Gastric Inhibitory Peptide Controls Adipose Insulin Sensitivity via Activation of cAMP-response Element-binding Protein and p110β Isoform of Phosphatidylinositol 3-Kinase

Mohammad, Sameer; Ramos, Lavoisier; Buck, Jochen; Levin, Lonny R.; Rubino, Francesco; McGraw, Timothy E.

doi:10.1074/jbc.m111.289009

Cited by 49 publications

(40 citation statements)

References 74 publications

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“…In both b-INS-1 cells and adipocytes, GIP stimulation was shown to increase CREB phosphorylation (39,40). Here we found that stimulation with GIP increases CREB phosphorylation in ECs but not in VSMCs, as assessed by Western blotting ( Fig.…”

Section: Creb Rather Than Nfat Mediates Gip-induced Opn Expressionsupporting

confidence: 50%

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

et al. 2015

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Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a “vascular disease–like” phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

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Section: Creb Rather Than Nfat Mediates Gip-induced Opn Expressionsupporting

confidence: 50%

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

et al. 2015

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“…acutely increases the insulin sensitivity of adipocytes (9). In those studies, we used insulin-stimulated translocation of GLUT4 to the plasma membrane of adipocytes as a measure of insulin action.…”

Section: Fig 5 Enhanced Desensitization Of E354q Gipr Is Due To Impaimentioning

confidence: 99%

“…4 and 6) impair GIPR control of insulin sensitivity. In previous studies, we have shown that GIP acutely sensitizes adipocytes to insulin, as measured by insulin-stimulated translocation of GLUT4 to the plasma membrane (9). Insulin-stimulated translocation of GLUT4 to the plasma membrane of adipocytes and muscle cells is a key mechanism underlying the disposal of dietary glucose and is a convenient quantitative functional measure of insulin action.…”

Section: Fig 5 Enhanced Desensitization Of E354q Gipr Is Due To Impaimentioning

confidence: 99%

“…A primary function of these hormones is to stimulate glucose-dependent insulin release from pancreatic beta cells (3)(4)(5). In addition to its effect on the pancreas, GIP functions to regulate several aspects of adipocyte metabolism, including increasing the sensitivity of adipocytes to insulin, thereby setting the tone for an optimal insulin response (e.g., see references [6][7][8][9][10][11][12][13]. GIP signals through the GIP receptor (GIPR), a Gprotein-coupled receptor (GPCR) coupled to the stimulatory G alpha subunit and elevated cyclic AMP (cAMP) levels (4,14,15).…”

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confidence: 99%

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A Naturally Occurring GIP Receptor Variant Undergoes Enhanced Agonist-Induced Desensitization, Which Impairs GIP Control of Adipose Insulin Sensitivity

