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This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D. [ABSTRACT FROM AUTHOR]

Background: Active surveillance (AS) is increasingly used to monitor patients with lower risk prostate cancer (PCa). The Prostate Cancer Active Lifestyle Study (PALS) was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with PCa on AS. Methods: Overweight/obese men (body mass index >25 kg/m2) diagnosed with PCa who elected AS were recruited. The intervention was a 6‐month, individually delivered, structured diet and exercise program adapted from the Diabetes Prevention Program with a 7% weight loss goal from baseline. Control participants attended one session reviewing the US Dietary and Physical Activity Guidelines. The primary outcome was change in glucose regulation from baseline to the end of the 6‐month intervention, which was measured by fasting plasma glucose, C‐peptide, insulin, insulin‐like growth factor 1, insulin‐like growth factor binding protein‐3, adiponectin, and homeostatic model assessment for insulin resistance. Results: Among 117 men who were randomized, 100 completed the trial. The mean percentage weight loss was 7.1% and 1.8% in the intervention and control arms, respectively (adjusted between‐group mean difference, −6.0 kg; 95% confidence interval, −8.0, −4.0). Mean percentage changes from baseline for insulin, C‐peptide, and homeostatic model assessment for insulin resistance in the intervention arm were −23%, −16%, and −25%, respectively, compared with +6.9%, +7.5%, and +6.4%, respectively, in the control arm (all p for intervention effects ≤.003). No significant between‐arm differences were detected for the other biomarkers. Conclusions: Overweight/obese men with PCa undergoing AS who participated in a lifestyle‐based weight loss intervention successfully met weight loss goals with this reproducible lifestyle intervention and experienced improvements in glucose‐regulation biomarkers associated with PCa progression. The Prostate Cancer Active Lifestyle Study was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with prostate cancer undergoing active surveillance. Overweight/obese men with prostate cancer on active surveillance who participated in a lifestyle‐based weight loss intervention successfully met weight loss goals and experienced improvements in glucose‐regulation biomarkers associated with prostate cancer progression. [ABSTRACT FROM AUTHOR]

Background: Insulin and insulin-like growth factor (IGF)-1 receptors are present in ocular tissues such as corneal epithelium, keratocytes, and conjunctival cells. Insulin plays a crucial role in the growth, differentiation, and proliferation of corneal epithelial cells, as well as in wound healing processes in various tissues. Purpose: This review explores the potential role of topical insulin in the treatment of ocular surface diseases. Specifically, it examines its impact on corneal nerve regeneration, sub-basal plexus corneal nerves, and its application in conditions like corneal epithelial defects, dry eye disease, and diabetic keratopathy. Methods: The review analyzes studies conducted over the past decade that have investigated the use of topical insulin in ocular surface diseases. It focuses on indications, drug preparation methods, side effects, efficacy outcomes, and variations in insulin concentrations and dosages used. Results: While off-label use of topical insulin has shown promising results in refractory corneal epithelial defects, its efficacy in dry eye disease is yet to be demonstrated. Variations in concentrations, dilutions, and dosing guidelines have been reported. However, limited data on ocular penetration, ocular toxicity, and systemic side effects pose challenges to its widespread utility. Conclusion: This review synthesizes findings from ocular investigations on topical insulin to assess its potential applicability in treating ocular surface and corneal diseases. By highlighting indications, preparation methods, side effects, and efficacy outcomes, it aims to provide insights into the current status and future prospects of using topical insulin in ophthalmic practice. [ABSTRACT FROM AUTHOR]

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion. [ABSTRACT FROM AUTHOR]

Nutrition and modulation of the hypermetabolic response to acute burns are reviewed in this article. Methods to determine caloric requirements are evaluated, including indirect calorimetry and predictive equations. Individual nutritional components of carbohydrates, fat, protein, vitamins, and trace elements are discussed specifically in relation to acute burn care. Selection of formula and route of administration are outlined, with an enteral high-carbohydrate, low-fat diet being preferable. Awareness and recognition of the signs and symptoms of malnutrition is critical in the management of variable caloric needs throughout hospitalization. Lastly, the catabolic state of acute burns is addressed through early excision and grafting and implementation of various pharmacologic agents, including growth hormone, insulin-like growth factor-1, insulin-like growth factor-binding protein-3, insulin, propranolol, and oxandrolone. Through a multipronged approach to nutrition, pediatric burn patients are provided the substrates for successful recovery and rehabilitation. [ABSTRACT FROM AUTHOR]

This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health—from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children's IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare. [ABSTRACT FROM AUTHOR]

Simple Summary: The corneal epithelium is a protective barrier and refractive structure in the eye maintained through a complex regenerative process involving the lacrimal gland, tear film, and corneal nerves. This review explores the insulin-like growth factor (IGF) system and its role in corneal epithelium homeostasis. Emphasis is placed on the significance of limbal epithelial stem cells and potential therapeutic applications targeting the system components. The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components. [ABSTRACT FROM AUTHOR]

Objective: Children born small for gestational age (SGA) are at a greater risk of developing insulin resistance, type 2 diabetes, and cardiovascular disease in adulthood. Gastrointestinal peptides, some secreted by intestinal L cells, regulate glucose and lipid metabolism and act on the hypothalamus to regulate energy homeostasis. The aim of this study was to explore whether gastrointestinal peptides are involved in metabolic disorders in SGA, which remains unclear. Methods: The secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were investigated in prepubertal children born SGA, the differences between catch-up growth and persistent short stature were compared, and correlation with glucose and lipid metabolism was analyzed. GLP-1, PYY, insulin-like growth factor 1, glucose, insulin, and lipid concentrations were analyzed in prepubertal children aged 4-10 years, stratified into three groups: short-SGA (SGA-s), catch-up growth SGA, and normal growth appropriate for gestational age (AGA). Results: Fasting GLP-1 and PYY concentrations were significantly lower in the SGA group than in the AGA group (p<0.05), and the GLP-1 level in infants born SGA with catch-up growth was lower than that in the SGA-s group (p<0.05). In the SGA population, GLP-1 showed a weak negative correlation with catch-up growth (r=-0.326) and positive correlation with fasting insulin (r=0.331). Conclusion: Lower GLP-1 concentrations may be associated with abnormal glucose metabolism in prepubertal children born SGA with catch-up growth. This is indirect evidence that impaired intestinal L cell function may be involved in the development of metabolic complications in SGA children. [ABSTRACT FROM AUTHOR]

