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Abstract

Glucose-dependent insulinotropic polypeptide (GIP) has pleiotropic actions on pancreatic endocrine function, adipose tissue lipid metabolism, and skeletal calcium metabolism. Recent data indicate a potential new role for GIP in the pathogenesis of cardiovascular disease. This review focuses on the emerging literature that highlights GIP’s role in inflammation—an established process in the initiation and progression of atherosclerosis. In vasculature tissue, GIP may reduce concentrations of circulating inflammatory cytokines, attenuate vascular endothelial inflammation, and directly limit atherosclerotic vascular damage. Important to recognize is that evidence exists to support both pro- and anti-inflammatory effects of GIP even within the same tissue/cell type. Therefore, future study designs must account for factors such as model heterogeneity, physiological relevance of doses/exposures, potential indirect effects on inflammatory pathways, and the glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist form. Elucidating the specific effects of enhanced GIP signaling in vascular inflammation and atherosclerosis is crucial given the existing widespread use of DPP4 inhibitors and the emergence of dual-incretin receptor agonists for type 2 diabetes treatment.

Keywords

glucose-dependent insulinotropic polypeptide cytokine vascular atherosclerosis adipose

Introduction

Glucose-dependent insulinotropic polypeptide (GIP) is a 42 amino acid peptide secreted by K-cells located in the proximal intestinal mucosa. GIP is an established potentiator of insulin secretion and exerts additional insulin-like and non–insulin-like actions across multiple tissues. Beyond islet activity, GIP directly regulates adipose tissue lipid and skeletal calcium metabolism and has cytoprotective and cellular proliferation actions in multiple cell types.¹ Although circulating GIP concentrations are maintained relatively high in the fasted state, GIP concentrations become elevated up to 10-fold following macronutrient ingestion and remain above fasted levels throughout much of the postprandial period.² Furthermore, the circulating half-life of GIP is approximately 5 min, comparable to that of insulin, while the GIP receptor (GIPR) is widely expressed across peripheral and central tissues and organs.³ Hence, GIP has significant cellular signaling activity and can exert considerable influence on whole-body physiology via conventional endocrine mechanisms.

Before the last decade, GIP remained understudied and overshadowed by interest in glucagon-like peptide-1 (GLP-1), its co-contributor in the incretin effect. The GLP-1 receptor (GLP1R) is an established pharmacologic target for blood glucose lowering in type 2 diabetes and, more recently, energy intake reduction in obesity.⁴ In contrast, no currently approved agent solely targets the GIPR: dipeptidyl peptidase 4 (DPP4) inhibitors exert their glucose lowering effects by increasing concentrations of both active GLP-1 and GIP in the circulation. Nevertheless, the GIPR is targeted in the promising new class of incretin receptor co-agonist molecules currently in clinical trials: these simultaneously target both the GLP1R and the GIPR.⁵

GIP has emerged as a broad metabolic signaling molecule with an array of important actions.¹ Among these, data on GIP’s regulation of inflammatory responses in vascular cells combined with an emerging clinical literature describing associations between circulating GIP and cardiovascular disease risk are of importance. The GIPR is expressed on circulating immune cells and throughout the circulatory system including on vascular endothelial cells and cardiac tissues.^6,7 An SNP in the GIPR (rs10423928) was found to be associated with stroke risk,⁸ and a recent prospective epidemiological study showed that higher fasting plasma GIP was associated with greater cardiovascular mortality.⁹ Additional new findings indicate that GIP signaling in cardiovascular tissues impacts: (1) cardiac tissue remodeling; (2) arterial endothelial damage in atherosclerosis models; and (3) release of inflammatory cytokines.^8,10,11

DPP4 inhibitors are an orally administered class of anti-diabetic drugs that inhibit endogenous DPP4 activity and thereby reduce the deactivation of both GIP and GLP-1 to increase active postprandial concentrations of both by up to 3-fold.^12,13 Cardiovascular outcomes from a safety standpoint were assessed in five DPP-4 inhibitor trials, and no trials found an improvement in cardiovascular outcomes.^14–17 However, use of the DPP4 inhibitors saxagliptin and alogliptin was associated with an increased risk for incident heart failure in two independent trials.^14–17 The specific effects of DPP4 inhibition on vascular tissue is unclear.^18–20 Given that DPP4 inhibitors affect not only GIP but also GLP-1 (and potentially a large array of additional peptides that are substrates for DPP4), it is not possible to attribute the cardiovascular effects of DPP4 inhibition to any one of its targets.

Given the overlap in intracellular signaling pathways stimulated, GLP-1-based pharmaceuticals may offer some insight into the potential vascular actions of GIP. Numerous clinical trials have evaluated cardiovascular outcomes in diabetes patients treated with glucagon-like peptide-1 receptor agonists (GLP1RA). Reduced myocardial infarction incidence and death from cardiovascular events were reported in patients treated with GLP1RA.^21–27 Although still at an early stage, trials on dual-incretin receptor agonists do not currently suggest any changes in cardiovascular outcomes.²⁸ Studies in animal models have shown that GLP-1RA can reduce plaque size, prevent vascular remodeling, and limit atherosclerosis development in animal models.^29–37 These effects of GLP1RA may be independent of body weight and cholesterol lowering and may be due to direct effects on plaque stability and inflammation.^34–37

Although GLP-1 has received most attention, a number of studies now offer evidence for a direct role of GIP signaling in vascular disease. When combined, these studies span cellular, animal, clinical, and epidemiological investigations and will be the focus of this review. In particular, an attempt is made to synthesize and contextualize emerging findings on the tissue-specific actions of GIP on inflammation. English language literature was identified in Medline using PubMed searches undertaken between 3 May 2021 and 12 August 2021.

