Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat

Abstract

Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell (EC) production of superoxide and a simultaneous reduction in the availability of the vasoprotective signaling radical NO. We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to IGF-1 (insulin-like growth factor-1)–mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in ECs in vivo. Methods and Results: We generated mice expressing mIGF-1Rs (mouse IGF-1 receptors), which form nonfunctioning hybrid receptors with native IRs (insulin receptors) and IGF-1R, directed to ECs under control of the Tie2 promoter-enhancer. Despite EC insulin and IGF-1 resistance, mIGFREO (mutant IGF-1R EC overexpressing) mice had enhanced insulin and IGF-1–mediated systemic glucose disposal, lower fasting free fatty acids, and triglycerides. In hyperinsulinemic-euglycemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased Nox (NADPH oxidase)-4 expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO ECs generated increased hydrogen peroxide (H 2 O 2 ), with no increase in superoxide. Treatment with catalase—a H 2 O 2 dismutase—restored insulin tolerance to WT (wild type) levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favorable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H 2 O 2 generation mediating enhanced whole-body insulin sensitivity.

Paracrine Role of the Endothelium in Metabolic Homeostasis in Health and Nutrient Excess

“…Among various regulatory factors reviewed here, NO, PGI 2 , PGE 2 , PDGF-CC, and the yet-to-be-identified PPARγ-activating lipid, share great therapeutic potential to upregulate energy expenditure by increasing adipocyte beiging, enhancing AT insulin sensitivity, and alleviating undesirable AT inflammation. Our recent report also suggested that endothelial-derived ROS plays a role in enhancing whole-body (including BAT) insulin sensitivity in response to short-term overnutrition ( 167 ). However, diseased upregulation of endothelial-derived ET-1, ROS, heparanse and pro-inflammatory mediators can bring detrimental metabolic and inflammatory outcomes by upregulating lipolysis and inducing insulin resistance.…”

“…In patients with obesity, higher levels of H 2 O 2 were determined in visceral AT and were suggested to correlate with insulin resistance ( 165 ) as a result of upregulated endothelial release of H 2 O 2 . In diet-induced obese mice, endothelial extracellular H 2 O 2 production is upregulated ( 166 ), predominantly by NOX4, and is suggested to mediate glucose disposal in BAT ( 167 ). We recently reported that endothelial insulin and IGF-1 signaling governs endothelial production of miR-25 which suppresses NOX4 expression ( 167 ).…”

“…In diet-induced obese mice, endothelial extracellular H 2 O 2 production is upregulated ( 166 ), predominantly by NOX4, and is suggested to mediate glucose disposal in BAT ( 167 ). We recently reported that endothelial insulin and IGF-1 signaling governs endothelial production of miR-25 which suppresses NOX4 expression ( 167 ). Endothelial-specific expression of mutant IGF-1R receptors which form non-functioning hybrid receptors with insulin receptors and IGF-1R improved insulin-stimulated glucose uptake in brown AT and muscle in mice, in a H 2 O 2 –dependent manner ( 167 ).…”

“…We recently reported that endothelial insulin and IGF-1 signaling governs endothelial production of miR-25 which suppresses NOX4 expression ( 167 ). Endothelial-specific expression of mutant IGF-1R receptors which form non-functioning hybrid receptors with insulin receptors and IGF-1R improved insulin-stimulated glucose uptake in brown AT and muscle in mice, in a H 2 O 2 –dependent manner ( 167 ). Our findings suggest that blunted endothelial NOX4 activity and subsequent blunted endothelial production of H 2 O 2 may contribute to impaired brown adipocyte glucose uptake and development of insulin-resistance in obesity ( 167 ).…”

Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction

“…Nox4 activity has also been shown to be increased in the serum of patients with type 2 diabetes mellitus [ 141 ]. More recently, however, in a unique murine model of EC insulin resistance with whole body insulin sensitivity, we demonstrated reduced EC expression of Nox2 and miR-25, but increased expression of Nox4 and an associated increased production of H 2 O 2 [ 142 ]. Furthermore, transgenic mice with endothelial targeted overexpression of NOX4 had increased H 2 O 2 production and H 2 O 2 -induced hyperpolarization (without affecting endothelial NO bioactivity) within their coronary microvascular ECs, resulting in significantly greater acetylcholine- or histamine-induced vasodilatation compared to their wild type littermates [ 143 ].…”