Altered Insulin Signaling Research Articles

Metabolic Analysis in Women with Polycystic Ovary Highlight Specific Biomarkers of Insulin Resistance

The aim of the paper is to detect insulin resistance (IR) biomarkers via metabolomics. It is important to understand the PCOS pathophysiology, diagnosis measures and, subsequently, to improve treatment type and time of IR in PCOS. In most cases, almost half of the women with PCOS have IR which is triggered by inflammation, glucotoxicity and lipotoxicity. In this work was conducted a systematic review of all the papers that used metabolomics for detecting IR biomarkers in PCOS women. The exclusion criteria were: reviews, study population with women bellow 18 years of age, studies including animals and articles not in English, remaining 4 records. The results from the literature shown that phosphatidylcholines were decreased in IR PCOS women when compared to controls. Nonetheless, trans-2-hexenoylcoa, linoleic acid, leucine, myristic acid and palmitic acid regarding lipid metabolism and tyrosine, lysine, phenylalanine a-aminoadipic acid regarding amino acid metabolism were also corelated to IR in PCOS women when compared with healthy or IR controls. Lactate was the only increased metabolite related to glucose metabolism in IR PCOS women. Metabolic alteration in PCOS women with IR when are compared with controls and results that those are brought by both PCOS and IR. Lyso-phosphatidylcholine have an important pro-inflammatory and altered insulin signaling effect, both alterations being considered hallmarks of PCOS women. Serine hyperphosphorylation of the receptor accentuates IR by decreasing the signaling of insulin receptor. Moreover, high levels of lactate correlated with IR in PCOS women may indicate high muscle glycolysis, hepatic glucose production and peripheral glucose uptake. IR biomarkers in PCOS women were evidenced by metabolomics technique.

Metabolic Analysis in Women with Polycystic Ovary Highlight Specific Biomarkers of Insulin Resistance

The aim of the paper is to detect insulin resistance (IR) biomarkers via metabolomics. It is important to understand the PCOS pathophysiology, diagnosis measures and, subsequently, to improve treatment type and time of IR in PCOS. In most cases, almost half of the women with PCOS have IR which is triggered by inflammation, glucotoxicity and lipotoxicity. In this work was conducted a systematic review of all the papers that used metabolomics for detecting IR biomarkers in PCOS women. The exclusion criteria were: reviews, study population with women bellow 18 years of age, studies including animals and articles not in English, remaining 4 records. The results from the literature shown that phosphatidylcholines were decreased in IR PCOS women when compared to controls. Nonetheless, trans-2-hexenoylcoa, linoleic acid, leucine, myristic acid and palmitic acid regarding lipid metabolism and tyrosine, lysine, phenylalanine a-aminoadipic acid regarding amino acid metabolism were also corelated to IR in PCOS women when compared with healthy or IR controls. Lactate was the only increased metabolite related to glucose metabolism in IR PCOS women. Metabolic alteration in PCOS women with IR when are compared with controls and results that those are brought by both PCOS and IR. Lyso-phosphatidylcholine have an important pro-inflammatory and altered insulin signaling effect, both alterations being considered hallmarks of PCOS women. Serine hyperphosphorylation of the receptor accentuates IR by decreasing the signaling of insulin receptor. Moreover, high levels of lactate correlated with IR in PCOS women may indicate high muscle glycolysis, hepatic glucose production and peripheral glucose uptake. IR biomarkers in PCOS women were evidenced by metabolomics technique. Keywords: Polycystic ovary syndrome, insulin resistance, metabolomics, women, plasma, metabolism, biomarkers

Leucine increases mitochondrial metabolism and lipid content without altering insulin signaling in myotubes