GIPR agonism and inflammatory responses

Overview

GIP is a 42-amino acid peptide secreted by intestinal enteroendocrine cells in response to luminal macronutrients. GIP was initially identified for its role in gastric acid secretion but was later established as an important incretin peptide, and therefore, a key driver of postprandial insulin secretion.¹ Physiological roles beyond those of insulinotropic and intestinal actions became apparent in the early 2000s, demonstrated in part by findings that showed GIPR expression across multiple diverse tissue types.¹² GIP is currently recognized as an important and complex endocrine signal linking nutrient intake with whole-body homeostasis. The GIPR is a G-protein-coupled receptor, and the GIPR signal is relayed intracellularly by cAMP signaling cascades.⁴

All available studies reporting direct effects of GIPR agonism in inflammation in vivo and in vitro are presented and are summarized in Table 1. Data from 31 model systems/experiments (including 2 human studies) described in 20 distinct publications are shown. Of these, 19 studied GIP signaling in adipose tissue or adipocyte cell lines. Although the majority (i.e., 13 of 19, 68%) of the adipose tissue studies found that GIPR agonism promoted proinflammatory cytokine or chemokine release from adipose tissue, evidence for an anti-inflammatory effect is also present in the literature (6 experiments reported across 4 publications). Similarly, 6 of the 12 remaining studies on non-adipose cells/tissues reported a proinflammatory cytokine or chemokine response to GIPR agonism. The results of these studies are reviewed in detail in this section.

Table 1.

Studies reporting direct effects of GIPR agonism on inflammatory cytokine and chemokine production.

Study		Model/tissue/cell	GIP exposure	Effects on tissue inflammation	Pathway/mechanism
Nagashima et al. (2011)	In vitro	Human aortic endothelial cells	5nmol/L GIP(1–42)	Anti-inflammatory. ↓MCP-1(CCL2), ↓VCAM-1, ↓ICAM-1, ↓PAI-1	• Down-regulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase 1
Szalowska et al. (2011)	In vivo	C57BL/6 male mice (normal diet)	0.12 mg/g [D-Ala2] GIP	Anti-inflammatory in adipose. ↓IL-6, ↓TNFα, ↓IL-1β. No effect on cytokines in serum	• Upregulation of APO and cytochrome P450 gene families
Kim et al. (2012)	In vivo	Male GIP over-expressing transgenic mice crossed with c57BL/6 females fed a high fat diet.	Endogenous GIP overexpression induced by oral ZnSO4 exposure. Resulting in 83.5X serum GIP under high-fat feeding	Anti-inflammatory in adipose. ↓ACE, ↓G6PD2, ↓MCP-1(CCL2), ↓IK-κB, ↓IL-4RA, ↓TNFrsF1B, ↓PAI-1	• Reduced macrophage ingress into adipose tissue
Nie et al. (2012)	In vitro	Mouse adipocyte cell line (3T3-L1 CAR) with GIPR overexpression	10 nM GIP(1–42)	Proinflammatory. ↑IL-6, ↑TNFα, ↑MCP-1(CCL2), ↑MCP-2, ↑MCP-3	• Phosphorylation of IK-κB via activation of cAMP-PKA pathway. • Activation of JNK pathway
Omar et al. (2012)	In vitro In vitro	Primary murine adipocytes 3T3-L1 adipocytes	1,10,20 nM GIP(1–42) 1,10,20 nM GIP(1–42)	Proinflammatory. ↑OPN ↑OPN	• NFAT • cAMP/PDE3B
Ben-Shlomo et al. (2013)	Ex vivo	Adipose tissue explants from rats and non-obese humans	100 nM GIP(1–42)	Anti-inflammatory. ↓TNFα, ↓PAI-1, ↑ADPN
	In vivo	High fat fed rats(F344/jcl)	20 μg/kg/day i.p. GIP(1–42)	↑ADPN
Ahlqvist et al. (2013)	In vitro	Primary rat adipocytes incubated in high glucose concentrations	0.1→100 nM GIP(1–42)	Proinflammatory. ↑OPN
Timper et al. (2013)	In vitro	Differentiated human preadipocyte-derived adipocytes	1nM GIP(1–42)	Proinflammatory. ↑IL-6, ↑IL-1β, ↑IL1Ra, --TNFα, --IL-8, --MCP-1(CCL2)	• PKA and IK-κB/NF-κB pathway activation
Varol et al. (2014)	In vivo Ex vivo	C57BL/6 male mice (high fat fed).Human mesenteric adipose tissue explant	0.12 µg/g [D-Ala2] GIP100 nM [D-Ala2] GIP	Anti-inflammatory in adipose. ↓CCL2 (MCP1), ↓CCL8, ↓CCL5, ↓IL-6, ↓IL-1β, ↓TNFα, ↓IFNγ, ↓OPN, ↑ADPN, ↑RETN.Anti-inflammatory in adipose. ↓IL-6, ↓IL-1β, ↓CCL8	• ↓ingress of macrophages, neutrophils, T-cell subtypes into adipose tissue. • ↓circulating proinflammatory monocytes & neutrophils
Gögebakan et al. (2015)	In vivo	Human subjects (obese) under eu/hyper-glycemic clamp	2pmol/kg/min GIP(1–42)	Proinflammatory in adipose. ↑MCP-1 (CCL2), ↑MCP-1 in plasma, ↑MCP-2, ↑IL-6, ↑CD68	• Macrophage recruitment into adipose
	In vitro In vitro	Primary human macrophages co-cultured with human adipocytes 3T3L1-adipocytes co-cultured with RAW 264.7 macrophages	100 nmol/L GIP(1–42)100 nmol/L GIP(1–42)	↑MCP-1 (CCL2)↑MCP-1 (CCL2)
Chen et al. (2015)	In vivo In vitro In vitro	Male db/db mice3T3-L1 adipocytes3T3-L1 adipocytes cultured with RAW264 macrophages	10 nmol/kg GIP(1–42) i.p.10 or 100 nM GIP(1–42)100 nM GIP(1–42)	Proinflammatory in adipose tissue. ↑MCP-1 (CCL2), ↑IL-6. –IL-1β, --TNFα.↑MCP-1 (CCL2), ↑IL-6.↑IL-6, ↑PAI-1, ↓ADPN.	• Macrophage recruitment into adipose. • Hypoxia inducible factor (HIF)-1α dependent pathway
Suzuki et al. (2016)	In vitro	Human monocyte cell line (THP-1)	10-7 −10-9 mol/L GIP(1–42)	Anti-inflammatory. ↓TNFα, ↓iNOS, ↓IL-1α, ↓IL-1β. (in presence of LPS)	• cAMP, PKA activation
Berglund et al. (2016)	Ex vivo In vivo In vitro	Intact mouse aorta cultureHealthy humans under hyperglycemic clampHuman microvascular endothelial cells & mouse aortic vascular smooth muscle cells	10-7 −10-14 mol/L GIP(1–42)240pmol/kg/hr i.v. GIP(1–42) in hyperglycemic clamp10-7 −10-14 mol/L GIP(1–42)	Proinflammatory. ↑OPN↑OPN in plasmaNo effect	• CREB and endothelin-1 not mediated by traditional cAMP-PKA pathway
Timper et al. (2016)	Ex vivo In vivo	Human and mouse pancreatic islets in culture.C57BL/6N mi	100 nmol/L GIP(1–42)70pmol/g GIP bolus	Proinflammatory. ↑IL-1β, ↑IL-6↑IL-6 in plasma	• cAMP, PKA activation • SGLT2
Joo et al. (2017)	In vitro	3T3-L1 adipocytes with DPP4 inhibitor	100 nmol/L GIP(1–42)	Proinflammatory. ↑IL-6, ↑SOCS3 (particularly in presence of TNFα)	• Active TNFα signaling
Mori et al. (2018)	In vivo	C57BL/6 & db/db male mice subject to femoral artery wire injury	50 nmol/kg/d GIP(1–42)	No effect on vascular inflammation. --IL-1β, --IL-6, --MCP-1, --TNFα, --OPN.
Kahles et al. (2018)	In vivo In vitro	C57BL/6 ApoE-/- male mice on a high fat/obesogenic dietMurine macrophages activated with LPS	Viral overexpression of GIP(1–42) in vivo10 nM GIP(1–42) 0.01, 0.1, 1 nM GIP(1–42)	Anti-inflammatory. ↓CCL5, ↓IFN-γ, ↓IL-12 in liver↓MMP-9, ↓IL-6	• Reduced NFkB activation, • Reduced phosphorylation of JNK, ERK, p38 (MAPK pathway)
Shah et al. (2018)	In vivo	C57BL/6J mice exposed to bacterial endotoxin	4pmol/kg/min GIP(1–42)	Anti-inflammatory in circulation. ↓IL-6, --IL-1β, --TNFα (antagonism of GIPR resulted in increased IL-6, IL-1β,TNFα)
Beaudry et al. (2019)	In vitro	Immortalized brown adipose tissue cell line	100 nM [D-Ala2] GIP	Proinflammatory in adipose. ↑IL-6, ↑IL-5
Fu et al. (2020)	In vivo	C57BL/6J male mice	30pmol bolus GIP(1-42) ICV, 60pmol [D-Ala2]-GIP i.p., and 300pmol GIP(1–42) i.p.	Proinflammatory in hypothalamus. ↑IL-1β, ↑IL-6, ↑TNFα	• Phosphorylation of IκB-kinaseβ. • EPAC signaling