Insulin resistance, also known as impaired insulin sensitivity, is the result of a decreased reaction of insulin signaling to blood glucose levels. This state is observed when muscle cells, adipose tissue, and liver cells, improperly respond to a particular concentration of insulin. Insulin resistance and related increased plasma insulin levels (hyperinsulinemia) may cause metabolic impairments, which are pathological states observed in obesity and type 2 diabetes mellitus. Observations of cancer patients confirm that hyperinsulinemia is a major factor influencing obesity, type 2 diabetes, and cancer. Obesity and diabetes have been reported as risks of the initiation, progression, and metastasis of several cancers. However, both of the aforementioned pathologies may independently and additionally increase the cancer risk. The state of metabolic disorders observed in cancer patients is associated with poor outcomes of cancer treatment. For example, patients suffering from metabolic disorders have higher cancer recurrence rates and their overall survival is reduced. In these associations between insulin resistance and cancer risk, an overview of the various pathogenic mechanisms that play a role in the development of cancer is discussed. [ABSTRACT FROM AUTHOR]

The relationship between intake of dietary supplements and biomarkers such as insulin and insulin-like growth factor has not been well explored. The primary aim of this cross-sectional study was to investigate the associations between supplement intake and biological and lifestyle factors. We hypothesized that dietary supplement intake was associated with healthier lifestyle behaviors. College students attending a Southeast university were recruited between January 2018 and April 2019. Blood samples were collected to measure insulin, insulin-like growth factor 1 (IGF-1) and alanine aminotransferase (ALT). Statistical tests employed were linear regression and analysis of variance. Ninety-eight participants completed the study and 91% reported taking at least one supplement, while 5.1% reported taking 9+ supplements once per week. There were no differences in levels of insulin, IGF-1 and ALT by levels of dietary supplement intake. Although there were no differences in HEI-2015 score among the groups, those who consumed five or more supplements met a higher percentage of the recommended intake for fruits, performed aerobic exercise for longer duration, and had lower body fat percentage compared to participants who consumed two or less supplements at least once per week. These findings are consistent with previous studies and suggest that dietary supplement intake is highly prevalent in college students, and it may be related to healthy lifestyle behaviors. Future studies should employ mixed methodology to examine reasons by which college students consume dietary supplements and to assess perceived and direct health benefits associated with consumption. [ABSTRACT FROM AUTHOR]

The paper aimed to explore the mechanism by which high mobility group box-1 and nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species enhance each other's influence on the amplitude of electroretinogram and the permeability of the vitreous. According to the purpose of the experiment, the experimental rats were separated into a control group, a diabetes group and a Shenling Baizhu powder group. The messenger ribonucleic acid expression of microRNA-23 and microRNA-27a in rat muscle tissue was quantitatively analyzed by real-time quantitative polymerase chain reaction. The contractility of rat soleus skeletal muscle was analyzed by electrical stimulation program. Western blot analysis of rat muscle growth protein synthesis and the expression of myostatin signaling pathway was carried out. The expression of renal fibrosis-related albumin was tested by Western blot. The messenger ribonucleic acid expression of microRNA-23, 27a in the diabetic group was lower than control group (p<0.05), and the expression in the Shenling Baizhu powder group was higher than diabetic group (p<0.05). Compared with the control group, the diabetic group had lower body weight (p<0.05), and raised blood glucose concentration and diabetes volume (p<0.05). The ratio of phosphorylated protein kinase B/protein kinase B and phospho forkhead box protein O1/forkhead box protein O1 protein expression in the Shenling Baizhu powder group was higher than diabetic group (p<0.05), while the phosphatase and tensin homolog protein expression was lower (p<0.05). The protein expression of myostatin, FBXO32 and TRIM63 in the diabetes group was higher than control group (p<0.05), and the expression in the Shenling Baizhu powder group was lower than diabetes group (p<0.05). Compared with the control group, the protein expression of transforming growth factor-beta, suppressor of mothers against decapentaplegic 2/3, alpha-smooth muscle actin, collagen-1a and fibronectin was higher in the diabetes group (p<0.05), and the expression in the Shenling Baizhu powder group was lower than diabetes group (p<0.05). Shenling Baizhu powder can improve diabetes-induced sarcopenia by up-regulating microRNA expression, activating the insulin-like growth factor 1/phosphoinositide 3-kinases/ protein kinase B signaling pathway and inhibiting the myostatin cascade. [ABSTRACT FROM AUTHOR]

Nutrient intake is obligatory for animal growth and development, but nutrients alone are not sufficient. Indeed, insulin and homologous hormones are required for normal growth even in the presence of nutrients. These hormones communicate nutrient status between organs, allowing animals to coordinate growth and metabolism with nutrient supply. Insulin and related hormones, such as insulin-like growth factors and insulin-like peptides, play important roles in development and metabolism, with defects in insulin production and signaling leading to hyperglycemia and diabetes. Here, we describe the insulin hormone family and the signal transduction pathways activated by these hormones. We highlight the roles of insulin signaling in coordinating maternal and fetal metabolism and growth during pregnancy, and we describe how secretion of insulin is regulated at different life stages. Additionally, we discuss the roles of insulin signaling in cell growth, stem cell proliferation and cell differentiation. We provide examples of the role of insulin in development across multiple model organisms: Caenorhabditis elegans, Drosophila, zebrafish, mouse and human. [ABSTRACT FROM AUTHOR]

The insulin-related hormones regulate key life processes in Metazoa, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin signalling axis (IIS). In humans the IIS axis is controlled by insulin, two insulin-like growth factors, two isoforms of the insulin receptor (hIR-A and -B), and its homologous IGF-1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1-7) and a single receptor (dmIR). This report describes the cryoEM structure of the dmIR ectodomain:DILP5 complex, revealing high structural homology between dmIR and hIR. The excess of DILP5 yields dmIR complex in an asymmetric 'T' conformation, similar to that observed in some complexes of human IRs. However, dmIR binds three DILP5 molecules in a distinct arrangement, showing also dmIR-specific features. This work adds structural support to evolutionary conservation of the IIS axis at the IR level, and also underpins a better understanding of an important model organism. Insulin hormones and their receptors regulate key life processes in animals: from metabolism to life span. Human insulin receptor has been studied extensively. Here, the authors show remarkable structural similarity of fruit fly and human insulin receptors, indicating their universal functioning. [ABSTRACT FROM AUTHOR]