Elevated circulating branched-chain amino acids (BCAA) such as leucine have been consistently correlated with increasing severity of insulin resistance across numerous populations. BCAA may promote insulin resistance through either mTOR-mediated suppression of insulin receptor substrate-1 or through the accumulation of toxic BCAA catabolites. Although the link between circulating BCAA and insulin resistance has been consistent, it has yet to be concluded if BCAA causally contribute to the development or worsening of insulin resistance. This work investigated the effect of leucine both with and without varying levels of insulin resistance on metabolism, metabolic gene expression, and insulin signaling. C2C12 myotubes were treated with and without varied concentrations of leucine up to 2 mM for 24 h both with and without varied levels of insulin resistance. Gene and protein expression were measured via qRT-PCR and Western blot, respectively. Mitochondrial metabolism was measured via O2 consumption. Leucine at 2 mM increased oxidative metabolism as well as gene expression of mitochondrial biogenesis, which was associated with increased cellular lipid content. Despite increased lipid content of leucine-treated cells, neither acute nor chronic leucine treatment at 2 mM affected insulin signaling in insulin sensitive, mildly insulin resistant, or severely insulin resistant cells. Similarly, leucine at lower concentrations (0.25 mM, 0.5 mM, and 1 mM) did not alter insulin signaling either, regardless of insulin resistance. Leucine appears to improve myotube oxidative metabolism and related metabolic gene expression. And despite increased lipid content of leucine-treated cells, leucine does not appear to alter insulin sensitivity either acutely or chronically, regardless of level of insulin resistance.

Alteration of insulin signaling to control insect pest by using transformed bacteria expressing dsRNA.

Insulin/insulin-like growth factor signaling (IIS) is known to mediate larval growth and adult reproduction in the legume pod borer, Maruca vitrata (Lepidoptera: Crambidae). Four IIS components (InR, FOXO, Akt, and TOR) play crucial roles in the IIS pathway. RNA interference (RNAi) against any of these four IIS component genes was effective in suppressing each target mRNA level by either hemocoelic injection or oral administration using gene-specific double-stranded RNAs (dsRNAs). These RNAi treatments interfered with larval growth, leading to small pupae or significant larval mortality. For massive production of dsRNA, transformed bacteria expressing dsRNAs of these four IIS components were prepared with L4440 expression vector and HT115 strain of Escherichia coli. The transformed bacteria killed the larvae in a dose-dependent manner by feeding administration. An ultra-sonication pretreatment was performed to impair bacterial membrane and increase dsRNA release from the bacteria in insect intestine. This pretreatment increased the insecticidal activity of these recombinant bacteria. To further increase dsRNA toxicity, its mixture with Bacillus thuringiensis (Bt) was prepared and showed significant increase of Bt insecticidal activity in the laboratory. The bacterial mixture also showed a high control efficacy (83.3%) in an adzuki bean (Vigna angularis) field infested by M. vitrata. Furthermore, such a dsRNA effect was specific for M. vitrata, but not for non-target insects. The bacteria expressing dsRNA specific to IIS components can be used to develop dsRNA insecticide. © 2019 Society of Chemical Industry.

Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity

ObjectivesPaternally inherited alterations in epigenetic programming are emerging as relevant factors in numerous disease states, including the growth and metabolic defects observed in fetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use induces fetal growth restriction, as well as sex-specific alterations in insulin signaling and lipid homeostasis in the offspring. Based on previous studies, we hypothesized that the observed metabolic irregularities are the consequence of paternally inherited alterations liver x receptor (LXR) activity. MethodsMale offspring of alcohol-exposed sires were challenged with a high-fat diet and the molecular pathways controlling glucose and lipid homeostasis assayed for LXR-induced alterations. ResultsSimilar to findings in studies employing LXR agonists we found that the male offspring of alcohol-exposed sires display resistance to diet-induced obesity and improved glucose homeostasis when challenged with a high-fat diet. This improved metabolic adaptation is mediated by LXRα trans-repression of inflammatory cytokines, releasing IKKβ inhibition of the insulin signaling pathway. Interestingly, paternally programmed increases in LXRα expression are liver-specific and do not manifest in the pancreas or visceral fat. ConclusionsThese studies identify LXRα as a key mediator of the long-term metabolic alterations induced by preconception paternal alcohol use.

