Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Kahles, Florian; Meyer, Christina; Diebold, Sandra S.; Foldenauer, Ann Christina; Stöhr, Robert; Möllmann, Julia; Lebherz, Corinna; Findeisen, Hannes M.; Lehrke, Michael

doi:10.1111/dom.12711

Cited by 18 publications

(12 citation statements)

References 15 publications

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“…We then focused on the possible involvement of enhanced inflammation in the adipose tissues of Lep ob/ob mice, as pro-inflammatory conditions in fat tissues were previously reported to contribute to insulin resistance and perturbation of glucose metabolism in Lep ob/ob mice [25,34]. Notably, in accord with our present study, the previous literature found that LPS induced GIP secretion [35]. They also showed that IL-1 signaling is required for the GIP secretion by LPS using IL-1R knockout mice.…”

Section: Discussionsupporting

confidence: 79%

Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms

Lee

Miedzybrodzka

Zhang

et al. 2019

IJMS

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As glucose-dependent insulinotropic polypeptide (GIP) possesses pro-adipogenic action, the suppression of the GIP hypersecretion seen in obesity might represent a novel therapeutic approach to the treatment of obesity. However, the mechanism of GIP hypersecretion remains largely unknown. In the present study, we investigated GIP secretion in two mouse models of obesity: High-fat diet-induced obese (DIO) mice and leptin-deficient Lepob/ob mice. In DIO mice, plasma GIP was increased along with an increase in GIP mRNA expression in the lower small intestine. Despite the robust alteration in the gut microbiome in DIO mice, co-administration of maltose and the α-glucosidase inhibitor (α-GI) miglitol induced the microbiome-mediated suppression of GIP secretion. The plasma GIP levels of Lepob/ob mice were also elevated and were suppressed by fat transplantation. The GIP mRNA expression in fat tissue was not increased in Lepob/ob mice, while the expression of an interleukin-1 receptor antagonist (IL-1Ra) was increased. Fat transplantation suppressed the expression of IL-1Ra. The plasma IL-1Ra levels were positively correlated with the plasma GIP levels. Accordingly, although circulating GIP levels are increased in both DIO and Lepob/ob mice, the underlying mechanisms differ, and the anti-obesity actions of α-GIs and leptin sensitizers may be mediated partly by the suppression of GIP secretion.

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Section: Discussionsupporting

confidence: 79%

Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms

Lee

Miedzybrodzka

Zhang

et al. 2019

IJMS

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“…Numerous studies have been reported an increase of GLP-1 secretion in human IBD patients and systemic plasma cytokines impact on intestinal hormone secretion. Many studies have shown that inflammatory cytokines accelerate GLP-1 secretion, while GIP secretion is stimulated with LPS and these secretions are mediated by the IL-1β-dependent pathway, but not IL-6 and TNFα [41]. Inflammatory stimuli are well known to be involved in intestinal hormone release, and we also observed high concentrations of plasma incretins as well as PYY (data not shown) in a GI-inflamed mouse model using DSS administration.…”

Section: Discussionsupporting

confidence: 47%

GI inflammation Increases Sodium-Glucose Cotransporter Sglt1

Park

Lee

Kim

et al. 2019

IJMS

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A correlation between gastrointestinal (GI) inflammation and gut hormones has reported that inflammatory stimuli including bacterial endotoxins, lipopolysaccharides (LPS), TNFα, IL-1β, and IL-6 induces high levels of incretin hormone leading to glucose dysregulation. Although incretin hormones are immediately secreted in response to environmental stimuli, such as nutrients, cytokines, and LPS, but studies of glucose-induced incretin secretion in an inflamed state are limited. We hypothesized that GI inflammatory conditions induce over-stimulated incretin secretion via an increase of glucose-sensing receptors. To confirm our hypothesis, we observed the alteration of glucose-induced incretin secretion and glucose-sensing receptors in a GI inflammatory mouse model, and we treated a conditioned media (Mϕ 30%) containing inflammatory cytokines in intestinal epithelium cells and enteroendocrine L-like NCI-H716 cells. In GI-inflamed mice, we observed that over-stimulated incretin secretion and insulin release in response to glucose and sodium glucose cotransporter (Sglt1) was increased. Incubation with Mϕ 30% increases Sglt1 and induces glucose-induced GLP-1 secretion with increasing intracellular calcium influx. Phloridzin, an sglt1 inhibitor, inhibits glucose-induced GLP-1 secretion, ERK activation, and calcium influx. These findings suggest that the abnormalities of incretin secretion leading to metabolic disturbances in GI inflammatory disease by an increase of Sglt1.

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“…Furthermore under physiological conditions GIP is secreted by intestinal K-cells [1] mainly following food intake. Since recent work demonstrated that GIP secretion can also be induced by inflammatory stimuli like IL-1, IL-6, and LPS independent from food intake [17] , [18] , we questioned whether the increase in GIP in our patient cohort was linked to inflammatory markers. However, we were unable to detect a significant association between GIP levels and the inflammatory markers CRP and WBC ( Supplemental Table 1 ), making this an unlikely explanation.…”

Section: Discussionmentioning

confidence: 98%

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation

Kahles

Liberman

Halim

et al. 2018

Molecular Metabolism

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ObjectiveThe incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease.Methods and resultsSerum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1–42) in ApoE−/− mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages.ConclusionElevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

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Glucose‐dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin‐1‐dependent manner in mice

Cited by 18 publications

References 15 publications

Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms

Diet-Induced Obese Mice and Leptin-Deficient Lepob/ob Mice Exhibit Increased Circulating GIP Levels Produced by Different Mechanisms

GI inflammation Increases Sodium-Glucose Cotransporter Sglt1

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE−/− mice by blocking monocyte/macrophage activation

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