Background: Obesity-related factors such as adipokines, insulin, insulin-like growth factors, and sex steroid hormones have been reported to be involved in breast carcinogenesis. Studies across the world suggest an important, but still controversial, role of obesity in breast cancer risk. This study aims to evaluate the association of obesity-related factors such as adipokines, insulin, insulin resistance, and sex steroid hormones with breast cancer risk in the Indian population. Materials and Methods: Anthropometric and biochemical measurements were taken in 60 newly diagnosed and histologically confirmed breast cancer patients and 50 healthy controls. Preoperative serum levels of adiponectin, leptin, insulin, estrogen, and testosterone were measured using ELISA (enzyme-linked immunosorbent assay). The data were analyzed and compared. Results: The mean serum total cholesterol (T.CHOL) and leptin levels were significantly higher (P = 0.047), whereas testosterone levels were significantly lower in patients than in controls. Waist circumference (WC) and leptin levels showed a significant positive association with breast cancer risk. Association of serum leptin levels with breast cancer risk persisted after adjusting for age, body mass index (BMI), and WC parameters (odds ratio [OR] = 1.042, P = 0.03). Leptin levels positively correlated with WC and triglycerides (TG), whereas insulin and insulin resistance positively correlated with BMI, WC, TG, and T.CHOL (P < 0.05). Among the tumor characteristics, serum adiponectin showed a positive correlation with lymph node involvement, whereas serum estradiol levels were positively correlated with ER (estrogen receptor) and PR (progesterone receptor) status. Conclusion: Together, our study supports the association of obesity (WC) with breast cancer risk and also suggests the potential role of leptin as a biomarker for breast cancer risk, independent of obesity. [ABSTRACT FROM AUTHOR]

The Insulin-like Growth Factor (IGF) system in breast cancer progression has been a matter of interest for decades, but targeting this system did not result in a successful clinical strategy. The system's complexity and homology of its two receptors—insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-1R)—are possible causes. The IGF system maintains cell proliferation and also regulates metabolism, making it a pathway to explore. To understand the metabolic phenotype of breast cancer cells, we quantified their real-time ATP production rate upon acute stimulation with ligands—insulin-like growth factor 1 (1GF-1) and insulin. MCF-7L cells express both IGF-1R and IR, while tamoxifen-resistant MCF-7L (MCF-7L TamR) cells have downregulated IGF-1R with unchanged IR levels. Treating MCF-7L cells with 5 nM IGF-1 increased the glycolytic ATP production rate, while 10 nM insulin did not affect metabolism when compared with the control. Neither treatment altered ATP production in MCF-7L TamR cells. This study provides evidence of the relationship between metabolic dysfunction, cancer, and the IGF axis. In these cells, IGF-1R, and not IR, regulates ATP production. [ABSTRACT FROM AUTHOR]

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin‐like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue‐derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low‐chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity‐related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a critical fetal growth hormone that has been proposed as a therapy for intrauterine growth restriction. We previously demonstrated that a 1-week IGF-1 LR3 infusion into fetal sheep reduces in vivo and in vitro insulin secretion suggesting an intrinsic islet defect. Our objective herein was to determine whether this intrinsic islet defect was related to chronicity of exposure. We therefore tested the effects of a 90-min IGF-1 LR3 infusion on fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion from isolated fetal islets. We first infused late gestation fetal sheep (n = 10) with either IGF-1 LR3 (IGF-1) or vehicle control (CON) and measured basal insulin secretion and in vivo GSIS utilizing a hyperglycemic clamp. We then isolated fetal islets immediately following a 90-min IGF-1 or CON in vivo infusion and exposed them to glucose or potassium chloride to measure in vitro insulin secretion (IGF-1, n = 6; CON, n = 6). Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion (P < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion compared to CON (P < 0.0001). Insulin secretion in isolated fetal islets was not different based on infusion at the time of islet collection. Therefore, we speculate that while acute IGF-1 LR3 infusion may directly suppress insulin secretion, the fetal β-cell in vitro retains the ability to recover GSIS. This may have important implications when considering the long-term effects of treatment modalities for fetal growth restriction. [ABSTRACT FROM AUTHOR]

Reference intervals are among the most widely used medical decision-making tools and are invaluable in the interpretation of laboratory results of patients. Moreover, when multiple biochemical analytes are measured on each patient, a multivariate reference region (MRR) is needed. Such regions are more desirable than separate univariate reference intervals since the latter disregard the cross-correlations among variables. Traditionally, assuming multivariate normality, MRRs have been constructed as ellipsoidal regions, which cannot detect componentwise extreme values. Consequently, MRRs are rarely used in actual practice. In order to address the above drawback of ellipsoidal reference regions, we propose a procedure to construct rectangular MRRs under multivariate normality. The rectangular MRR is computed using a prediction region criterion. However, since the population correlations are unknown, a parametric bootstrap approach is employed for computing the required prediction factor. Also addressed in this study is the computation of mixed reference intervals, which include both two-sided and one-sided prediction limits, simultaneously. Numerical results show that the parametric bootstrap procedure is quite accurate, with estimated coverage probabilities very close to the nominal level. Moreover, the expected volumes of the proposed rectangular regions are substantially smaller than the expected volumes obtained from Bonferroni simultaneous prediction intervals. We also explore the computation of covariate-dependent MRRs in a multivariate regression setting. Finally, we discuss real-life applications of the proposed methods, including the computation of reference ranges for the assessment of kidney function and for components of the insulin-like growth factor system in adults. [ABSTRACT FROM AUTHOR]

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-f at high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pa thway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis. [ABSTRACT FROM AUTHOR]

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Early-life malnutrition increases adult disease risk in humans, but the causal changes in gene regulation, signaling, and metabolism are unclear. In the roundworm Caenorhabditis elegans, early-life starvation causes well-fed larvae to develop germline tumors and other gonad abnormalities as adults. Furthermore, reduced insulin/IGF signaling during larval development suppresses these starvationinduced abnormalities. How early-life starvation and insulin/IGF signaling affect adult pathology is unknown. We show that early-life starvation has pervasive effects on adult gene expression which are largely reversed by reduced insulin/IGF signaling following recovery from starvation. Early-life starvation increases adult fatty-acid synthetase fasn-1 expression in daf-2 insulin/IGF signaling receptor-dependent fashion, and fasn-1/FASN promotes starvation-induced abnormalities. Lipidomic analysis reveals increased levels of phosphatidylcholine in adults subjected to early-life starvation, and supplementation with unsaturated phosphatidylcholine during development suppresses starvation-induced abnormalities. Genetic analysis of fatty-acid desaturases reveals positive and negative effects of desaturation on development of starvation-induced abnormalities. In particular, the ω3 fatty-acid desaturase fat-1 and the Δ5 fatty-acid desaturase fat-4 inhibit and promote development of abnormalities, respectively. fat-4 is epistatic to fat-1, suggesting that arachidonic acid-containing lipids promote development of starvation-induced abnormalities, and supplementation with ARA enhanced development of abnormalities. This work shows that early-life starvation and insulin/IGF signaling converge on regulation of adult lipid metabolism, affecting stem-cell proliferation and tumor formation. [ABSTRACT FROM AUTHOR]