Mice lacking angiotensin type 2 receptor exhibit a sex-specific attenuation of insulin sensitivity

The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.

Endoplasmic Reticulum Stress Activates Unfolded Protein Response Signaling and Mediates Inflammation, Obesity, and Cardiac Dysfunction: Therapeutic and Molecular Approach.

Obesity has been implicated as a risk factor for insulin resistance and cardiovascular diseases (CVDs). Although the association between obesity and CVD is a well-established phenomenon, the precise mechanisms remain incompletely understood. This has led to a relative paucity of therapeutic measures for the prevention and treatment of CVD and associated metabolic disorders. Recent studies have shed light on the pivotal role of prolonged endoplasmic reticulum stress (ERS)-initiated activation of the unfolded protein response (UPR), the ensuing chronic low-grade inflammation, and altered insulin signaling in promoting obesity-compromised cardiovascular system (CVS). In this aspect, potential ways of attenuating ERS-initiated UPR signaling seem a promising avenue for therapeutic interventions. We review intersecting role of obesity-induced ERS, chronic inflammation, insulin resistance, and oxidative stress in the discovery of targeted therapy. Moreover, this review highlights the current progress and strategies on therapeutics being explored in preclinical and clinical research to modulate ERS and UPR signaling.

Chronic Light Cycle Disruption Alters Central Insulin and Leptin Signaling as well as Metabolic Markers in Male Mice.

Recent evidence suggests that the circadian timing system plays a role in energy and glucose homeostasis, and disruptions to this system are a risk factor for the development of metabolic disorders. We exposed animals to a constantly shifting lighting environment comprised of a 6-hour advance, occurring every 6 days, to chronically disrupt their circadian timing system. This treatment caused a gradual increase in body weight of 12 ± 2% after 12 phase shifts, compared with a 6 ± 1% increase in mice under control lighting conditions. Additionally, after the fifth phase shift, light cycle-disrupted (CD) animals showed a reversal in their diurnal pattern of energy homeostasis and locomotor activity, followed by a subsequent loss of this rhythm. To investigate potential molecular mechanisms mediating these metabolic alterations, we assessed central leptin and insulin sensitivity. We discovered that CD mice had a decrease in central leptin signaling, as indicated by a reduction in the number of phosphorylated signal transducer and activator of transcription 3 immunoreactive cells in the arcuate nucleus of the hypothalamus. Furthermore, CD animals exhibited a marked increase in fasting blood glucose (269.4 ± 21.1 mg/dL) compared with controls (108.8 ± 21.3 mg/dL). This dramatic increase in fasting glucose levels was not associated with an increase in insulin levels, suggesting impairments in pancreatic insulin release. Peripheral hyperglycemia was accompanied by central alterations in insulin signaling at the level of phospho Akt and insulin receptor substrate 1, suggesting that light cycle disruption alters central insulin signaling. These results provide mechanistic insights into the association between light cycle disruption and metabolic disease.

Pterostilbene reverses palmitic acid mediated insulin resistance in HepG2 cells by reducing oxidative stress and triglyceride accumulation

Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3β. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.

Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway.

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two to fourfold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid, and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-β and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in vivo in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.

1774-P: Maternal Apical Periodontitis Promotes Insulin Resistance in Adult Offspring

