Acute effects of hyperinsulinemia and hyperglycemia on vascular inflammatory biomarkers and endothelial function in overweight and obese humans

Abstract

We investigated the separate and combined effects of hyperglycemia and hyperinsulinemia on markers of endothelial function, proinflammatory and proatherothrombotic responses in overweight/obese nondiabetic humans. Twenty-two individuals (13 F/9 M, BMI 30.1 ± 4.1 kg/m(2)) were studied during four randomized, single-blind protocols. The pancreatic clamp technique was combined with 4-h glucose clamps consisting of either 1) euinsulinemia-euglycemia, 2) euinsulinemia-hyperglycemia, 3) hyperinsulinemia-hyperglycemia, or 4) hyperinsulinemia-euglycemia. Insulin levels were higher (998 ± 66 vs. 194 ± 22 pmol/l) during hyperinsulinemia compared with euinsulinemia. Glucose levels were 11.1 mmol/l during hyperinsulinemia compared with 5.1 ± 0.1 mmol/l during euglycemia. VCAM, ICAM, P-selectin, E-selectin, IL-6, adiponectin, and PAI-1 responses were all increased (P < 0.01-0.0001), and endothelial function was decreased (P < 0.0005) during euinsulinemia-hyperglycemia compared with other protocols. Hyperinsulinemia in the presence of hyperglycemia prevented the increase in proinflammatory and proatherothrombotic markers while also normalizing vascular endothelial function. We conclude that 4 h of moderate hyperglycemia can result in increases of proinflammatory markers (ICAM, VCAM, IL-6, E-selectin), platelet activation (P-selectin), reduced fibrinolytic balance (increased PAI-1), and disordered endothelial function in a group of obese and overweight individuals. Hyperinsulinemia prevents the actions of moderate hyperglycemia to reduce endothelial function and increase proinflammatory and proatherothrombotic markers.

Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells

“…We conclude that in ASCs cultured in 17.5 mM glucose, a large set of IR genes is not expressed but harbors promoters and enhancers marked by hPTMs suggestive of potential for transcriptional activation; thus, these genes lie in chromatin environment permissive for expression. This is consistent with the immuno-regulatory properties of cells in adipose tissue [22] and with their response to metabolic changes, such as development of insulin resistance [23]. This condition results in hyperglycemia and cellular exposure to excess glucose, leading to an inflammatory response.…”

Clinical Update: Cardiovascular Disease in Diabetes Mellitus

“…In vitro studies and in vivo models in which hyperglycemia is induced in the absence of elevated lipids are consistent with a direct effect of hyperglycemia on endothelial dysfunction, 42,43 atherosclerotic lesion severity and complexity, 44 and plaque burden. 23 A commonly used pre-clinical diabetes model involves streptozotocin-treatment, 45,46 which is toxic to pancreatic β-cells, in an atherosclerosis-prone animal such as an LDL-receptor or apo-E deficient mouse.…”

“…Acute hyperglycemia can attenuate endothelial function and reduce nitric oxide (NO) bioavailability 51 while increasing endothelial cell leukocyte adhesion, 43,52 mediated in part by increased oxidative stress and inflammation. Increased flux through the aldose reductase pathway, 53 synthesis of diacylglycerol with protein kinase C activation, 54 and production of advanced glycation end (AGE) products contribute to activation of endothelial cell receptor for AGEs.…”

Comparative effects of acute hypoglycemia and hyperglycemia on pro-atherothrombotic biomarkers and endothelial function in non-diabetic humans

“…Moderate hyperglycemia or hypoglycemia have been demonstrated to acutely induce a wide spectrum of pro-inflammatory, pro-atherothrombotic and pro-coagulant responses in healthy and diabetic individuals (4, 5, 16, 39, 40, 42). Additionally, both stresses can result in reductions in brachial artery flow mediated dilation.…”