imd-0354 and Diabetes-Mellitus--Type-2

Previous studies supported a role of hypothalamic inflammation in fine ambient particulate matter (PM2.5) exposure-mediated diabetes development. We therefore investigated the effects of PM2.5 exposure on insulin resistance and the disorders of hepatic glucose and lipid metabolism via hypothalamic inflammation. KKAy mice, a genetically susceptible model of type II diabetes mellitus, were administered intra-cerebroventricularly with IKK2 inhibitor (IMD-0354) and were exposed to either concentrated PM2.5 or filtered air (FA) for 4 weeks simultaneously via a versatile aerosol concentration exposure system. At the end of the exposure, fasting blood glucose and serum insulin were evaluated before epididymal adipose tissue and liver were collected, flow cytometry, quantitative PCR and Western blot were performed at euthanasia. We observed that intracerebroventricular administration of IMD-0354 attenuated insulin resistance, inhibited macrophage polarization to M1 phenotype in epididymal adipose tissue in response to PM2.5 exposure. Although the treatment did not affect hepatic inflammation or endoplasmic reticulum stress, it inhibited the expression of the enzymes for gluconeogenesis and lipogenesis in the liver. Therefore, our current finding indicates an important role of hypothalamic inflammation in PM2.5 exposure-mediated hepatic glucose and lipid metabolism disorder.

Topics: Adipose Tissue; Air Pollutants; Air Pollution; Animals; Benzamides; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Hypothalamus; I-kappa B Kinase; Inflammation; Injections, Intraventricular; Lipid Metabolism; Liver; Mice, Inbred Strains; Particulate Matter

Epidemiological studies have found that individuals with diabetes mellitus (DM) display an increased susceptibility for adverse cardiovascular outcomes when exposed to air pollution. This study was conducted to explore the potential mechanism linking ambient fine particles (PM2.5) and heart injury in a Type 2 DM (T2DM) animal model. The KKay mouse, an animal model of T2DM, was exposed to concentrated ambient PM2.5 or filtered air for 8 weeks via a versatile aerosol exposure and concentrator system. Simultaneously, an inhibitor of IκB kinase-2 (IKK-â) (IMD-0354), which is a blocker of nuclear factor κB (NF-κB) nuclear translocation, was administrated by intracerebroventricular injection (ICV) to regulate the NF-êB pathway. The results showed that ambient PM2.5 induced the increase of, NF-êB, cyclooxygenase-2 (COX-2) and mitogen activated protein kinase (MAPK) expression in cardiac tissue, and that IMD-0354 could alleviate the inflammatory injury. The results suggested that the NF-êB pathway plays an important role in mediating the PM2.5-induced cardiovascular injury in the T2DM model. Inhibiting NFκB may be a therapeutic option in air-pollution-exacerbated cardiovascular injury in diabetes mellitus.

Topics: Air Pollutants; Animals; Benzamides; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Gene Expression Regulation; Heart Diseases; I-kappa B Kinase; Inflammasomes; Mice; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Particulate Matter

Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development.. KKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4-8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4-5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest.. PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5.. Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Benzamides; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Hypothalamus; I-kappa B Kinase; Inflammation; Infliximab; Inhalation Exposure; Injections, Intraventricular; Insulin; Insulin Resistance; Interleukin-6; Mice; Oxygen Consumption; Particulate Matter; Protein Kinase Inhibitors; Risk Assessment; RNA, Messenger; Thermogenesis; Time Factors; Tumor Necrosis Factor-alpha