Abbreviations: GIP(1–42): the normal endogenous “native” and unmodified form of glucose-dependent insulinotropic polypeptide; [D-Ala2] GIP: a GIP receptor agonist which has similar cAMP stimulating properties with greater resistance to DPP4 degradation versus native GIP; MCP-1: monocyte chemoattractant protein-1 also CCL2; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule-1; PAI-1: Plasminogen activator inhibitor-1; CD36: cluster of differentiation 36; IL-6: interleukin-6; TNFα: tumor necrosis factor alpha; IL-1 β: interleukin 1 beta; ACE: angiotensin converting enzyme; G6PD2: Glucose-6-phosphate 1-dehydrogenase; IK-κB: inhibitor of nuclear factor kappa B kinase subunit beta; NFκB: nuclear factor kappa B; IL-4RA: interleukin-4 Receptor Subunit Alpha; TNFrsF1B: TNF Receptor Superfamily Member 1B; MCP-2: monocyte chemoattractant protein-2, MCP3: monocyte chemoattractant protein-3; OPN: osteopontin; ADPN: adiponectin; cAMP-PKA: cyclic AMP-phosphokinase A pathway; JNK: c-Jun N-terminal kinases; NFAT: Nuclear factor of activated T-cells; IL-1RA: interleukin-1 receptor antagonist; IL-8: interleukin-8; CCL5: C-C Motif Chemokine Ligand 5; CCL8: C-C Motif Chemokine Ligand 8; INFγ: interferon gamma; RETN: resistin; CD68: cluster of differentiation 68-monocyte/macrophage marker; LPS: lipopolysaccharide; iNOS: inducible nitric oxide synthase; IL-1α: interleukin-1 alpha; CREB: cAMP-response element binding protein; SGLT: sodium-glucose linked transporter; SOCS3: Suppressor of cytokine signaling 3; IL-12: interleukin-12; MMP-9: matrix metallopeptidase 9; ERK: also known as protein kinase B (PKB); MAPK: mitogen activated protein kinase; IL-5: interleukin-5; EPAC: exchange protein activated by cAMP; ICV: intracerebroventricular; i.p.: intraperitoneal.

