A randomised trial examining inflammatory signaling in acutely induced hyperinsulinemia and hyperlipidemia in normal weight women-the reprometabolic syndrome

Abstract

Context Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin. Objective To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction. Design, setting, participants Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center. Intervention Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained. Main outcome measures Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions. Results Except for Macrophage Inflammatory Protein-1β (MIP-1β), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested. Conclusion Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.

A randomized clinical trial demonstrating cell type specific effects of hyperlipidemia and hyperinsulinemia on pituitary function

“…However, cortisol, was also unaffected by infusion conditions, suggesting adrenal axis was not impacted by lipid/insulin infusions and did not contribute to the observed difference in TSH levels. TSH has also been shown to also be downregulated by inflammatory cytokines [ 20 ] but we previously demonstrated that the acute infusion of insulin and lipid did not significantly impact levels of inflammatory cytokines in this study [ 14 ].…”

“…Adipocytokine response to lipid and insulin was investigated as described [ 14 ]. Leptin and high molecular weight adiponectin were measured in serum pooled from 12 participants (between 180 and 230 min during steady state levels of insulin and free fatty acids) in both saline and insulin/lipid infusions.…”

Severe hyperglycemia and insulin resistance in patients with SARS-CoV-2 infection: a report of two cases

“…When evaluated in the setting of obesity-related insulin resistance, high doses of insulin may be pro-inflammatory. In both obese mice and humans, hyperinsulinemia results in elevated adipose tissue cytokine levels [ 22 – 25 ], while this does not occur in healthy, non-obese and non-insulin resistant patients [ 26 ]. In contrast, many studies have demonstrated that insulin treatment in the setting of sepsis is anti-inflammatory.…”

Obesity-Related Hypogonadism in Women

“…In addition, peak gonadotropin levels were blunted following GnRH stimulation, indicating reduced pituitary sensitivity (peak LH and peak FSH were ∼12 IU/L and 22 IU/L in the lipid/infusion group vs 16 IU/L and 14 IU/L in saline groups) ( 113 ). The same protocol did not alter proinflammatory cytokine levels ( 114 ) or other pituitary hormone levels such as TSH, prolactin, and or cortisol ( 115 ), suggesting an effect specific to gonadotropins.…”