Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System.

Ethanol use during pregnancy is a risk factor for developing adverse outcomes. Its metabolism by cytochrome P450 2E1 (CYP2E1) produces radical oxygen species (ROS), promoting cellular injury and apoptosis. To date, no studies have been conducted to elucidate the teratogenic effects due to both IGF-1 deficiency and ethanol consumption in mice placentas. The aim of this study is to determine the effect of ethanol consumption on the placenta and liver of partially IGF-1-deficient mice, the role of metabolism via CYP2E1, and the antioxidant enzyme system. Heterozygous (HZ, Igf1+/-) pregnant female mice were given water or 10% ethanol. Wild-type (WT, Igf1+/+) female mice were used as controls. At gestational day 19, pregnant dams were euthanized, and maternal liver and placentas were collected. Pregnant HZ dams were smaller than controls, and this effect was higher due to ethanol consumption. Cyp2e1 gene was overexpressed in the liver of HZ pregnant dams exposed to ethanol; at the protein level, CYP2E1 is reduced in placentas from all genotypes. The antioxidant enzymatic system was altered by ethanol consumption in both the maternal liver and placenta. The results in this work hint that IGF-1 is involved in intrauterine development because its deficiency exacerbates ethanol's effects on both metabolism and the placenta.

The Placenta as a Target for Alcohol During Pregnancy: The Close Relation with IGFs Signaling Pathway.

Alcohol is one of the most consumed drugs in the world, even during pregnancy. Its use is a risk factor for developing adverse outcomes, e.g. fetal death, miscarriage, fetal growth restriction, and premature birth, also resulting in fetal alcohol spectrum disorders. Ethanol metabolism induces an oxidative environment that promotes the oxidation of lipids and proteins, triggers DNA damage, and advocates mitochondrial dysfunction, all of them leading to apoptosis and cellular injury. Several organs are altered due to this harmful behavior, the brain being one of the most affected. Throughout pregnancy, the human placenta is one of the most important organs for women's health and fetal development, as it secretes numerous hormones necessary for a suitable intrauterine environment. However, our understanding of the human placenta is very limited and even more restricted is the knowledge of the impact of toxic substances in its development and fetal growth. So, could ethanol consumption during this period have wounding effects in the placenta, compromising proper fetal organ development? Several studies have demonstrated that alcohol impairs various signaling cascades within G protein-coupled receptors and tyrosine kinase receptors, mainly through its action on insulin and insulin-like growth factor 1 (IGF-1) signaling pathway. This last cascade is involved in cell proliferation, migration, and differentiation and in placentation. This review tries to examine the current knowledge and gaps in our existing understanding of the ethanol effects in insulin/IGFs signaling pathway, which can explain the mechanism to elucidate the adverse actions of ethanol in the maternal-fetal interface of mammals.

Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study.

PURPOSE: To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). METHODS: This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). RESULTS: Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. CONCLUSIONS: Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.

Altered Body Composition and Increased Resting Metabolic Rate Associated with the Postural Instability/Gait Difficulty Parkinson's Disease Subtype.