Adipose tissue studies

Adipose tissue inflammation is an established component of the metabolic dysregulation that accompanies obesity, insulin resistance, and chronic metabolic disease. Several in vitro studies offer evidence for a proinflammatory effect of GIP signaling in adipose tissue, but a smaller number of studies report the reverse effect and are important to describe. The earliest evidence for an anti-inflammatory role of GIP in adipose tissue was demonstrated in vivo in normal chow-fed mice using the DPP4-resistant and long-lasting GIP analog D-Ala²-GIP.³⁸ Szalowska et al. found reduced mRNA expression of the proinflammatory genes interluekin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1 β) in the white adipose tissue of mice fed a normal chow diet but not in mice fed a high fat diet, they did not detect any effect on serum cytokines in either normal diet or high fat-fed mice. Importantly, all mice administered D-Ala²-GIP at the (very high) study dose of 0.12 mg/kg/day (24 nM/kg/d) lost significantly more weight than the control mice: this loss of body weight may have contributed to the relatively small anti-inflammatory effect reported. Similarly, Kim et al.³⁹ reported reduced expression of number of proinflammatory pathway genes and less macrophage ingress into the adipose tissue of GIP overexpressing transgenic mice with circulating GIP concentrations 80 times those of wild type mice. The GIP overexpressing mice also had less weight gain and lower fat masses compared to the wild-type mice. Ben-Shlomo et al. also reported an adipose tissue phenotype consistent with an anti-inflammatory effect of GIP in rat and human adipose explants exposed to a high concentration (100 nM) of GIP(1–42) for 24 h⁴⁰ Of note, the cytokine effect was only observed in the vascular stromal fraction cells of the adipose explants while an increase in adiponectin expression was replicated in vivo in rats given 10 μg/kg GIP(1–42) injections twice daily. Stronger evidence for an anti-inflammatory effect of GIPR agonism in adipose is given by Varol et al.⁴¹ They showed a large reduction in inflammatory cytokine (incl. Il-6, IL-1β, TNF α) and chemokine expression in adipose along with reductions in both plasma and adipose tissue proinflammatory macrophages/monocytes and neutrophils in high fat-fed mice receiving a daily i.p. dose of 0.12 μg/g of D-Ala²-GIP. The GIP treated mice did not differ from controls in body weight or fat mass at the end of the study. Varol et al. further substantiated these in vivo findings by showing reductions in IL-6 and IL-1β in human mesenteric adipose tissue explants exposed to 100 nM of D-Ala²-GIP for 24 h. Although these putative anti-inflammatory effects of GIP in adipose tissue have been reported in both in vivo and ex vivo experiments, very large doses of either native GIP or D-Ala²-GIP were used.^39–41 In addition, interpretation of anti-inflammatory findings in two of the in vivo rodent experiments is complicated as most studies also reported weight loss or lesser weight gain as a result of the GIP treatment: GIP-induced weight loss may have resulted in reduced inflammation rather than any direct effects of GIP signaling on immunoregulation per se.^38,39

As indicated previously, the majority of studies report a proinflammatory action of GIP on adipose tissue. Four independent studies exposed the mouse adipocyte cell line 3T3-LI to concentrations of GIP(1–42) ranging from 1 to 100 nM and all reported a proinflammatory effect with 3 reporting increased IL-6 release into culture medium,^42–44 and one reporting increased osteopontin (OPN) release in 3T3-LI cells and also in primary murine adipocytes.⁴⁵ Nie et al. demonstrated that exposure of the 3T3-L1 mouse adipocyte cell line with adenovirus-mediated GIPR overexpression to 10 nM concentrations of unmodified GIP peptide (GIP1-42) elicits a significant increase in gene expression of proinflammatory cytokines IL-6, TNF-α, and monocyte chemoattractant proteins (MCP).⁴² GIP exposure increased inhibitor of nuclear factor kappa B kinase subunit beta (IKκB) phosphorylation, consistent with nuclear factor kappa B (NFκB) pathway activation which is involved in proinflammatory cytokine production. In addition, the adipocytes had activation of the jun N-terminal kinase (JNK) pathway which is part of the cellular response to cytokines. Omar et al. showed that an overnight incubation of primary rat adipocytes with GIP at concentrations of 1 nM GIP(1–42) increased expression of the proinflammatory protein osteopontin (OPN) but not at 0.1 nM GIP. This effect was replicated in 3T3-LI with a GIP concentration of 100 nM. No dose response effect was observed with concentrations of 1 nM to 10 nM GIP exposure. In agreement with Nie et al., two additional studies showed that GIP(1–42) stimulated IL-6 gene expression and protein production in 3T3-L1 adipocytes at 10 nM concentrations,^43,44 with one study also demonstrating an increase in the expression of the chemoattractant MCP-1.⁴³ Beaudry et al. also showed an increase in IL-6 and IL-5 through exposure to 100 nM D-Ala²-GIP in brown adipose cell line.⁴⁶ Largely consistent with these findings, Timper et al. showed an increase in proinflammatory IL-6, IL-1β, and IL1Ra mRNA expression with an order of magnitude lower GIP(1–42) exposure (1 nM) in human pre-adipocyte derived adipocytes in culture.⁴⁷ Interestingly, TNF-α and MCP-1 were not increased at this more physiological GIP concertation. Evidence for activation of IkκB and NFκB as the mechanism for GIP’s pro-inflammatory effect were also reported in this study. In line with a pro-inflammatory action of GIP, Ahlqvist et al. also reported a dose-dependent increase in the expression of OPN in primary rat adipocytes exposed to GIP(1–42) at concentrations as low as 0.1 nM in the presence of glucose(5 mM) and insulin(1 nM).⁴⁸

Clinical support for GIP’s proinflammatory effects on adipose was published by Gögebakan et al. in which an acute GIP(1–42) infusion of 2pmol/kg/min was designed to generate normal physiological postprandial GIP concentrations for 240 min in obese adults. The infusion was shown to result in higher IL-6, MCP-1, and MCP-2 mRNA expression in subsequent adipose tissue biopsy samples along with increased circulating plasma MCP-1.⁴⁹ Moreover, a higher CD68 expression indicated increased adipose macrophage ingress after GIP exposure. Increased MCP-1 mRNA transcript expression in human and mouse adipocyte and macrophage co-cultures after GIP exposure (100 nmol/L), an effect not observed in the single, isolated cell cultures, was also reported. When combined, these data are consistent with an intriguing role for GIP in providing a link between overnutrition (i.e., higher dietary energy intakes and higher GIP secretion and exposure) and the well-established phenomenon of increased macrophage infiltration into adipose tissue that drives inflammation in obesity.⁴⁹ Further in vivo evidence for the proinflammatory effect of GIP was given by Chen et al. who showed that i.p. GIP(1–42) injection (10 nmol/kg) in the db/db mice (leptin receptor defect diabetes model) resulted in increased macrophage ingress into adipose tissue and an increase in the expression of MCP-1 and IL-6 but not TNF-α and IL-1β.⁴³ These findings were further substantiated by showing that cocultures of 3T3-L1 adipocytes and macrophages exposed to 100 nM GIP(1–42) had increased IL-6 production.⁴³