Aims: Physical frailty is highly prevalent and predictive of worse outcomes in heart failure (HF). Candidate biomarker analysis may help in understanding the mechanisms underlying physical frailty in HF. We aimed to identify candidate biomarkers associated with physical frailty in HF using a multimarker strategy of distinct pathophysiological processes. Methods and results: We collected data and plasma samples from 113 adults with New York Heart Association Functional Class I–IV HF. Physical frailty was measured with the Frailty Phenotype Criteria. Plasma biomarkers included: N-terminal pro-B-type natriuretic peptide, norepinephrine, dihydroxyphenylglycol, soluble tumour necrosis factor alpha receptor-1, adiponectin, insulin, glucose, insulin-like growth factor-1 (IGF-1), and myostatin. Comparative statistics and multivariate linear regression were used to test group differences and associations. The average age was 63.5 ± 15.7 years, half were women (48%), and most had a non-ischaemic aetiology of HF (73%). Physical frailty was identified in 42% and associated with female sex, higher body mass index and percent body fat, more comorbidities, and HF with preserved ejection fraction. Adjusting for Seattle HF Model projected survival score, comorbidities, body composition, and sex, physical frailty was associated with significantly lower plasma adiponectin [β ± standard error (SE) −0.28 ± 0.14, P = 0.047], IGF-1 (β ± SE −0.21 ± 0.10, P = 0.032), and myostatin (β ± SE −0.22 ± 0.09, P = 0.011). In sex-stratified analyses, IGF-1 and myostatin were significantly associated with physical frailty in men but not women. Conclusion: We identified biomarkers involved in adipose tissue and skeletal muscle development, maintenance, and function that were associated with physical frailty in HF. Graphical Abstract Graphical Abstract Abbreviations: HF, heart failure [ABSTRACT FROM AUTHOR]

The review describes the problem of studying progressive changes of hormones concentrations (parathyroid hormone, insulin, somatotropin, prolactin) in patients with chronic renal failure on the pre-dialysis and dialysis stages. The pathogenetic relationships between kidney function deterioration and hormone concentrations as well as changes of their biological effects were evaluated. Parathyroid hormone is considered as an uraemic toxin, since its concentration in the blood begins to increase when the glomerular filtration rate decreases below 50 ml/min. All stages of chronic kidney disease are accompanied by disorders of calcium-phosphorus metabolism. Prolonged excess of parathyroid hormone leads to bone loss and to the progression to secondary hyperparathyroidism that is a frequent complication in patients with the later stages of chronic renal failure and, especially, in those on dialysis treatment. The elevation of insulin level in chronic renal failure is the consequence of progressive decrease in glomerular filtration rate and insulin excretion by proximal tubules. So, it results in insulin half-life prolongation. Long-term dialysis therapy eliminates factors that reduce the degradation of insulin by extrarenal tissues, which results in an improvement of their insulin sensitivity. Experimental and clinical studies have shown that an excess of somatotropin can adversely affect the kidneys that leads to glomerular hyperfiltration and the progression to glomerulosclerosis. The risk of possible side effects on kidneys should be taken into account when prescribing recombinant human insulin-like growth factor. The prolactin concentration is usually increased in chronic kidney disease due to reduced clearance and increased secretion. Hyperprolactinemia manifests as galactorrhea and hypogonadism. Dialysis therapy can’t normalize the increased concentration of prolactin. Modern options for pathogenetic treatment of endocrine disorders in patients with chronic renal failure are outlined in this article. It was found that kidneys play an important role in regulating hormones concentrations in the blood. Endocrine disorders are one of the most important components of the uraemic syndrome, which requires further clinical studies, aimed on the searching of better treatment strategies and prevention of hormonal imbalance on the pre-dialysis and dialysis stages of chronic kidney disease. [ABSTRACT FROM AUTHOR]

Low energy availability (LEA), and subsequent relative energy deficiency in sport, has been observed in endurance, aesthetic, and team sport athletes, with limited data on prevalence in athletes in short-burst activities such as sprinting. We examined prevalence of signs and symptoms of LEA in elite female sprinters at the start of the training season (PRE), and at the end of a 5-month indoor training period (POST). Four of 13 female sprinters (31%) presented at PRE testing with at least one primary (amenorrhea, low bone mineral density, low follicle-stimulating hormone, luteinizing hormone, or estradiol, resting metabolic rate ≤29 kcal/kg fat-free mass, Low Energy Availability in Females Questionnaire score ≥8) and one secondary indicator of LEA (fasting blood glucose <4 mmol/L, free triiodothyronine <3.5 pmol/L, ferritin <25 μg/L, low-density lipoprotein cholesterol >3.0 mmol/L, fasting insulin <20 pmol/L, low insulin-like growth factor-1, systolic blood pressure <90 mmHg, and/or diastolic blood pressure <60 mmHg). At POST, seven out of 13 athletes (54%) presented with at least one primary and one secondary indicator of LEA, three of whom had also presented with indicators of LEA at PRE. Five out of 13 (39%) athletes had previous stress fracture history, though this was not associated with current indicators of LEA (PRE: r =.52, p =.07; POST: r = −.07, p =.82). In conclusion, elite female sprinters may present with signs and symptoms of LEA, even after off-season rest. Medical and coaching staff should be aware of the signs and symptoms of LEA and relative energy deficiency in sport and should include appropriate screening and intervention strategies when working with sprinters. [ABSTRACT FROM AUTHOR]

The term Relative Energy Deficiency in Sport was introduced by the International Olympic Committee in 2014. It refers to the potential health and performance consequences of inadequate energy for sport, emphasizing that there are consequences of low energy availability (EA; typically defined as <30 kcal·kg−1 fat-free mass·day−1) beyond the important and well-established female athlete triad, and that low EA affects populations other than women. As the prevalence and consequences of Relative Energy Deficiency in Sport become more apparent, it is important to understand the current knowledge of the hormonal changes that occur with decreased EA. This paper highlights endocrine changes that have been observed in female and male athletes with low EA. Where studies are not available in athletes, results of studies in low EA states, such as anorexia nervosa, are included. Dietary intake/appetite-regulating hormones, insulin and other glucose-regulating hormones, growth hormone and insulin-like growth factor 1, thyroid hormones, cortisol, and gonadal hormones are all discussed. The effects of low EA on body composition, metabolic rate, and bone in female and male athletes are presented, and we identify future directions to address knowledge gaps specific to athletes. [ABSTRACT FROM AUTHOR]

