Metabolic Syndrome and Acute Hyperglycemia Are Associated With Endoplasmic Reticulum Stress in Human Mononuclear Cells

Abstract

Endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) have been implicated in a number of complications associated with diabetes mellitus including micro‐ and macrovascular dysfunction. In this study we examine ER stress levels in blood cells isolated from human subjects with metabolic syndrome and in healthy controls. Total RNA and protein were isolated from leukocytes and the levels of specific ER stress markers were quantified by real‐time‐PCR and immunoblot analysis. Our results indicate that, compared to healthy controls, individuals with metabolic syndrome have elevated mRNA levels of genes indicative of ER stress; including spliced XBP‐1 (sXBP‐1), Grp78, and CHOP. Induced ER stress levels correlate with blood glucose but not plasma lipid concentration. Furthermore, in healthy individuals, a standard 75 g oral glucose challenge produced a significant elevation in spliced XBP‐1 (1.3 fold), Grp78 (2.0 fold), and calreticulin (3.5 fold) mRNA 60 min post challenge and a significant increase in Grp78 (2.0 fold), calreticulin (2.7 fold) protein levels 2 h postchallenge, relative to fasting levels. The UPR was also activated ex vivo, in human leukocytes cultured in the presence of 15 mmol/l glucose, supporting a specific role for glucose. The oral glucose challenge was associated with a significant increase in the expression of inflammatory cytokines, including interleukin (IL)‐1α/β, IL‐6, and IL‐8, that may result from ER stress. These findings suggest that there is an association between both acute and chronic dysglycemia and ER stress in humans.

(−)-Epicatechin mitigates high-fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress

“…Several pathogenic phenotypes of MetS, including inflammatory cytokines [62], hyperglycemia [63, 64]; obesity [36], high cholesterol [65], high fatty acids [62, 66] trigger ER stress in different cells and tissues. Importantly, markers of increased ER stress are observed in human mononuclear cells from MetS patients [64], and in adipose tissue from obese and insulin resistant individuals [67], which improve after weight loss [68]. Notably, chemical chaperones that relieve ER stress in liver cells, increase systemic insulin sensitivity and reduce fatty liver disease in obese mice [69].…”

Interleukin-1 signaling contributes to acute islet compensation

“…Conversely, IL-1β potentiates glucose-stimulated insulin secretion by almost 2-fold in islets from obese donors, indicating an obesity-associated sensitization of islets to the stimulatory effects of IL-1β. IL-1β levels are elevated in obese patients (60,61); are increased following acute, postprandial hyperglycemia (42); and are upregulated in islets following a 4-day exposure to high glucose or free fatty acids (4,45). A sensitization to the insulinotropic effects of this cytokine may represent a compensatory mechanism to metabolic stress.…”

“…IL-1β transcript expression in peripheral leukocytes (42). Metabolic stress also induces upregulation of IL-1β, with an elevation of the IL-1β target gene, inducible nitric oxide synthase, observed as early as 3 days in white adipose tissue from high fat diet-fed (HFD-fed) mice (40).…”

“…Inflammation is induced rapidly upon exposure to metabolic stress (40), with several reports observing postprandial elevations in inflammatory markers (41)(42)(43)(44). Acute hyperglycemia has been shown to increase IL-1β is a well-established inducer of both insulin resistance and impaired pancreatic islet function.…”

Stress-tolerance tests and postprandial low-grade inflammation response

“…The oral glucose challenge has been associated with a significant increase in the expression of proinflammatory cytokines, including interleukin IL-1α/β, IL-6, and IL-8 which may result from endoplasmic reticulum stress (29).…”