Background: Adverse stimuli applied during early fetal development can increase the risk of diseases in adulthood. Aim: This study investigated the plasma concentrations of glucose, insulin, and tumor necrosis factor-α (TNF-α) of rats with maternal apical periodontitis (AP). We also explored the effect of maternal inflammation on the initial steps of insulin signaling and the inflammatory pathway in the gastrocnemius muscle (GM) of adult offspring. Methodology: Fifteen female Wistar rats were distributed into control group (CN), group with 1 AP (1AP) and group with 4 AP (4AP). Thirty days following induction of AP, female rats from all groups were mated with healthy male rats. When male offspring reached 75 days of age, plasma concentrations of glucose, insulin, and TNF-α were quantified. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR) index. Phosphorylation status of pp185 tyrosine, insulin receptor substrate 1 (IRS-1) serine, IκB kinase α/β (IKKα/β), and c-Jun N-terminal kinase (JNK) in the GM were measured by western blot. Results: Maternal AP promotes insulin resistance, impairs the initial steps of insulin signaling, increases plasma concentrations of insulin and TNF-α, and enhances IKKα/β phosphorylation in the GM of adult offspring. However, maternal AP does not seem to affect fasting glycemia and JNK phosphorylation in the GM of adult offspring. Conclusions: Maternal AP promotes important alterations in insulin signaling and inflammation pathways, and leads to insulin resistance in adult offspring. Disclosure T.V. Tsosura: None. F.Y. Chiba: None. M.S. Mattera: None. R.F. Pereira: None. C.A. Garbin: None. L.T. Cintra: None. D.H. Sumida: None. Funding São Paulo Research Foundation (2017-01128-1)

271-LB: Intranasal Insulin Treatment Causes Sex-Specific Differences in Metabolism and Behavior in Mice

Brain insulin action regulates metabolism and behavior. Conversely in diabetes, brain insulin resistance associates with obesity and behavioral abnormalities. Intranasal insulin (INI) treatment activates brain insulin signaling in rodents and humans with a more prominent effect on metabolism in males. Recently, we have shown that INI treatment reduces diet-induced high fat diet (HFD) weight gain in males. Here, we investigated whether INI treatment reduces metabolic and behavioral abnormalities in males and females fed a HFD. We investigated the effect of 1h 1.75U INI treatment on metabolism and behavior in 12 weeks old C57BL/6N male and female mice fed a normal chow diet (NCD) and HFD for two weeks. We analyzed brain insulin signaling using ELISA, qPCR and western blot technique and assessed metabolic parameters as well as behavior using a dark-light box and novelty-suppressed feeding test. We show that acute INI treatment activates the insulin cascade in a region-dependent manner with highest activation in olfactory bulbus, caudate putamen and hypothalamus in males. INI treatment caused a two-fold increase in insulin levels in the cerebrospinal fluid (CSF) without altering blood glucose and insulin levels. INI reduced anxiety in males fed a NCD using a dark-light box test and novelty-suppressed feeding test. Yet, INI treatment did not alter insulin signaling and behavior in mice fed a HFD. Though male and female mice exhibited equal amounts of insulin receptor signaling proteins in the brain, INI treatment did not alter food intake, body weight gain or behavior in females fed a NCD or a HFD. In females, basal insulin levels in the CSF were comparable to insulin levels of INI-treated males and did not drastically increase further after INI treatment indicating optimal insulin action under basal conditions. Overall, we show that INI treatment activates the insulin signaling throughout the brain and improves in a sex-dependent manner metabolism and behavior only in healthy conditions. Disclosure C. Chudoba: None. A. Kleinridders: None. Funding German Federal Ministry of Education and Research; State of Brandenburg (82DZD00302)

Title: Biochemical linkage of type 2 diabetes mellitus and Alzheimer’s disease

Type 2 diabetes mellitus (T2DM) is a common disease in the elderly, affecting around 20% of geriatrics. In cross-sectional studies, T2DM had various adverse health effects, including cognitive impairment. The association of T2DM with decreased cognitive function suggests that T2DM can contribute to Alzheimer's disease (AD) The relationship between T2DM and AD continues to grow rapidly. It has been suggested that AD can be considered type 3 diabetes”. Along with the processing of amyloid precursor protein (APP) and tau phosphorylation, the molecular links between T2DM and AD provide clues for new therapeutic targets such as glucagon-like peptide-1 (GLP-1), butyrylcholinesterase and receptor for advanced glycosylation end products (AGE). A possible mechanism correlating T2DM and AD is the alteration in insulin signaling in the brain. Insulin signaling is involved in several neuronal functions, and plays a vital role in the pathophysiology of AD. Therefore, the modification of neuronal insulin signaling by diabetic conditions may contribute to AD progression. Another possible mechanism is cerebrovascular changes, a common pathological change observed in both diseases. The importance of amyloid beta peptide (Aβ) induced cerebrovascular dysfunction in AD has been reported, indicating that pathological interactions between AGE receptor and Aβ have a role in this disorder.