In dairy cows, metabolic disorders are mainly found in the last weeks of the dry period and the first weeks after calving (transit period). Therefore, the purpose of this study was to investigate the hormonal regulation of the concentration of glucose and its derivatives in the blood of dairy cows during the transit period. The study was conducted on cows of 2-4 lactations, with a capacity of 7.8-8.2 thousand kg of milk for previous lactation. Blood for research was taken from cows 7-10 days before calving and Days 2-4, Days 10-14, and Days 30-40 after calving. The concentration of glucose in blood plasma was determined by the glucose oxidase method, pyruvate - by the modified Umbright method, lactate -- by reaction with paraoxydyphenyl, and hormone content -- by enzyme-linked immunosorbent assay. It was established that high-performance dairy cows during the transit period experience substantial changes in carbohydrate metabolism and the functional state of organs and systems, which are aimed at ensuring high productivity. Thus, hypoglycaemia is found in cows within two weeks after calving. At the same time, with a decrease in the concentration of glucose in the blood plasma of cows, the content of pyruvate and lactate increases, as well as the lactate/pyruvate ratio, which indicates an increase in gluconeogenesis. Negative energy balance and increased gluconeogenesis lead to a decrease in the synthesis of insulin and insulin-like growth factor. Compared to the final dry period, on Days 2-4 of lactation, the concentration of leptin in the blood plasma of cows decreased threefold and stayed at a low level until Day 40 of lactation. Plasma cortisol levels were highest on Days 2-4 and 10-14 of lactation. Intensive cortisol synthesis during the period of energy deficiency increases gluconeogenesis, which is possible due to lipolysis and proteolysis. In the first days after calving, the content of thyroxine and triiodothyronine in the blood plasma of cows decreased. Inhibition of thyroid hormone production is a consequence of the physiological regulatory features of this period. Thus, in highly productive cows during the transit period, attention should be paid to maintaining vital body functions and their well-coordinated endocrine regulation, which will ensure a physiologically balanced metabolic rate, successful calving, high milk productivity, and animal health [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g. , macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: β-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies. [ABSTRACT FROM AUTHOR]

Insulin is a peptide hormone known for chiefly regulating glucose level in blood among several other metabolic processes. Insulin remains the most effective drug for treating diabetes mellitus. Insulin is synthesized in the pancreatic β-cells where it exists in a compact hexameric architecture although its biologically active form is monomeric. Insulin exhibits a sequence of conformational variations during the transition from the hexamer state to its biologically-active monomer state. The structural transitions and the mechanism of action of insulin have been investigated using several experimental and computational methods. This review primarily highlights the contributions of molecular dynamics (MD) simulations in elucidating the atomic-level details of conformational dynamics in insulin, where the structure of the hormone has been probed as a monomer, dimer, and hexamer. The effect of solvent, pH, temperature, and pressure have been probed at the microscopic scale. Given the focus of this review on the structure of the hormone, simulation studies involving interactions between the hormone and its receptor are only briefly highlighted, and studies on other related peptides (e.g., insulin-like growth factors) are not discussed. However, the review highlights conformational dynamics underlying the activities of reported insulin analogs and mimetics. The future prospects for computational methods in developing promising synthetic insulin analogs are also briefly highlighted. [ABSTRACT FROM AUTHOR]

Insulin and insulin-like peptides (ILP) help to maintain glucose homeostasis, whereas insulin-like growth factor (IGF) promotes the growth and differentiation of cells in both vertebrates and invertebrates. It is sometimes difficult to distinguish between ILP and IGF in invertebrates, however, because in some cases ILP has the same function as IGF. In the present review, therefore, we refer to these peptides as ILP/IGF signaling (IIS) in invertebrates, and discuss the role of IIS in memory formation after classical conditioning in invertebrates. In the arthropod Drosophila melanogaster , IIS is involved in aversive olfactory memory, and in the nematode Caenorhabditis elegans , IIS controls appetitive/aversive response to NaCl depending on the duration of starvation. In the mollusk Lymnaea stagnalis , IIS has a critical role in conditioned taste aversion. Insulin in mammals is also known to play an important role in cognitive function, and many studies in humans have focused on insulin as a potential treatment for Alzheimer's disease. Although analyses of tissue and cellular levels have progressed in mammals, the molecular mechanisms, such as transcriptional and translational levels, of IIS function in cognition have been far advanced in studies using invertebrates. We anticipate that the present review will help to pave the way for studying the effects of insulin, ILPs, and IGFs in cognitive function across phyla. [ABSTRACT FROM AUTHOR]

Intermittent fasting (IF) is a dietary strategy that involves alternating periods of abstention from calorie consumption with periods of ad libitum food intake. There is significant interest in the body of literature describing longitudinal adaptations to IF. Less attention has been given to the acute physiological responses that occur during the fasting durations that are commonly employed by IF practitioners. Thus, the purpose of this review was to examine the physiological responses – including alterations in substrate metabolism, systemic hormones, and autophagy – that occur throughout an acute fast. Literature searches were performed to locate relevant research describing physiological responses to acute fasting and short-term starvation. A single fast demonstrated the ability to alter glucose and lipid metabolism within the initial 24 hours, but variations in protein metabolism appeared to be minimal within this time frame. The ability of an acute fast to elicit significant increases in autophagy is still unknown. The information summarized in this review can be used to help contextualize existing research and better inform development of future IF interventions. [ABSTRACT FROM AUTHOR]

Objectives: There are many endogenous and exogenous factors that cause acne formation. This study aimed to determine whether the acne severity in patients with various age ranges is associated with serum insulin‐like growth factor, insulin, and glucose and to identify how much they affect the acne severity. Materials and Methods: In this case‐control prospective study, 44 patients with acne vulgaris and 44 age‐ and gender‐matched control subjects without acne were evaluated. Patients and the control group were divided into two age‐groups as adolescence and post‐adolescence. According to the Global Acne Scoring System (GASS) of the acne group, the acne score grades between 0 and 44 were calculated. The correlations between the IGF‐1, insulin, glucose levels, and acne grades were calculated in each group. Results: In our study, the acne scores and serum IGF‐1 levels were found to be significantly higher in patients under the age of 21 than patients over the age of 21. There was a statistically significant difference in acne score between the two groups. However, there was no statistically significant difference between the serum IGF‐1, insulin, and glucose levels of the acne group and the control group. Conclusion: In this study, it has been revealed that IGF‐1 is effective at the pathogenesis of acne in adolescence. [ABSTRACT FROM AUTHOR]

Insulin receptor signaling shows significant cross-talks with the IGF-1 receptor type 1, and with FSH and LH signaling, acting as a co-gonadotropin in granulosa and theca cells. It is generally recognized that in most phases of life, insulin resistance in PCOS is associated with an increased risk of developing type 2 diabetes and, possibly, with an increased risk of cardiovascular disease [[11]]. Insulin has pleiotropic effects, and is of importance both as a key regulator of glucose metabolism and as a growth factor. [Extracted from the article]