BACKGROUND: Weight loss in Parkinson's disease (PD) patients is a common but poorly understood manifestation. Several studies have reported that weight changes could be related to motor symptoms, drug side effects, dysphagia, depression, and/or dementia. Weight loss in PD is not a benign phenomenon and it has several clinical and prognostic implications with increased morbidity and mortality. Thus, it is crucial to determine nutritional changes in PD patients in order to prevent malnutrition and improve their quality of life. OBJECTIVE: To compare body composition and resting metabolic rates between PD patients and controls. METHODS: A total of 64 PD patients and 52 controls were studied. The Hoehn-Yahr scale was used to determine the disease stage, clinical and epidemiological data were recorded from verbal questionnaire, Inbody S10® was used to collect corporal parameters, and FitMate system was used to assess the resting metabolic rate. RESULTS: No significant differences were found between both experimental groups in age, gender, height, cholesterol levels, and the presence of hypertension, diabetes, and hypo/hyperthyroidism. However, the PD group showed lower body fat mass, whole-body fat percentage, and greater resting metabolic rate compared to controls (p < 0.05), with no significant differences in musculoskeletal mass. Parkinson's disease postural instability/gait difficulty (PD-PIGD) subtype showed lower body fat parameters, increased fat-free mass, and higher resting metabolic rates. CONCLUSIONS: These results suggest that PD patients present an increased resting metabolic rate associated with the postural instability/gait difficulty PD subtype, allowing a selective decrease of body fat mass and not musculoskeletal mass. Of note, several disease-related factors may contribute to this weight loss in PD patients, being a complex and multifactorial consequence. Our findings could likely be one of the many contributing factors. However, present findings may further add to our understanding of the phenomenon of weight loss in patients with PD.

Is insulin-like growth factor-1 involved in Parkinson's disease development?

Parkinson's disease (PD) is a neurodegenerative disorder that results in the death of dopaminergic neurons within the substantia nigra pars compacta and the reduction in dopaminergic control over striatal output neurons, leading to a movement disorder most commonly characterized by akinesia or bradykinesia, rigidity and tremor. Also, PD is less frequently depicted by sensory symptoms (pain and tingling), hyposmia, sleep alterations, depression and anxiety, and abnormal executive and working memory related functions. On the other hand, insulin-like growth factor 1 (IGF-1) is an endocrine, paracrine and autocrine hormone with several functions including tissue growth and development, insulin-like activity, proliferation, pro-survival, anti-aging, antioxidant and neuroprotection, among others. Herein this review tries to summarize all experimental and clinical data to understand the pathophysiology and development of PD, as well as its clear association with IGF-1, supported by several lines of evidence: (1) IGF-1 decreases with age, while aging is the major risk for PD establishment and development; (2) numerous basic and translational data have appointed direct protective and homeostasis IGF-1 roles in all brain cells; (3) estrogens seem to confer women strong protection to PD via IGF-1; and (4) clinical correlations in PD cohorts have confirmed elevated IGF-1 levels at the onset of the disease, suggesting an ongoing compensatory or "fight-to-injury" mechanism.

A 42-Year-Old Woman with Untreated Growth Hormone Insensitivity, Diabetic Retinopathy, and Gene Sequencing Identifies a Variant of Laron Syndrome.

BACKGROUND Growth hormone insensitivity and reduced levels of insulin-like growth factor-1 (IGF-1) are associated with metabolic syndrome that includes obesity, hyperglycemia, type 2 diabetes mellitus, and dyslipidemia. Laron syndrome is a rare autosomal recessive condition associated with insensitivity to growth hormone that results in short stature and metabolic syndrome and is usually diagnosed in childhood. This report is of a 42-year-old Mexican woman with untreated growth hormone insensitivity and diabetic retinopathy, in whom gene sequencing supported the identification of a variant of Laron syndrome. CASE REPORT A 42-year-old Mexican woman with untreated growth hormone insensitivity, metabolic syndrome, and type 2 diabetes mellitus was diagnosed with cataracts, severe retinopathy and hearing loss. She was investigated for genetic causes of reduction in IGF-1. Next-generation sequencing (NGS) showed genetic changes in the growth hormone and IGF-1 axis. The patient's phenotype and genetic changes were consistent with Laron syndrome. CONCLUSIONS The early detection of reduced IGF-1 and identification of the cause of growth hormone insensitivity require international consensus on the approach to diagnosis and treatment methods, including effective IGF-1 replacement therapy. Early diagnosis may reduce the clinical consequences of complications that include short stature the development of metabolic syndrome, type 2 diabetes mellitus, and retinopathy.

Neurotrophic Factors and Their Receptors Are Altered by the Mere Partial IGF-1 Deficiency.

