidence: 99%

“…The background and generation of GIPR-deficient mice used in this study has been previously described [17]. Age-matched wildtype (WT) mice with the same C57BL/6 genetic background were used as controls (Harlan Ltd., Oxon, UK).…”

Section: Animalsmentioning

confidence: 99%

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Gaudin-Audrain¹,

Irwin²,

Mansur³

et al. 2013

Bone

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“…15 The hepatoportal sensor has been shown to control multiple physiological function. 5 Its activation stimulates first-phase insulin secretion, 16,17 increases hepatic glucose clearance, 18 stimulates, in an insulin-independent manner, peripheral tissue glucose uptake, 8,19 suppresses glucagon secretion (see below) and terminates feeding. 20,21 Thus, the combination of physiological as well as pharmacological and genetic studies has provided strong evidence for an important role of the hepatoportal sensor in the regulation of several homeostatic functions.…”

Section: Sites and Mechanisms Of Glucose Sensingmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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“…The GLP-1 receptor knock out mice (GLP-1R-/-) were in a mixed C57BL/6 and SV129 background and have been extensively characterized (Scrocchi et al, 1996). The GIP receptor knockout mice (GIPR -/-) were in a mixed C57BL/6 and SV129 background and have been extensively characterized (Preitner et al, 2004).…”

Section: Mice Models and Surgical Proceduresmentioning

confidence: 99%

“…A major characteristic of both incretin secretion and action is a strict glucose-dependency, which confers a therapeutic advantage for incretin-based approaches for the treatment of type 2 diabetes (Zander et al, 2002). Whereas considerable evidence supports a direct pancreatic effect of these peptides for the control of glucoseinduced insulin secretion, recent data support a role for extrapancreatic GLP-1 actions, including activation of the portal glucose sensor in the control of glucose homeostasis (Balkan et al, 1999;Knauf et al, 2005;Preitner et al, 2004). Activation of the portal glucose sensor depends on the absorption of glucose from the gut, triggering of glucose sensitive cells located in the enteric/hepatoportal area.…”

Section: Introductionmentioning

confidence: 99%

GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

Cani

Holst²,

Drucker

et al. 2007

Molecular and Cellular Endocrinology

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Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) are incretins secreted in response to oral glucose ingestion by intestinal L and K cells, respectively. The molecular mechanisms responsible for intestinal cell glucose sensing are unknown but could be related to those described for β-cells, brain and hepatoportal sensors.We determined the role of GLUT2, GLP-1 or GIP receptors in glucose-induced incretins secretion, in the corresponding knockout mice. GLP-1 secretion was reduced in all mutant mice, while GIP secretion did not require GLUT2. Intestinal GLP-1 content was reduced only in GIP and GLUT2 receptors knockout mice suggesting that this impairment could contribute to the phenotype. Intestinal GIP content was similar in all mice studied. Furthermore, the impaired incretins secretion was associated with a reduced glucose-stimulated insulin secretion and an impaired glucose tolerance in all mice. In conclusion, both incretin secretion depends on mechanisms involving their own receptors and GLP-1 further requires GLUT2.

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Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Cited by 116 publications

References 52 publications

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion

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