Two studies, (see Table 2), employed GIPR knockout specifically inside adipose tissue and are also consistent with a proinflammatory role for GIP in adipose tissue.^44,46 Of note, Joo et al. demonstrated that loss-of-function of the GIPR in white adipose resulted in a reduction in adipose IL-6 expression and circulating IL-6 concentrations in mice: a reduction in suppressor of cytokine signaling-3 (SOCS3) was also reported in these mice. In contrast, Beaudry et al. found no cytokine or chemokine alteration in brown adipose with specific GIPR knockout. Bone marrow GIPR loss-of-function and its concomitant inflammatory effects on adipose have been evaluated in two studies.^50,51 Both studies found that bone marrow specific GIPR knockout resulted in increased adipose inflammation with one study concluding that GIP signaling in white adipose promotes normal type 2 immunity, appropriately regulating immune system activity within the tissue. Suzuki et al. found that whole body GIPR knockout mice had less gingival tissue inflammation in an experimental periodontitis model.⁵²

Table 2.

Studies reporting direct effects of GIP loss-of-function on inflammatory cytokine and chemokine production.

Study	Model	Effects of GIP signal loss on tissue inflammation	Pathway/mechanism
Efimova et al. (2021)	Male C57BL6/6J OlaHsd with bone marrow GIPR knockout fed a high fat diet.	Proinflammatory in white adipose. ↓IL-33, ↑IL-10, ↓MetEnk, ↑ATM in WAT, ↓Eosinophils	Increased S100A8/A9
Beaudry et al. (2019)	Male C57BL6/6J with brown adipose tissue GIPR knockout fed a high fat diet.siRNA mediated knockdown of GIPR in brown adipose	Anti-inflammatory in brown adipose in vitro only. --IL-6, --IL-5, --IL-12 --TNFα, --CCL2(MCP-1), -- NF-κB.↓IL-6, ↓IL-5, ↓TNFα, ↓CCL2(MCP-1), ↓c-Jun
Mantelmacher et al. (2019)	Male C57BL/6JOlaHsd mice irradiated with subsequent reconstitution of bone marrow with GIPR KO mouse bone marrow to generate bone marrow specific GIPR-/- mice fed a high fat diet.	Proinflammatory in white adipose & hepatic tissue. ↑CCL2(MCP1), ↑CXCL1, ↑CXCL2, --IL-6, --IL-1β	Increased S100A8/A9
Suzuki et al. (2016)	GIPR knockout mice with ligature-induced experimental periodontitis	Proinflammatory in gingival tissues. ↑macrophage infiltration, ↑TNFα, ↑iNOS.
Joo et al. (2017)	Adipose tissue specific GIPR knockout mice fed a high fat diet	Anti-inflammatory in white adipose and liver tissues.↓IL-6(also in blood), ↓SOCS3, --TNFα, --MCP-1(CCL2), --IL-1β, --ADPN.

Abbreviations. IL-33: interleukin 33; IL-10: interleukin-10; Met-Enk: Met-enkephalin; IL-12: interleukin-12; IL-5: interleukin-5, IL-6: interleukin-6; ATM: adipose tissue macrophages; IK-κB: inhibitor of nuclear factor kappa B kinase subunit beta; NFκB: nuclear factor kappa B; MCP: monocyte chemoattractant protein; CXCL: C-X-C Motif Chemokine Ligand; JNK: c-Jun N-terminal kinases; TNFα: tumor necrosis factor alpha; iNOS: inducible nitric oxide synthase; SOCS3: suppressor of cytokine signaling 3; IL-1β: interleukin 1 beta; ADPN: adiponectin.

GIPR agonism and inflammation in vascular and immune cells

Nagashima et al. were the first to perform in vitro studies of GIPR agonism on immune responses in vascular cells.⁵³ They showed evidence for an anti-inflammatory effect on human aortic endothelial cells at a GIP(1–42) concentration of 5 nmol/L (2 h exposure) with reduced mRNA expression of the important pro-atherosclerotic and thrombotic molecules MCP-1, vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and plasminogen-activator inhibitor 1(PAI-1). In contrast, Berglund et al. found evidence (ex vivo and in vivo) for a proinflammatory effect of GIP(1–42) on OPN protein expression in mouse aortal tissues in culture and in the plasma of healthy human volunteers following acute GIP(1–42) infusion under hyperglycemic (and hyperinsulinemic) conditions.⁸ Furthermore, they reported evidence for increased GIPR and OPN mRNA in carotid artery tissues from patients with stroke and transient ischemic heart attacks. They also showed that levels of these transcripts were positively correlated with characteristics of unstable and inflammatory plaques including with cytokines IL-1β, IL-6, IL-10, and with CD68(macrophage marker), MCP-1, platelet-derived growth factor, and interferon-gamma (INF-γ). No inflammatory effect of GIP was found on human microvascular or mouse aortic smooth muscle cells in vitro.⁸ Mori et al. found no effect of chronic GIP(1–42) infusion on arterial cell expression of cytokines (IL-1β, IL-6, and TNF-α) and chemokines (MCP-1) or OPN in vivo in two femoral artery wire injury mouse models, despite reporting beneficial arterial remodeling effects of GIP in the mice.¹¹ Beyond the previously mentioned adipocyte-macrophage co-culture experiments,^43,49 two studies assessed GIP’s direct effects on immune cells. Suzuki et al. reported an anti-inflammatory effect (incl. reduced IL-1β and TNFα) of GIP(1–42) exposure in a human monocyte cell line stimulated with lipopolysaccharide.⁵² These findings were consistent with those of another study that used a murine macrophage cell line in which concentrations of GIP(1–42) as low as 0.01 nM potently reduced IL-6 production.⁵⁴