Neurotrophic factors (NTFs) are a relevant group of secreted proteins that modulate growth, differentiation, repair, and survival of neurons, playing a role in the maintenance of the synaptic unions, dendrites, and axons and also being crucial for peripheral nervous system development and regulating plasticity in the adult central nervous system. On the other hand, insulin-like growth factor 1 (IGF-1) has been ascertained multiple beneficial actions in the brain: neuro-development, -protection, -genesis and plasticity. To further investigate the possible mechanisms underlying IGF-1 deficiency in the establishment of neurological disease, microarray and reverse transcription polymerase chain reaction gene expression analyses coupled with in silico processing were performed in an experimental model of partial IGF-1 deficiency. Results show that the mere IGF-1 deficiency seems to be responsible for an altered expression of genes coding for neurotrophic factors (particularly ciliary neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor), their receptors and signaling pathways (specially RET). The presented findings support that IGF-1 deficiency might be involved in the establishment and progression of neurodegenerative disorders.

Primary growth hormone insensitivity and psychomotor delay.

We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF-1 levels had suggested GH deficiency, while response to therapy indicated GH insensitivity. Molecular evaluation of the GH/IGF-1 axis should be performed in these cases to improve diagnosis and therapy.

Insulin-Like Growth Factor 1 in the Cardiovascular System.

Non-communicable diseases, such as cardiovascular diseases, are the leading cause of mortality worldwide. For this reason, a tremendous effort is being made worldwide to effectively circumvent these afflictions, where insulin-like growth factor 1 (IGF1) is being proposed both as a marker and as a central cornerstone in these diseases, making it an interesting molecule to focus on. Firstly, at the initiation of metabolic deregulation by overfeeding, IGF1 is decreased/inhibited. Secondly, such deficiency seems to be intimately related to the onset of MetS and establishment of vascular derangements leading to atherosclerosis and finally playing a definitive part in cerebrovascular and myocardial accidents, where IGF1 deficiency seems to render these organs vulnerable to oxidative and apoptotic/necrotic damage. Several human cohort correlations together with basic/translational experimental data seem to confirm deep IGF1 implication, albeit with controversy, which might, in part, be given by experimental design leading to blurred result interpretation.

Mexican case report of a never-treated Laron syndrome patient evolving to metabolic syndrome, type 2 diabetes, and stroke.

Glucose and lipid profile together with blood pressure should always be considered for low sera-IGF-1 patients. Even when adulthood is reached, IGF-1 therapy in these patients should be pursued as metabolic and protective cellular effects could be triggered. Real incidence of growth hormone insensitivity is still to be uncovered.

Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins.

Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions.

Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency.

BACKGROUND: Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl4)-induced liver damage compared to healthy controls (Wt Igf +/+). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/-). METHODS: Three groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+) were included in the protocol: untreated controls (Wt). Controls that received CCl4 (Wt + CCl4) and Wt + CCl4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl4 + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/-) groups were studied: untreated Hz, Hz + CCl4, and Hz + CCl4 + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM. RESULTS: An altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl4 + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl4. Moreover, there was a correlation between MDA levels and the histological damage score (Pearson's r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma. CONCLUSIONS: IGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.

Fanconi Anemia and Laron Syndrome.

BACKGROUND: Fanconi anemia (FA) is a condition characterized by genetic instability and short stature, which is due to growth hormone (GH) deficiency in most cases. However, no apparent relationships have been identified between FA complementation group genes and GH. In this study, we thereby considered an association between FA and Laron syndrome (LS) (insulin-like growth factor 1 [IGF-1] deficiency). METHODS: A 21-year-old female Mexican patient with a genetic diagnosis of FA was referred to our research department for an evaluation of her short stature. Upon admission to our facility, her phenotype led to a suspicion of LS; accordingly, serum levels of IGF-1 and IGF binding protein 3 were analyzed and a GH stimulation test was performed. In addition, we used a next-generation sequencing approach for a molecular evaluation of FA disease-causing mutations and genes involved in the GH-IGF signaling pathway. RESULTS: Tests revealed low levels of IGF-1 and IGF binding protein 3 that remained within normal ranges, as well as a lack of response to GH stimulation. Sequencing confirmed a defect in the GH receptor signaling pathway. CONCLUSIONS: To the best of our knowledge, this study is the first to suggest an association between FA and LS. We propose that IGF-1 administration might improve some FA complications and functions based upon IGF-1 beneficial actions observed in animal, cell and indirect clinical models: erythropoiesis modulation, immune function improvement and metabolic regulation.

Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment.

Cirrhosis represents the final stage of chronic liver damage, which can be due to different factors such as alcohol, metabolic syndrome with liver steatosis, autoimmune diseases, drugs, toxins, and viral infection, among others. Nowadays, cirrhosis is an important health problem and it is an increasing cause of morbidity and mortality, being the 14th most common cause of death worldwide. The physiopathological pathways that lead to fibrosis and finally cirrhosis partly depend on the etiology. Nevertheless, some common features are shared in this complex mechanism. Recently, it has been demonstrated that cirrhosis is a dynamic process that can be altered in order to delay or revert fibrosis. In addition, when cirrhosis has been established, insulin-like growth factor-1 (IGF-1) deficiency or reduced availability is a common condition, independently of the etiology of chronic liver damage that leads to cirrhosis. IGF-1 deprivation seriously contributes to the progressive malnutrition of cirrhotic patient, increasing the vulnerability of the liver to establish an inflammatory and oxidative microenvironment with mitochondrial dysfunction. In this context, IGF-1 deficiency in cirrhotic patients can justify some of the common characteristics of these individuals. Several studies in animals and humans have been done in order to test the replacement of IGF-1 as a possible therapeutic option, with promising results.

Clinical and molecular diagnosis of a cartilage-hair hypoplasia with IGF-1 deficiency.

Cartilage-hair hypoplasia syndrome (CHH) is a rare autosomal recessive condition characterized by metaphyseal chondrodysplasia and characteristic hair, together with a myriad of other symptoms, being most common immunodeficiency and gastrointestinal complications. A 15-year-old Mexican male initially diagnosed with Hirschsprung disease and posterior immunodeficiency, presents to our department for genetic and complementary evaluation for suspected CHH. Physical, biochemical, and genetic studies confirmed CHH together with IGF-1 deficiency. For this reason, we propose IGF-1 replacement therapy for its well-known actions on hematopoiesis, immune function and maturation, and metabolism. © 2016 Wiley Periodicals, Inc.

Partial IGF-1 deficiency induces brain oxidative damage and edema, which are ameliorated by replacement therapy.

Insulin-like growth factor 1 (IGF-1) induces multiple cytoprotective effects on every tissue, including the brain. Since the mechanisms by which IGF-1 produces neuroprotection are not fully understood, the aim of this work was to delve into the underlying mechanisms. IGF-1 deficient mice (Hz) were compared with wild type (WT) and Hz mice treated with low doses of IGF-1 (2 µg/100 g body weight/day) for 10 days (Hz + IGF). Gene expression, quantitative PCR, histology, and magnetic resonance imaging were performed in the three groups. IGF-1 deficiency induced increased oxidative damage determined by markers of lipid peroxidation and hypoxia, as well as gene expression of heat shock proteins, antioxidant enzymes, and molecules involved in inflammation, apoptosis, and mitochondrial protection. These changes correlated with edema and learning impairment in Hz mice. IGF-1 therapy improved all these alterations. In conclusion, IGF-1 deficiency is responsible for increased brain oxidative damage, edema, and impaired learning and memory capabilities which are rescued by IGF-1 replacement therapy.

Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy.