The effects of maternal nutrition around the time of conception on the health of the offspring

The incidence of prematurity, diabetes and cardiovascular disease have been increasing in both the developed and developing world. Increasing numbers of human studies suggest that these serious health outcomes may have developmental origins originating from nutritional deficits in the periconceptional period, with maternal nutrition around the time of conception now shown to have important effects on the length of gestation, trajectory of fetal growth and on postnatal growth and health. Biomedical research using the pregnant sheep has been widely employed to gain a deeper understanding of the underlying mechanisms involved. There is growing awareness that this field of research has major implications for the livestock production industry. From our own studies on sheep we have evidence that maternal undernutrition during the periconceptional period results in altered fetal hypothalamic-pituitary-adrenal axis (HPAA) development, an increased rate of premature birth, altered fetal pancreatic function, insulin signalling and amino acid metabolism, and also alterations in maternal adaptation to pregnancy. We are currently studying the postnatal consequences of these changes. Other research groups have shown that restricted nutrition of sheep in the early part of pregnancy alters postnatal muscle development, fat deposition, cardiovascular regulation and HPAA function. One aim of this review is to illustrate how biomedical research using animals such as the sheep has been used to gain a better understanding of the consequences of reduced maternal nutrition during the periconceptional period. We suggest that there are equally important consequences of this research for the livestock production industries.

Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

Cardio-metabolic complications of obstructive sleep apnea: Impact of chronic intermittent hypoxia on cardiac insulin signaling

Chronic intermittent hypoxia (IH) is the major feature of obstructive sleep apnea syndrome (OSA), well known to induce cardiac remodeling and contractile dysfunction as well as systemic insulin resistance. Currently, no studies have investigated the impact of IH on cardiac insulin signaling. Thus, we aimed to highlight the effects of chronic IH in both lean and obese mice on: – cardiac insulin signaling; – cardiac function and remodeling. C57BL/6 J male mice were fed either low-fat (LF) or high-fat (HF) diet for 20 weeks, and exposed to IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N) for the last 6 weeks. Systemic insulin sensitivity was evaluated by an insulin tolerance test (ITT). Cardiac remodeling and contractile function were assessed by echocardiography. Ultimately, hearts were withdrawn for biochemical analysis of the main effectors of the insulin signaling. In LF mice, IH induced systemic insulin resistance and altered cardiac insulin signaling (insulin-induced PAkt: 1,05 vs. 3,01 fold increase vs. NaCl in IH and N respectively, P < 0,05). In addition, despite an increased-cardiac contractility, IH significantly reduced the response to isoproterenol (EF: 34,21 ± 1,50 vs. 41,44 ± 2,08% increase, in LF IH and N respectively, P < 0,05), without any effect on cardiac remodeling. In the HF diet group, IH did not exert any additional effect, nor on insulin sensitivity and signaling, nor on cardiac function and remodeling. We highlighted a novel role for IH in the development of cardiac insulin resistance, which was associated with a blunted cardiac response to β-adrenergic stimulation. Further studies are now needed to better understand the relationship between these two mechanisms.

Maternal apical periodontitis is associated with insulin resistance in adult offspring.