Mohammad

Patel

Bruno

et al. 2014

Molecular and Cellular Biology

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101

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dGlucose-dependent insulinotropic polypeptide (GIP), an incretin hormone secreted from gastrointestinal K cells in response to food intake, has an important role in the control of whole-body metabolism. GIP signals through activation of the GIP receptor (GIPR), a G-protein-coupled receptor (GPCR). Dysregulation of this pathway has been implicated in the development of metabolic disease. Here we demonstrate that GIPR is constitutively trafficked between the plasma membrane and intracellular compartments of both GIP-stimulated and unstimulated adipocytes. GIP induces a downregulation of plasma membrane GIPR by slowing GIPR recycling without affecting internalization kinetics. This transient reduction in the expression of GIPR in the plasma membrane correlates with desensitization to the effects of GIP. A naturally occurring variant of GIPR (E354Q) associated with an increased incidence of insulin resistance, type 2 diabetes, and cardiovascular disease in humans responds to GIP stimulation with an exaggerated downregulation from the plasma membrane and a delayed recovery of GIP sensitivity following cessation of GIP stimulation. This perturbation in the desensitization-resensitization cycle of the GIPR variant, revealed in studies of cultured adipocytes, may contribute to the link of the E354Q variant to metabolic disease. G lucose-dependent insulinotropic polypeptide (GIP) is secreted by K cells of the gastrointestinal tract in response to food (1, 2). GIP together with the other incretin hormone, glucagon-like peptide 1, have prominent roles in the control of wholebody energy metabolism. A primary function of these hormones is to stimulate glucose-dependent insulin release from pancreatic beta cells (3-5). In addition to its effect on the pancreas, GIP functions to regulate several aspects of adipocyte metabolism, including increasing the sensitivity of adipocytes to insulin, thereby setting the tone for an optimal insulin response (e.g., see references 6-13). GIP signals through the GIP receptor (GIPR), a Gprotein-coupled receptor (GPCR) coupled to the stimulatory G alpha subunit and elevated cyclic AMP (cAMP) levels (4,14,15).In individuals with type 2 diabetes mellitus (T2DM), GIP-mediated insulinotropic effects are attenuated despite normal to elevated levels of blood . This GIP resistance potentially contributes to the pathophysiology of T2DM. The importance of GIP function in metabolic homeostasis is highlighted by the discovery in genome-wide association studies of a number of single nucleotide polymorphisms in the GIPR gene linked to an increased risk of metabolic diseases, including insulin resistance, T2DM, and cardiovascular diseases (19-21). One of these variants results in the substitution of glutamine for glutamic acid at position 354 (E354Q) of GIPR, which has been shown in various studies to be associated with insulin resistance (22), cardiovascular disease (21), and defects in beta-cell function (23).Despite extensive characterization of GIP's effects on metabolism, little is known about the beha...

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“…In vitro costimulation of adipocytes with insulin and GIP elicits GLUT-4 (the insulin-sensitive glucose transporter) translocation to the membrane, demonstrating that GIP can enhance insulin sensitivity in adipose tissue (60). Moreover, in rat adipocytes, GLP-1 increased insulin-stimulated 2-DG uptake and triggered rises in glycogen synthesis and oxidation (72).…”

Section: G647mentioning

confidence: 99%

Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

Fournel

Marlin

Abot

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases.glucosensing; glucose homeostasis; diabetes GLUCOSE REPRESENTS ONE of the major sources of energy circulating throughout the body. The tight and continuous control of glycemia in the face of fluctuations in glucose absorption, storage, and production is crucial for all living organisms. Not surprisingly, the gastrointestinal tract constitutes the first anatomic site for the detection of nutrients, including glucose. Glucose detection involves specialized cells referred to as glucosensors (21,44,64). These cells, which are present in the oral cavity as well as the small intestine, pancreas, and portal vein, express various glucose transporters and G proteincoupled receptors (GPCRs) implicated in the physiological response to glucosensing (21,44,64). Glucosensing by these cells evokes complex neural and endocrine responses that control glucose metabolism. Moreover, glucose detection in the gastrointestinal tract also transmits afferent nervous impulses to the brain, which, in turn, controls peripheral glucose utilization. Indeed, the brain, specifically the hypothalamus, is a key player in the regulation of glucosensing mechanisms. In addition to receiving information via the gut-brain axis, the hypothalamus also contains glucosensitive cells able to detect glucose (91). Upon the integration of these messages, the hypothalamus sends specific signals to the tissues involved in glucose metabolism via the autonomous nervous system (ANS).Metabolic disorders such as type 2 diabetes (T2D) are considered as ...

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Gastric Inhibitory Peptide Controls Adipose Insulin Sensitivity via Activation of cAMP-response Element-binding Protein and p110β Isoform of Phosphatidylinositol 3-Kinase

Cited by 49 publications

References 74 publications

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

A Naturally Occurring GIP Receptor Variant Undergoes Enhanced Agonist-Induced Desensitization, Which Impairs GIP Control of Adipose Insulin Sensitivity

Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

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