Context: Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference defined criteria for validation of IGF-I assays and for establishment of normative data. Objectives: Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness. Setting and Participants: We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0–94 years of age). Main Outcome Measures: We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay. Results: A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals. Conclusions: Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.

Free radicals, reactive oxygen/nitrogen species (ROS/RNS), hydrogen sulphide, and hydrogen peroxide play an important role in both intracellular and intercellular signaling; however, their production and quenching need to be closely regulated to prevent cellular damage. An imbalance, due to exogenous sources of free radicals and chronic upregulation of endogenous production, contributes to many pathological conditions including cardiovascular disease and also more general processes involved in aging. Nuclear factor erythroid 2‐like 2 (NFE2L2; commonly known as Nrf2) is a transcription factor that plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes, through binding to and activating expression of promoters containing the antioxidant response element (ARE). Nrf2 activity is regulated by many mechanisms, suggesting that tight control is necessary for normal cell function and both hypoactivation and hyperactivation of Nrf2 are indicated in playing a role in different aspects of cardiovascular disease. Targeted activation of Nrf2 or downstream genes may prove to be a useful avenue in developing therapeutics to reduce the impact of cardiovascular disease. We will review the current status of Nrf2 and related signaling in cardiovascular disease and its relevance to current and potential treatment strategies.

The prevalence of cardiovascular disease (CVD) is increasing over time. CVD is a comorbidity in diabetes and contributes to premature death. Citrus flavonoids possess several biological activities and have emerged as efficient therapeutics for the treatment of CVD. Citrus flavonoids scavenge free radicals, improve glucose tolerance and insulin sensitivity, modulate lipid metabolism and adipocyte differentiation, suppress inflammation and apoptosis, and improve endothelial dysfunction. The intake of citrus flavonoids has been associated with improved cardiovascular outcomes. Although citrus flavonoids exerted multiple beneficial effects, their mechanisms of action are not completely established. In this review, we summarized recent findings and advances in understanding the mechanisms underlying the protective effects of citrus flavonoids against oxidative stress, inflammation, diabetes, dyslipidemia, endothelial dysfunction, and atherosclerosis. Further studies and clinical trials to assess the efficacy and to explore the underlying mechanism(s) of action of citrus flavonoids are recommended.

OBJECTIVE—Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that intake of purified insoluble oat fiber may improve whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS—A randomized, controlled, single-blind, cross-over study was performed, and 17 overweight or obese subjects with normal glucose metabolism were analyzed. After consumption of nine macronutrient-matched portions of fiber-enriched bread (white bread enriched with 31.2 g insoluble fiber/day) or control (white bread) over a time period of 72 h, whole-body insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Energy intake was individually adjusted by providing standardized liquid meals. Hydrogen breath tests were performed to control for dietary adherence. RESULTS—When analyzing the entire cohort, whole-body glucose disposal was improved after fiber consumption (M value 6.56 ± 0.32 vs. 6.07 ± 0.27 mg · min⁻¹ · kg⁻¹; P = 0.043). Thirteen subjects had increased hydrogen breath test concentrations after fiber consumption, indicating probable dietary adherence. Restricting analysis to these subjects, improvements in M value (6.85 ± 0.34 vs. 6.06 ± 0.32 mg · min⁻¹ · kg⁻¹; P = 0.003) and insulin sensitivity, expressed as M/I ratio (M value divided by mean serum insulin at steady state: 3.73 ± 0.23 vs. 3.21 ± 0.27; P = 0.02), after fiber consumption were more pronounced. Plasma lipids, serum magnesium, ghrelin, and adiponectin concentrations, as well as substrate utilization and body weight, were not significantly changed by fiber intake (P > 0.15). CONCLUSIONS—Increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity. These data suggest a potential mechanism linking cereal fiber intake and reduced risk of type 2 diabetes.

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.