OBJECTIVE: To determine whether insulin-like growth factor (IGF-1) deficiency can cause testicular damage and to examine changes of the testicular morphology and testicular function-related gene expression caused by IGF-1 deficiency. Therefore, this study aims to determine the benefits of low doses of IGF-1 and to explore the mechanisms underlying the IGF-1 replacement therapy. MATERIALS AND METHODS: A murine model of IGF-1 deficiency was used to avoid any factor that could contribute to testicular damage. Testicular weight, score of histopathological damage, and gene expressions were studied in 3 experimental groups of mice: controls (wild-type Igf1(+/+)), heterozygous Igf1(+/-) with partial IGF-1 deficiency, and heterozygous Igf1(+/-) treated with IGF-1. RESULTS: Results show that the partial IGF-1 deficiency induced testicular damage and altered expression of genes involved in IGF-1 and growth hormone signaling and regulation, testicular hormonal function, extracellular matrix establishment and its regulation, angiogenesis, fibrogenesis, inflammation, and cytoprotection. In addition, proteins involved in tight junction expression were found to be reduced. However, low doses of IGF-1 restored the testicular damage and most of these parameters. CONCLUSION: IGF-1 deficiency caused the damage of the blood-testis barrier and testicular structure and induced the abnormal testicular function-related gene expressions. However, low doses of IGF-1 constitute an effective replacement therapy that restores the described testicular damage. Data herein show that (1) cytoprotective activities of IGF-1 seem to be mediated by heat shock proteins and that (2) connective tissue growth factor could play a relevant role together with IGF-1 in the extracellular matrix establishment.

IGF-I increases markers of osteoblastic activity and reduces bone resorption via osteoprotegerin and RANK-ligand.

BACKGROUND: Bone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone. METHODS: Several proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice, Igf+/+, n=10), heterozygous Igf+/- group with partial IGF-I deficiency (Hz, n=10), and heterozygous Igf+/- mice treated with IGF-I for 10 days (Hz+IGF-I, n=10). RESULTS: Data in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity. CONCLUSIONS: Low doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

Human conditions of insulin-like growth factor-I (IGF-I) deficiency.

Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.

Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats.

BACKGROUND: GH and IGFs serum levels decline with age. Age-related changes appear to be associated to decreases in these anabolic hormones. We have previously demonstrated that IGF-I replacement therapy improves insulin resistance, lipid metabolism and reduces oxidative damage (in brain and liver) in aging rats. Using the same experimental model, the aim of this work was to study whether the exogenous administration of IGF-II, at low doses, acts analogous to IGF-I in aging rats. METHODS: Three experimental groups were included in this study: young healthy controls (yCO, 17 weeks old); untreated old rats (O, 103 weeks old); and aging rats treated with IGF-II (O+IGF-II, 2 µg * 100 g body weight⁻¹ * day⁻¹) for 30 days. Analytical parameters were determined in serum by routine laboratory methods using an autoanalyzer (Cobas Mira; Roche Diagnostic System, Basel, Switzerland). Serum levels of hormones (testosterone, IGF-I and insulin) were assessed by RIA. Serum Total Antioxidant Status was evaluated using a colorimetric assay. Mitochondrial membrane potential was evaluated using rhodamine 123 dye (adding different substrates to determine the different states). ATP synthesis in isolated mitochondria was determined by an enzymatic method. RESULTS: Compared with young controls, untreated old rats showed a reduction of IGF-I and testosterone levels with a decrease of serum total antioxidant status (TAS). IGF-II therapy improved serum antioxidant capability without modifying testosterone and IGF-I circulating concentrations. In addition, IGF-II treatment reduced oxidative damage in brain and liver, improving antioxidant enzyme activities and mitochondrial function. IGF-II was also able to reduce cholesterol and triglycerides levels increasing free fatty acids concentrations. CONCLUSIONS: We demonstrate that low doses of IGF-II induce hepatoprotective, neuroprotective and metabolic effects, improving mitochondrial function, without affecting testosterone and IGF-I levels.