GIPR agonism and inflammation in other tissues and cells

Human and mouse pancreatic islets exposed to 100 nmol/L GIP(1–42) exhibit a proinflammatory response (increased IL-1β and IL-6), whilst in the same study, mice given a 70pmol/kg bolus of GIP(1–42) responded with an increase in circulating IL-6.⁴⁷ In contrast, Shah et al. found that a GIP(1–42) infusion blunted the circulating IL-6 response to bacterial endotoxin in C57BL/6J mice in vivo: an effect which was reversed through use of a GIPR antagonist.⁵⁵ In line with these findings, overexpression of GIP in ApoE knockout mice, the most widely used murine model for atherosclerosis, generates an anti-inflammatory phenotype (reduced chemokine ligand 5, INF-γ, and IL-12) in liver tissue and reduced plaque macrophage ingress and therefore lesser plaque inflammation in vivo without altering body weight or glucose tolerance.⁵⁴ A recent study provides evidence for a proinflammatory effect of brain GIP signaling where intracerebroventricular GIP and D-Ala²GIP were reported to increase hypothalamic concentrations of IL-6, IL-1β, and TNFα in mice.⁵⁶

GIP and macrophage activity

Monocytes have a central role in atherosclerotic lesion progression. Inside vessel walls, monocytes differentiate into macrophages and ingest lipoproteins to form foam cells whose release of proinflammatory cytokines, chemokines, and reactive oxygen species promote localized plaque inflammation.⁵⁷ The GIPR is expressed on the vascular endothelium and on multiple immune cell types including human and murine monocytes.^8,49,53,58 Higher GIPR mRNA expression was found in biopsied carotid artery plaques from patients with stroke or ischemic heart attack vs. asymptomatic patients, while both GIPR and OPN expression in the plaques were correlated with the extent of lipid build-up and macrophage infiltration.⁸

A 4-week chronic infusion of GIP was shown to reduce the ingression of macrophages and resultant foam cell formation in atherosclerotic lesions of APOE knockout mice in vivo resulting in smaller plaque and lesion sizes: an effect that was reversed with co-infusion of the GIPR antagonist.⁵³ Similar findings were reported by the same group in diabetic APOE knockout where chronic GIP infusion (25 nmol/kg/day) led to a 50% reduction in foam cell formation within lesions: the effect was reversed through use of a GIPR antagonist.⁵⁹ A GIP overexpression study replicated these findings by showing that GIP significantly reduced the macrophage content of atherosclerotic plaques in APOE knockout mice.⁵⁴ In addition, as described previously, in vitro experiments in this study also suggested that GIP reduces MCP-1-induced monocyte migration into plaques and hence, prevents proinflammatory macrophage activation and reduce IL-6 release.⁵⁴ While not finding any effects on monocyte/macrophages or inflammatory cytokine/chemokine responses, Mori et al. showed that chronic GIP administration dose dependently reduced neointimal hyperplasia in an artery wire injury mouse model promoting favorable endothelial recovery.¹¹ Together, these finding suggest an important role for GIP in minimizing vascular damage during the development of atherosclerosis.

The effects of GIP on adipose tissue macrophages in vivo were evaluated in several studies.^{39,41,43,49-51,58} Two studies found that very high GIP doses reduced macrophage infiltration^39,41 and inflammatory T-cell population⁴¹ ingression into murine adipose tissues. In line with these findings, GIPR gene specific removal from the bone marrow of mice with the subsequent absence of a functional GIPR in immune cells led to dysregulated immune activity in visceral fat depots including reduced expression of anti-inflammatory cytokines.⁵⁰ In the same model under high fat feeding, the absence of immune cell GIP signaling led to myelopoiesis in the blood and adipose tissue together with increased proinflammatory chemokine expression and an increase in the proinflammatory molecule alarmin S100A8.⁵¹ When combined, these findings suggest an anti-inflammatory role for GIP in immune cell population regulation and phenotype presentation, albeit under considerable non-physiological conditions of very higher GIP exposure or GIPR loss-of-function.

In contrast, two studies have shown that acute infusions of GIP to generate more physiologically appropriate elevations have the reverse effect. An acute continuous GIP infusion in human subjects resulted in increased adipose CD68 expression and higher circulating concentrations of MCP-1 (in keeping with the greater macrophage content of adipose) in otherwise healthy obese male subjects.⁴⁹ Consistent results were also found in db/db mice where an acute 10 nmol/kg GIP dose increased plasma MCP-1 and increased macrophage ingression into adipose tissue.⁴³ Gögenbaken et al. also showed that co-cultures of macrophage and adipocyte cell lines exposed to GIP had increased MCP-1 expression: this effect seemed to be driven by the macrophage cells.⁴⁹ In keeping with these findings and in contrast to the other bone marrow GIPR knockout studies described above,^50,51 another bone marrow GIPR knockout study showed evidence for increased circulating proinflammatory monocytes and decreased anti-inflammatory monocytes in response to high fat feeding⁵⁸: all consistent with an anti-inflammatory effect of GIP signaling.