Background: Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. Methods: Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. Results: INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. Conclusions: The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients. [ABSTRACT FROM AUTHOR]

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related. [ABSTRACT FROM AUTHOR]

What is known and objective: Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic‐pituitary‐gonadal axis activity and sexual function in men with low testosterone levels. Methods: The study included 28 men with late‐onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120 mg in three equal doses), 12 of whom had been treated with oral metformin (1.7–3 g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone‐ and metformin‐treated men with late‐onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone‐sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin‐growth factor‐1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF‐15). Results and discussion: Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformin‐treated patients, and by 52% and 54% in metformin‐naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin‐naïve men, follow‐up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin‐naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow‐up levels of the remaining hormones. In metformin‐naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group. What is new and conclusion: The obtained results suggest that metformin treatment mitigates the unfavourable effect of discontinuation of testosterone treatment on hypothalamic‐pituitary‐testicular axis activity and sexual function in men with late‐onset hypogonadism. [ABSTRACT FROM AUTHOR]

Insulin‐degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid‐β peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin‐like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non‐proteolytic functions such as: a chaperone/dead‐end chaperone, an E1‐ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid‐β, and α‐synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

For example, IGF-1 mimics some of the insulin actions and promotes insulin sensitivity, while GH is anti-insulinemic and promotes insulin resistance; IGF-1 promotes fat deposition, while GH is lipolytic (Figure 2) ([39]; [59]; [23]). Keywords: insulin/insulin-like growth factor signaling; mammalian aging; growth hormone; lifespan; healthspan EN insulin/insulin-like growth factor signaling mammalian aging growth hormone lifespan healthspan 1 5 5 11/26/21 20211124 NES 211124 A report of extended longevity in mice homozygous for a mutation producing growth hormone (GH) deficiency ([10]) was quickly followed by the demonstration of extensive homology between one of the key longevity genes in a worm, Caenorhabditis elegans, and genes coding for insulin and insulin-like growth factor-1 (IGF-1) receptors in mammals ([24]). Insulin Resistance in the Liver-specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex: Relative Roles of Growth Hormone and IGF-1 in Insulin Resistance. [Extracted from the article]

Cardiometabolic diseases are prevalent in aging Americans. Although some studies have implicated greater intake of dairy products, it is not clear how dairy intake is related to biomarkers of cardiometabolic health. Our aim was to test the hypothesis that associations of dairy foods with biomarkers of lipid metabolism, insulin-like growth factor signaling, and chronic inflammation may provide clues to understanding how dairy can influence cardiometabolic health. This was a cross-sectional study in the Women's Health Initiative using baseline food frequency questionnaire data to calculate dairy intake. Participants were 35,352 postmenopausal women aged 50 to 79 years at 40 clinical centers in the United States. Baseline (1993-1998) concentrations of 20 circulating biomarkers were measured. Multivariable-adjusted linear regression was used to estimate percent difference in biomarker concentrations per serving of total dairy and individual foods (milk, cheese, yogurt, butter, and low-fat varieties). Lower triglyceride concentrations were associated with greater intake of total dairy (–0.8% [95% CI –1.2% to –0.3%]), mainly driven by full-fat varieties. Individual dairy foods had specific associations with circulating lipid components. For example, greater total milk intake was associated with lower concentrations of total cholesterol (–0.4% [95% CI –0.7% to –0.2%]) and high-density lipoprotein cholesterol (–0.5% [95% CI –0.9% to –0.1%]), whereas greater butter intake was associated with higher total cholesterol (0.6% [95% CI 0.2% to 1.0%]) and high-density lipoprotein cholesterol (1.6% [95% CI 1.1% to 2.0%]) concentrations. In contrast, higher total yogurt intake was associated with lower total cholesterol (–1.1% [95% CI –2.0% to –0.2%]) and higher high-density lipoprotein cholesterol (1.8% [95% CI 0.5% to 3.1%]). Greater total dairy intake (regardless of fat content), total cheese, full-fat cheese, and yogurt were consistently associated with lower concentrations of glucose, insulin, and C-reactive protein. However, milk and butter were not associated with these biomarkers. Higher dairy intake, except butter, was associated with a favorable profile of lipids, insulin response, and inflammatory biomarkers, regardless of fat content. Yet, specific dairy foods might influence these markers uniquely. Findings do not support a putative role of dairy in cardiometabolic diseases observed in some previous studies. [ABSTRACT FROM AUTHOR]

Type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor and a mediator of the biologic effects of insulin-like growth factor (IGF)-I and -II. Inhibitors of IGF-1R signaling were tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target; essentially all IGF-1R inhibitors failed to provide an additional benefit compared with standard-of-care therapy. In this review, we will evaluate the role the insulin receptor (IR) plays in mediating IGF signaling and subsequent metabolic and mitogenic effects as 1 possible reason for these failures. IR is expressed as 2 isoforms, with the fetal isoform IR-A derived from alternative splicing and loss of exon 11, the adult isoform (IR-B) includes this exon. Cancer frequently re-expresses fetal proteins and this appears to be the case in cancer with a re-expression of the fetal isoform and an increased IR-A:IR-B ratio. The biological effects of IR isoform signaling are complex and not completely understood although it has been suggested that IR-A could stimulate mitogenic signaling pathways, play a role in cancer cell stemness, and mediate tolerance to cancer therapies. From a clinical perspective, the IR-A overexpression in cancer may explain why targeting IGF-1R alone was not successful. However, given the predominance of IR-A expression in cancer, it may also be possible to develop isoform specific inhibitors and avoid the metabolic consequences of inhibiting IR-B. If such inhibitors could be developed, then IR-A expression could serve as a predictive biomarker, and cotargeting IR-A and IGF-1R could provide a novel, more effective therapy method. [ABSTRACT FROM AUTHOR]

Increased animal but not plant protein intake has been associated with increased mortality in epidemiological studies in humans and with reduced lifespan in animal species. Protein intake increases the activity of the IGF-1 system which may provide a link to reduced lifespan. We, therefore, compared the effects of animal versus plant protein intake on circulating levels of IGF-1 and the IGF-binding proteins (IGFBP)-1 and IGFBP-2 over a 6-week period. Thirty seven participants with type 2 diabetes consumed isocaloric diets composed of either 30% energy (EN) animal or plant protein, 30% EN fat and 40% EN carbohydrates for 6 weeks. The participants were clinically phenotyped before and at the end of the study. Both diets induced similar and significant increases of IGF-1 which was unaffected by the different amino acid compositions of plant and animal protein. Despite improvements of insulin sensitivity and major reductions of liver fat, IGFBP2 decreased with both diets while IGFBP-1 was not altered. We conclude that animal and plant protein similarly increase IGF-1 bioavailability while improving metabolic parameters and may be regarded as equivalent in this regard. [ABSTRACT FROM AUTHOR]

