Proinflammatory and Hyperinsulinemic Dietary Patterns Are Associated With Specific Profiles of Biomarkers Predictive of Chronic Inflammation, Glucose-Insulin Dysregulation, and Dyslipidemia in Postmenopausal Women

Background: Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer. EDIH was developed using plasma C-peptide, whereas EDIP was based on plasma C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha receptor 2 (TNF-αR2). We investigated whether these dietary patterns were associated with a broader range of relevant biomarkers not previously tested.Methods: In this cross-sectional study, we included 35,360 women aged 50–79 years from the Women's Health Initiative with baseline (1993–1998) fasting blood samples. We calculated EDIH and EDIP scores from baseline food frequency questionnaire data and tested their associations with 40 circulating biomarkers of insulin response/insulin-like growth factor (IGF) system, chronic systemic inflammation, endothelial dysfunction, lipids, and lipid particle size. Multivariable-adjusted linear regression was used to estimate the percent difference in biomarker concentrations per 1 standard deviation increment in dietary index. FDR-adjusted p < 0.05 was considered statistically significant.Results: Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) were significantly associated with altered concentrations of 25 of the 40 biomarkers examined. For EDIH, the percent change in biomarker concentration in the insulin-related biomarkers ranged from +1.3% (glucose) to +8% (homeostatic model assessment for insulin resistance) and −9.7% for IGF-binding protein-1. EDIH impacted inflammation and endothelial dysfunction biomarkers from +1.1% (TNF-αR2) to +7.8% (CRP) and reduced adiponectin by 2.4%; and for lipid biomarkers: +0.3% (total cholesterol) to +3% (triglycerides/total cholesterol ratio) while reducing high-density lipoprotein cholesterol by 2.4%. EDIP showed a similar trend of associations with most biomarkers, although the magnitude of association was slightly weaker for the insulin-related biomarkers and stronger for lipids and lipid particle size.Conclusions: Dietary patterns with high potential to contribute to insulin hypersecretion and to chronic systemic inflammation, based on higher EDIH and EDIP scores, were associated with an unfavorable profile of circulating biomarkers of glucose-insulin dysregulation, chronic systemic inflammation, endothelial dysfunction and dyslipidemia. The broad range of biomarkers further validates EDIH and EDIP as mechanisms-based dietary patterns for use in clinical and population-based studies of metabolic and inflammatory diseases.

Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incretin based therapies that have gradually emerged as alternatives for insulin based therapy due to its inherent drawback of resistance has been briefly discussed.

Changes Associated with the Peri-Ovulatory Period, Age and Pregnancy in ACTH, Cortisol, Glucose and Insulin Concentrations in Mares

Although there are many hormonal changes associated with reproduction, the effects of ovulation and early pregnancy on adrenocorticotropic hormone (ACTH) and insulin concentrations are poorly described. We hypothesise that both ovulation and early pregnancy will alter ACTH and insulin concentrations in healthy mares. Eighteen mares showing no clinical signs suggestive of, or laboratory findings consistent with, pituitary pars intermedia dysfunction PPID and insulin dysregulation (ID) are enrolled. ACTH, cortisol, insulin and glucose concentrations are measured over their peri-ovulatory period, as determined via ultrasounds and progesterone concentrations. The mares are grouped by age and gestation status, and a two-way repeated-measures ANOVA is used to determine the effects of age and early pregnancy, along with the peri-ovulatory period, on analyte concentrations. No significant effect of age, ovulation or early pregnancy is detected on the mares’ cortisol, insulin or glucose concentrations; however, there is a significant effect of early pregnancy and ovulation on ACTH concentrations (p = 0.04 and p = 0.04 respectively). ACTH concentrations change around ovulation and with early pregnancy. Therefore, knowledge of a mare’s reproductive status might be beneficial when interpreting ACTH concentrations.

Metabolic impact of weight variations in Icelandic horses

Background Insulin dysregulation (ID) is an equine endocrine disorder, which is often accompanied by obesity and various metabolic perturbations. The relationship between weight variations and fluctuations of the insulin response to oral glucose tests (OGT) as well as the metabolic impact of ID have been described previously. The present study seeks to characterize the concomitant metabolic impact of variations in the insulin response and bodyweight during repeated OGTs using a metabolomics approach. Methods Nineteen Icelandic horses were subjected to five OGTs over one year and their bodyweight, insulin and metabolic response were monitored. Analysis of metabolite concentrations depending on time (during the OGT), relative bodyweight (rWeight; defined as the bodyweight at one OGT divided by the mean bodyweight across all OGTs) and relative insulin response (rAUCins; defined accordingly from the area under the insulin curve during OGT) was performed using linear models. Additionally, the pathways significantly associated with time, rWeight and rAUCins were identified by rotation set testing. Results The results suggested that weight gain and worsening of ID activate distinct metabolic pathways. The metabolic profile associated with weight gain indicated an increased activation of arginase, while the pathways associated with time and rAUCins were consistent with the expected effect of glucose and insulin, respectively. Overall, more metabolites were significantly associated with rWeight than with rAUCins.

Metabolic profile distinguishes laminitis-susceptible and -resistant ponies before and after feeding a high sugar diet

Background Insulin dysregulation (ID) is a key risk factor for equine endocrinopathic laminitis, but in many cases ID can only be assessed accurately using dynamic tests. The identification of other biomarkers could provide an alternative or adjunct diagnostic method, to allow early intervention before laminitis develops. The present study characterised the metabolome of ponies with varying degrees of ID using basal and postprandial plasma samples obtained during a previous study, which examined the predictive power of blood insulin levels for the development of laminitis, in ponies fed a high-sugar diet. Samples from 10 pre-laminitic (PL – subsequently developed laminitis) and 10 non-laminitic (NL – did not develop laminitis) ponies were used in a targeted metabolomic assay. Differential concentration and pathway analysis were performed using linear models and global tests. Results Significant changes in the concentration of six glycerophospholipids (adj. P ≤ 0.024) and a global enrichment of the glucose-alanine cycle (adj. P = 0.048) were found to characterise the response of PL ponies to the high-sugar diet. In contrast, the metabolites showed no significant association with the presence or absence of pituitary pars intermedia dysfunction in all ponies. Conclusions The present results suggest that ID and laminitis risk are associated with alterations in the glycerophospholipid and glucose metabolism, which may help understand and explain some molecular processes causing or resulting from these conditions. The prognostic value of the identified biomarkers for laminitis remains to be investigated in further metabolomic trials in horses and ponies.