Observational studies on GIP and inflammation and CVD

Data from human observational studies conducted in European populations show positive associations between circulating GIP and both circulating inflammatory markers and cardiovascular morbidity. Nitz et al. reported early evidence for an association between the GIPR polymorphism rs2291726 and CVD in the EPIC-Potsdam cohort.⁶⁰ Berglund et al. also report an increased risk of stroke among type 2 diabetes patients who carried the A allele of the GIPR SNP rs10423928.⁸ A study undertaken in Poland found that higher fasting concentrations of GIP are associated with a proinflammatory plasma profile (elevated IL-6, MCP-1, sVCAM-1, and sE-Selectin) along with an altered inflammatory gene expression profile in circulating blood cells in obese humans.⁶¹ An analysis of the large Finnish PPP-Botnia Study found that fasted GIP was associated with incident CVD and cardiovascular mortality over 8.8 yrs of follow-up with an additional Mendelian Randomization analysis finding evidence for a relationship between higher GIP and both coronary artery disease and myocardial infarction.⁹ Berglund et al. also showed that fasting GIP concentrations were higher among patients with a history of cardiovascular disease compared to controls,⁸ while higher circulating GIP was also observed among patients with peripheral artery disease.⁵⁴ In line with this, findings from an elderly population in Sweden indicated that fasting GIP concentrations are positively associated with increased intima-media thickness in the common carotid artery, and therefore, indicative of a relationship between GIP and subclinical atherosclerosis (the reverse was reported for GLP1).⁹ The aforementioned observational studies do not enable a determination on whether GIP promotes the pathogenesis and progression of vascular disease or whether, as suggested by some,⁵⁴ GIP release is upregulated in a protective role during vascular disease development. Prospective studies will be required to determine the role of GIP in the natural history of cardiovascular disease.

Discussion

The existing data are equivocal on the effect of GIP on inflammation in most tissue types, including in vascular tissues. Whether GIP exerts a proinflammatory or anti-inflammatory action is likely to be tissue-dependent and may vary according to the metabolic state (e.g., insulin resistance, hyperglycemia, and overnutrition) or the atherosclerosis stage of an individual. Several factors that potentially explain the discrepancies between studies are as follows: (1) non-physiologic GIP doses; (2) challenges in the interpretation of in vivo studies due to the multiple actions of GIP; and (3) potential for different inflammatory effects in different tissue types. These factors are discussed in detail below along with potential pathways leading from GIPR stimulation to inflammatory effects. An overview of the effects are given in Figure 1.

Figure 1.

Putative roles of GIP signaling in adipose and vascular tissue inflammation.

Non-physiologic GIP exposure

In vitro studies using very high GIP(1–42) concentrations of 100 nM and/or similarly high doses of very long-lasting GIP analogs such as D-Ala²-GIP may generate effects beyond what would be likely in normal physiology or even under typical pharmaceutical stimulation in vivo.⁴ A more systematic approach will be crucial in future studies: a clearer translation of normal endogenous GIP exposure to in vitro and in vivo experiments will be important including perhaps the use of species-appropriate forms of the endogenous peptide. Furthermore, some^43,48,52,54 but not all studies show a dose–response trend for a pro- or anti-inflammatory effect of GIP in vitro and, largely in keeping with the other literature, half found a proinflammatory^43,48 while half an anti-inflammatory^52,54 effect of GIP. Only a few of the studies reviewed employed GIPR antagonism to verify the GIP effects^53,55,59 and more clarity could be generated with the inclusion of an antagonist arm in future studies: care should be taken in the choice of antagonist according to species and model system under study.⁶²

Interpretation of GIP actions in vivo

A clearer understanding of the inflammatory actions of GIP in vivo are necessary. Given the broad tissue distribution of the GIP receptor, GIP signaling elicits significant effects on whole-body physiology. Therefore, the interpretation of GIP’s tissue inflammation effects should be undertaken within this broader signaling context. Unfortunately, the available loss-of-function studies do not help to clarify the direction of the inflammatory action of GIP signaling in vascular or in adipose tissue in vivo. There is potential for a compensation to occur and subsequently confound interpretation in loss-of-function/gene knockout studies: there is evidence for a compensatory effect in incretin receptor knockout mice and, in the case of GIPR knockout, GLP-1 signaling activity is shown to be upregulated in response to loss of the GIPR in mice.⁴ In vivo studies using GIPR agonism or antagonism are also complicated as GIP’s actions on whole body energy balance, lipid metabolism, and glucose metabolism make interpretation of direct inflammatory effects difficult. The effects of GIP on body weight regulation are particularly important when interpreting its actions on inflammation at the whole organism level. As described above, GIPR agonists in vivo may reduce inflammation secondary to body weight/fat mass reduction and not through any direct effect of GIP signaling. Robust designs with usage of experimental methods such as pair-feeding may help to overcome these limitations.

Adipose tissue studies

Despite the inconsistency in the available data, some clarity can be derived for effects on adipose tissue. Approximately two-thirds (68%) of the experiments (in vitro, ex vivo, in vivo murine, and clinical) support a proinflammatory cytokine/chemokine releasing and proinflammatory macrophage infiltration role for GIP in adipose tissue or adipocyte cells. Moreover, the only human study to investigate GIP’s role in adipose inflammation found clear evidence for a proinflammatory effect when insulin and glucose were infused to generate elevated concentrations of each. Therefore, in the postprandial state when glucose and insulin concentrations are elevated, GIP signaling in adipose tissue is likely to be proinflammatory.⁴⁹ Increased circulating OPN concentrations, suggesting increased inflammation, were also reported in human subjects under acute GIP infusion.⁸ Although four of the murine in vivo studies reviewed found GIP to be anti-inflammatory in adipose tissue, two used D-Ala²-GIP^38,41 while the third was a GIP overexpression study that resulted in concentrations more than 80-fold of normal.³⁹ The other study showed an effect of GIP to increase adipose adiponectin expression only and did not measure other biomarkers of inflammation.⁴⁰ Hence, when taken together, the available evidence offers relatively strong support for a proinflammatory effect of GIP signaling in adipose tissue. Therefore, a role for GIP as an intermediary signal linking overnutrition and subsequent obesity to adipose tissue inflammation is an attractive hypothesis and is favored by the current evidence.