Introduction: Isotretinoin is the only effective agent at all stages of acne vulgaris, but its effects on certain systems remain unkown. Objective: To evaluate the effects of isotretinoin and other acne treatments on insulin growth factor-1 (IGF-1), insulin-like growth factor-3 binding protein (IGFBP-3), insulin, C-peptide, glucose and glycated hemoglobin A1c (HbA1c), and HOMA-IR. Material and methods: Eighty one patients with acne vulgaris were divided into two groups: the first group was treated with isotretinoin and the second group treated with systemic minocycline and topical benzoyl peroxide (in combined treatment). IGF-1, IGFBP3, insulin, HOMA-IR, C-peptide, glucose and HbA1c serum levels were assessed in two groups. Results: IGFBP-3 levels were significantly increased in patients receiving isotretinoin treatment for 3 months. When isotretinoin and combined treatment groups were compared, a significant rise in the IGF-1 level was found in the combined treatment group. Unlike the literature, our results showed that the commonly used acne treatments did not change the serum levels of IGF-1, insulin, C-peptide, glucose and HbA1c significantly. Conclusions: Consequently, we showed that isotretinoin did not impair glucose metabolism in patients who were previously not obese or insulin resistant. Since IGF-1, IGFBP-3 parameters have effects on cell growth and proliferation, we suggest that they play an effective role in acne pathogenesis and treatment mechanism. [ABSTRACT FROM AUTHOR]

Obesity, a global epidemic, is an independent risk factor for the occurrence and development of a variety of tumorigenesis, such as breast cancer, pancreatic cancer, ovarian cancer and colorectal cancer. Adipocytes are important endocrine cells in the tumor microenvironment of obesity-related tumors, which can secrete a variety of adipokines (such as leptin, adiponectin, estrogen, resistin, MIF and MCP-1, etc.), among which leptin, adiponectin and estrogen are the most in-depth and valuable ones. These adipokines are closely related to tumorigenesis and the progression of tumors. In recent years, more and more studies have shown that under chronic inflammatory conditions such as obesity, adipocytes secrete more adipokines to promote the tumorigenesis and development of tumors. However, it is worth noting that although adiponectin is also secreted by adipocytes, it has an anti-tumor effect, and can cross-talk with other adipokines (such as leptin and estrogen) and insulin to play an anti-tumor effect together. In addition, obesity is the main cause of insulin resistance, which can lead to the increase of the expression levels of insulin and insulin-like growth factor (IGF). As important regulators of blood glucose and lipid metabolism, insulin and IGF also play an important role in the progress of obesity related tumors. In view of the important role of adipokines secreted by adipocytes and insulin/IGF in tumors, this article not only elaborates leptin, adiponectin and estrogen secreted by adipocytes and their mechanism of action in the development of obesity- related tumors, but also introduces the relationship between insulin/IGF, a regulator of lipid metabolism, and obesity related tumors. At the same time, it briefly describes the cancer-promoting mechanism of resistin, MIF and MCP-1 in obesity-related tumors, and finally summarizes the specific treatment opinions and measures for various adipokines and insulin/insulin-like growth factors in recent years. [ABSTRACT FROM AUTHOR]

Background. Some insulin/IGF-related peptides (irps) stimulate a receptor tyrosine kinase (RTK) that transfers the extracellular hormonal signal into an intracellular response. Other irps, such as relaxin, do not use an RTK, but a G-protein coupled receptor (GPCR). This is unusual since evolutionarily related hormones typically either use the same or paralogous receptors. In arthropods three different irps, i.e. arthropod IGF, gonadulin and Drosophila insulin-like peptide 7 (dilp7), likely evolved from a gene triplication, as in several species genes encoding these three peptides are located next to one another on the same chromosomal fragment. These arthropod irps have homologs in vertebrates, suggesting that the initial gene triplication was perhaps already present in the last common ancestor of deuterostomes and protostomes. It would be interesting to know whether this is indeed so and how insulin might be related to this trio of irps. Methodology. Genes encoding irps as well as their putative receptors were identified in genomes and transcriptomes from echinoderms and hemichordates. Results. A similar triplet of genes coding for irps also occurs in some ambulacrarians. Two of these are orthologs of arthropod IGF and dilp7 and the third is likely a gonadulin ortholog. In echinoderms, two novel irps emerged, gonad stimulating substance (GSS) and multinsulin, likely from gene duplications of the IGF and dilp7-like genes respectively. The structures of GSS diverged considerably from IGF, which would suggest they use different receptors from IGF, but no novel irp receptors evolved. If IGF and GSS use different receptors, and the evolution of GSS from a gene duplication of IGF is not associated with the appearance of a novel receptor, while irps are known to use two different types of receptors, the ancestor of GSS and IGF might have acted on both types of receptors while one or both of its descendants act on only one. There are three ambulacrarian GPCRs that have amino acid sequences suggestive of being irp GPCRs, two of these are orthologs of the gonadulin and dilp7 receptors. This suggests that the third might be an IGF receptor, and that by deduction, GSS only acts on the RTK. The evolution of GSS from IGF may represent a pattern, where IGF gene duplications lead to novel genes coding for shorter peptides that activate an RTK. It is likely this is how insulin and the insect neuroendocrine irps evolved independently from IGF. Conclusion. The local gene triplication described from arthropods that yielded three genes encoding irps was already present in the last common ancestor of protostomes and deuterostomes. It seems plausible that irps, such as those produced by neuroendocrine cells in the brain of insects and echinoderm GSS evolved independently from IGF and, thus, are not true orthologs, but the result of convergent evolution. [ABSTRACT FROM AUTHOR]

