Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

Abstract

Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.

Nonglycemic effects of incretins in patients with long-term type 1 diabetes mellitus and chronic kidney disease

“…В исследовании K. Timper и соавт. [39] отмечено увеличение ИР на фоне длительного воз-действия ГИП на адипоциты. Таким образом, ГИП об-ладает непосредственной стимулирующей активностью в отношении процессов системного воспаления и ИР в адипоцитах человека.…”

“…Не определено влияние ГИП на продукцию провоспалительных цитоки-нов и развитие системного воспаления. Имеются данные о потенцировании ГИП процессов, лежащих в основе развития ожирения и инсулинорезистентности (ИР), у пациентов с исходно высоким индексом массы тела (ИМТ) [11]. В основном работы по изучению инкретинов и их эф-фектов проводятся на моделях СД 2-го типа (СД-2).…”

The Role of Insulin and Incretins in Neuroinflammation and Neurodegeneration

“…However in the periphery, GIP acts as a pro-inflammatory mediator and induces the secretion of IL-6 and IL-1β from adipose tissue [5] . Infusions of GIPR agonists in apolipoprotein E deficient (apoE -/-) mice inhibited monocyte/macrophage infiltration into aortic walls [66] ; thus, GIP may inhibit monocyte/macrophage infiltration into the CNS in a similar fashion.…”

“…Insulin normalizes rising blood glucose levels by signaling to the liver, muscle and adipose cells to take up glucose and store it as glycogen, making insulin and incretins vital to the maintenance of energy homeostasis within the body [1][2][3] . In addition to their metabolic roles, insulin, GLP-1 and GIP have all shown to behave as inflammatory signaling molecules in the peripheral tissues [4][5][6] . Insulin negatively regulates nuclear factor kappa B (NFκB) in monocytes, thereby exhibiting its anti-inflammatory actions [7] .…”

“…GIP acts as a pro-inflammatory mediator by inducing the secretion of interleukin (IL)-6 and IL-1β from adipose tissue [5] , while GLP-1 reduces macrophage infiltration into adipose tissue in obese mice and directly…”