Vascular tissue studies

A very limited number of studies have assessed the role of GIP in vascular endothelial inflammation and their results are equivocal.^8,11,53 In vitro studies indicate both proinflammatory and anti-inflammatory effects of GIP in aortic cells: one study that looked at human aortic endothelial cells found GIP to be both anti-inflammatory and anti-atherogenic⁵³ while the other found GIP to increase OPN in intact mouse aorta samples ex vivo. Mori et al. found no changes in vascular tissue expression of inflammatory cytokines in vivo after 7 days of GIP in a wire injury mouse model of atherosclerosis.¹¹ Given the small number of studies, it is impossible to determine a clear role for GIP in vascular cell inflammation.

Nevertheless, studies of GIP’s effects on circulating inflammatory molecules and on atherosclerosis development in vivo do provide some clarity. The majority of these studies report data consistent with reduced circulating inflammatory markers under exogenous GIP stimulation.^41,55 Furthermore, several studies support a protective effect of GIP in suppressing macrophage-driven lesions, reducing or stabilizing atherosclerotic plaque development, and lessening arterial remodeling in vivo in both wire damage and apolipoprotein E knockout models of atherosclerosis.^11,53,54,59 GIPR agonism was also shown to reduce macrophage conversion to foam cells ex vivo⁶³ and may have a blood pressure lowering effect.⁶⁴ Therefore, the weight of evidence favors a vasculoprotective role of GIP signaling and is consistent with an anti-inflammatory role for GIP in the vasculature.

In summary, the available evidence suggests that GIP exerts a proinflammatory effect on adipose tissue. In contrast, GIP may reduce concentrations of circulating inflammatory cytokines and endothelial inflammation and plays a protective role in atherosclerotic vascular damage. As described above, model heterogeneity, different study design, and type of GIPR agonist/antagonist may contribute to the considerable inconsistency in the available data. Moreover, the inconsistency in the direction of this influence may depend on the timepoint or stage of disease progression at which exogenous GIP is introduced. This putative temporal component of GIP’s effects will be important to evaluate and necessitates detailed in vivo evaluations using the appropriate translational models.

Mechanisms

Although largely preliminary, several of the studies outlined in Table 1 reported evidence for molecular pathways that may underlie GIP’s effects on inflammatory cytokine or chemokine production. As would be hypothesized, adipocyte studies showing a proinflammatory effect of GIP indicate that the NFκB-IKκB is involved in GIP-induced cytokine expression^42,47 as did a study showing a proinflammatory effect of GIP in the hypothalamus of mice.⁵⁶ Importantly, GIP also seems to regulate OPN production.^8,45,48 Evidence indicates that OPN regulates the synthesis of extracellular matrix and influences the proliferation and migration of endothelial and vascular smooth muscle cells during remodeling vascular remodeling.⁶⁵ OPN may be an important mediator of GIP’s effects on vascular and adipose tissues.

Implications for the use of incretin receptor co-agonists

The use of GIPR and GLP1R co-agonist drugs (e.g., Tirzepatide) is currently under active investigation in the type 2 diabetes therapeutic area.⁵ Initial rodent studies revealed that stimulation of both incretin receptors led to greater than expected improvements in blood glucose and body weight.⁶⁶ Subsequent studies have strongly replicated the synergistic effects of combined GIPR and GLP1R agonism on glucose metabolism and body weight.¹ It is important to recognize that the effects of the co-agonism are consistent with those of GLP1R agonism, but the body weight lowering effect would not have been predicted based on the known metabolic effects of GIPR agonism. Hence, it is likely that the metabolic effects of GIP are not completely understood and, as highlighted above, it is important to evaluate the effects of GIP in the context of other metabolic signals.

The effects of incretin receptor co-agonism on inflammation are not known at present. GLP1 has established effects on immunity and has been shown to reduce inflammation in vivo.⁶⁷ At least some of these effects are likely to be attributable to the weight loss associated with chronic GLP-1 therapy.¹ The effect of simultaneous activation of both the GLP1R and GIPR on inflammation has not been studied. Given that GLP1R agonism has been shown to promote both anti-inflammatory and general anti-atherogenic effects on vascular tissues, co-activation of both the GIPR and GLP1R may complement any potential anti-inflammatory effect of GIPR signaling in the vasculature.^1,68 Moreover, the potential pro-inflammatory effects of GIPR signaling in adipose may be attenuated or offset in the presence of increased GLP1 signaling with the sue of co-agonists. An evaluation of the inflammatory actions of these peptides should be undertaken

Conclusion

GIP is likely to play a role in the pathophysiology of atherosclerosis and heart disease. GIP’s effects on inflammatory pathways are likely to contribute to this effect, but emerging data also suggest a role for GIP in tissue remodeling. In the vasculature, GIP may reduce concentrations of circulating inflammatory cytokines, attenuate vascular endothelial inflammation, and directly limit atherosclerotic vascular damage. A better understanding of the specific effects of enhanced GIP signaling in vascular inflammation and atherosclerosis will be crucial given the widespread use of DPP4 inhibitors and the emergence of dual-incretin receptor agonists for type 2 diabetes treatment.

Footnotes

Acknowledgments

The author acknowledges the support of Dr. Rengui Liu and Dr. Shaobo Wang, of the First Affiliated Hospital of Dali University, in the preparation of this manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Xiaoming He

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Regul Pept 2013; 183: 54–61.

Glucose-dependent insulinotropic polypeptide and tissue inflammation: Implications for atherogenic cardiovascular disease

Abstract

Keywords

Introduction

GIPR agonism and inflammatory responses

Overview

Adipose tissue studies

GIPR agonism and inflammation in vascular and immune cells

GIPR agonism and inflammation in other tissues and cells

GIP and macrophage activity

Observational studies on GIP and inflammation and CVD

Discussion

Non-physiologic GIP exposure

Interpretation of GIP actions in vivo

Adipose tissue studies

Vascular tissue studies

Mechanisms

Implications for the use of incretin receptor co-agonists

Conclusion

Footnotes

Acknowledgments

Declaration of conflicting interests

Funding

ORCID iD

References