A pair of Y-organs (YOs) are the molting glands of decapod crustaceans. They synthesize and secrete steroid molting hormones (ecdysteroids) and their activity is controlled by external and internal signals. The YO transitions through four physiological states over the molt cycle, which are mediated by molt-inhibiting hormone (MIH; basal state), mechanistic Target of Rapamycin Complex 1 (mTORC1; activated state), Transforming Growth Factor-β (TGFβ)/Activin (committed state), and ecdysteroid (repressed state) signaling pathways. MIH, produced in the eyestalk X-organ/sinus gland complex, inhibits the synthesis of ecdysteroids. A model for MIH signaling is organized into a cAMP/Ca2+-dependent triggering phase and a nitric oxide/cGMP-dependent summation phase, which maintains the YO in the basal state during intermolt. A reduction in MIH release triggers YO activation, which requires mTORC1-dependent protein synthesis, followed by mTORC1-dependent gene expression. TGFβ/Activin signaling is required for YO commitment in mid-premolt. The YO transcriptome has 878 unique contigs assigned to 23 KEGG signaling pathways, 478 of which are differentially expressed over the molt cycle. Ninety-nine contigs encode G protein-coupled receptors (GPCRs), 65 of which bind a variety of neuropeptides and biogenic amines. Among these are putative receptors for MIH/crustacean hyperglycemic hormone neuropeptides, corazonin, relaxin, serotonin, octopamine, dopamine, allatostatins, Bursicon, ecdysis-triggering hormone (ETH), CCHamide, FMRFamide, and proctolin. Contigs encoding receptor tyrosine kinase insulin-like receptor, epidermal growth factor (EGF) receptor, and fibroblast growth factor (FGF) receptor and ligands EGF and FGF suggest that the YO is positively regulated by insulin-like peptides and growth factors. Future research should focus on the interactions of signaling pathways that integrate physiological status with environmental cues for molt control. [ABSTRACT FROM AUTHOR]

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in b-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth. [ABSTRACT FROM AUTHOR]

Insulin-like peptides are a group of hormones crucial for regulating metabolism, growth, and development in animals. Invertebrates, such as C. elegans , have been instrumental in understanding the molecular mechanisms of insulin-like peptides. Here, we review the 40 insulin-like peptide genes encoded in the C. elegans genome. Despite the large number, there is only one C. elegans insulin-like peptide receptor, called DAF-2. The insulin and insulin-like growth factor signaling (IIS) pathway is evolutionarily conserved from worms to humans. Thus C. elegans provides an excellent model to understand how these insulin-like peptides function. C. elegans is unique in that it possesses insulin-like peptides that have antagonistic properties, unlike all human insulin-like peptides, which are agonists. This review provides an overview of the current literature on C. elegans insulin-like peptide structures, processing, tissue localization, and regulation. We will also provide examples of insulin-like peptide signaling in C. elegans during growth, development, germline development, learning/memory, and longevity. [ABSTRACT FROM AUTHOR]

The regulatory subunits (P60 in insects, P85 in mammals) determine the activation of the catalytic subunits P110 in phosphatidylinositol 3-kinases (PI3Ks) in the insulin pathway for cell proliferation and body growth. However, the regulatory subunits also promote apoptosis via an unclear regulatory mechanism. Using Helicoverpa armigera, an agricultural pest, we showed that H. armigera P60 (HaP60) was phosphorylated under insulin-like peptides (ILPs) regulation at larval growth stages and played roles in the insulin/ insulin-like growth factor (IGF) signaling (IIS) to determine HaP110 phosphorylation and cell membrane translocation; whereas, HaP60 was dephosphorylated and its expression increased under steroid hormone 20-hydroxyecdysone (20E) regulation during metamorphosis. Protein tyrosine phosphatase non-receptor type 6 (HaPTPN6, also named tyrosine-protein phosphatase corkscrew-like isoform X1 in the genome) was upregulated by 20E to dephosphorylate HaP60 and HaP110. 20E blocked HaP60 and HaP110 translocation to the cell membrane and reduced their interaction. The phosphorylated HaP60 mediated a cascade of protein phosphorylation and forkhead box protein O (HaFOXO) cytosol localization in the IIS to promote cell proliferation. However, 20E, via G protein-coupled-receptor-, ecdysone receptor-, and HaFOXO signaling axis, upregulated HaP60 expression, and the non-phosphorylated HaP60 interacted with phosphatase and tensin homolog (HaPTEN) to induce apoptosis. RNA interference-mediated knockdown of HaP60 and HaP110 in larvae repressed larval growth and apoptosis. Thus, HaP60 plays dual functions to promote cell proliferation and apoptosis by changing its phosphorylation status under ILPs and 20E regulation, respectively. Author summary: The regulatory subunits of phosphatidylinositol 3-kinases (PI3Ks) play very important roles in various pathways by promoting cell proliferation or apoptosis. However, the upstream regulatory mechanism of their opposite functions is unclear. Using a seriously agricultural pest Helicoverpa armigera as a model, we show that ILPs induce HaP60 phosphorylation to increase HaP110 phosphorylation and cell membrane location to promote cell proliferation. 20E promotes HaP60 and HaP110 dephosphorylation that resulted in the cytosol localization and inhibition of PI3K activity. Moreover, 20E elevates HaP60 expression to promote apoptosis. Our study revealed that HaP60 plays dual functions to regulate cell proliferation and apoptosis by changing its phosphorylated status. [ABSTRACT FROM AUTHOR]

The regulation of energy homeostasis is controlled by the brain and, besides requiring high amounts of energy, it relies on functional insulin/insulin‐like growth factor (IGF)‐1 signalling in the central nervous system. This energy is mainly provided by mitochondria in form of ATP. Thus, there is an intricate interplay between mitochondrial function and insulin/IGF‐1 action to enable functional brain signalling and, accordingly, propagate a healthy metabolism. To adapt to different nutritional conditions, the brain is able to sense the current energy status via mitochondrial and insulin signalling‐dependent pathways and exerts an appropriate metabolic response. However, regional, cell type and receptor‐specific consequences of this interaction occur and are linked to diverse outcomes such as altered nutrient sensing, body weight regulation or even cognitive function. Impairments of this cross‐talk can lead to obesity and glucose intolerance and are linked to neurodegenerative diseases, yet they also induce a self‐sustainable, dysfunctional 'metabolic triangle' characterised by insulin resistance, mitochondrial dysfunction and inflammation in the brain. The identification of causal factors deteriorating insulin action, mitochondrial function and concomitantly a signature of metabolic stress in the brain is of utter importance to offer novel mechanistic insights into development of the continuously rising prevalence of non‐communicable diseases such as type 2 diabetes and neurodegeneration. This review aims to determine the effect of insulin action on brain mitochondrial function and energy metabolism. It precisely outlines the interaction and differences between insulin action, insulin‐like growth factor (IGF)‐1 signalling and mitochondrial function; distinguishes between causality and association; and reveals its consequences for metabolism and cognition. We hypothesise that an improvement of at least one signalling pathway can overcome the vicious cycle of a self‐perpetuating metabolic dysfunction in the brain present in metabolic and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R , may influence risk of BE. [ABSTRACT FROM AUTHOR]

The article summarizes available literature on hormonal response to resistance exercise and training in youth and addresses only the hormones that were examined in relation to resistance exercise or resistance training in children and adolescents. Topics discussed include various response to exercise and training which depends on genetic predisposition and the importance of growth hormone, insulin-like growth factor-1 (GH-IGF-1) hormonal axis for musculosketal system in childhood and adulthood.