To investigate the plasma concentrations of glucose, insulin and tumour necrosis factor-α (TNF-α) of rats with maternal apical periodontitis (AP) and to explore the effect of maternal inflammation on the initial steps of insulin signalling and the inflammatory pathway in the gastrocnemius muscle (GM) and periepididymal white adipose tissue (pWAT) of adult offspring. Fifteen female Wistar rats were distributed into a control group (CN), a group with 1 tooth with AP (1AP) and a group with 4 teeth with AP (4AP). Thirty days following induction of AP, female rats from all groups were mated with healthy male rats. When male offspring reached 75days of age, plasma concentrations of glucose, insulin and TNF-α were quantified. Insulin resistance was evaluated by the homoeostasis model assessment of insulin resistance (HOMA-IR) index. Phosphorylation status of pp185 tyrosine, insulin receptor substrate 1 (IRS-1) serine, IκB kinase α/β (IKKα/β) and c-Jun N-terminal kinase (JNK) in the GM and pWAT were measured by Western blot. Analysis of variance was performed, followed by the Tukey's post hoc test. P values <0.05 were considered to be statistically significant. Maternal AP promoted insulin resistance, impaired the initial steps of insulin signalling, significantly increased plasma concentrations of insulin (P<0.001) and TNF-α (P<0.05), and enhanced IKKα/β phosphorylation in the GM and pWAT (P<0.05) of adult offspring. However, maternal AP did not affect fasting glycaemia and JNK phosphorylation in the GM and pWAT of adult offspring. Maternal AP was associated with insulin resistance in adult offspring through alterations in insulin signalling and inflammation pathways. The study provides information on the impact of maternal AP on the development of metabolic alterations such as insulin resistance in adult offspring and reinforces the importance of preventing maternal AP in order to maintain the general health of offspring.

Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity

Biliverdin reductase-A (BVR-A) is a serine/threonine/tyrosine kinase involved in the regulation of insulin signaling. In vitro studies have demonstrated that BVR-A is a substrate of the insulin receptor and regulates IRS1 by avoiding its aberrant activation, and in animal model of obesity the loss of hepatic BVR-A has been associated with glucose/insulin alterations and fatty liver disease. However, no studies exist in humans. Here, we evaluated BVR-A expression levels and activation in peripheral blood mononuclear cells (PBMC) from obese subjects and matched lean controls and we investigated the related molecular alterations of the insulin along with clinical correlates. We showed that BVR-A levels are significantly reduced in obese subjects and associated with a hyper-activation of the IR/IRS1/Akt/GSK-3β/AS160/GLUT4 pathway. Low BVR-A levels also associate with the presence of obesity, metabolic syndrome, NASH and visceral adipose tissue inflammation. These data suggest that the reduction of BVR-A may be responsible for early alterations of the insulin signaling pathway in obesity and in this context may represent a novel molecular target to be investigated for the comprehension of the process of insulin resistance development in obesity.

Effect of maternal periodontitis on GLUT4 and inflammatory pathway in adult offspring

Maternal periodontal disease leads to low birth weight (LBW), insulin resistance (IR), increased TNF-α levels, and alterations in insulin signaling in adult offspring. TNF-α has been associated with the stimulation of IKKβ/NF-κB, resulting in the decreased expression of GLUT4. Another mechanism that may be involved in decreasing GLUT4 expression is DNA methylation. This study aimed to evaluate in the adult offspring of rats with periodontal disease: IR, inflammatory pathways, DNA methylation, and expression of GLUT4. Female Wistar rats were distributed into control and experimental periodontal disease groups. Seven days after induction of periodontal disease, both groups were mated with healthy male rats. After weaning, male offspring were distributed into control offspring (CN-o) and periodontal disease offspring (PED-o) groups. Body weights were measured from 0-75 days of age. At day 75, the following were measured in the offspring: IR (HOMA-IR index); TNF-α and NF-κBp65 content in the gastrocnemius muscle (GM) by western blotting; IKKα/β, JNK, ERK 1/2, NF-κBp65, and NF-κBp50 phosphorylation status in the GM by western blotting; DNA methylation by restriction digest and real-time PCR(qAMP); and expression of GLUT4 mRNA in the GM by real-time PCR. LBW, IR, increases in TNF-α, IKKα/β, ERK 1/2, NF-κBp65, and NF-κBp50 decreased expression of GLUT4 mRNA were observed in the PED-o rats. No differences were identified in JNK phosphorylation status and DNA methylation in the evaluated regions of the GLUT4-encoding gene Slc2a4. Maternal periodontal disease causes LBW, IR, activation of inflammatory pathways, and decreased GLUT4 expression in the GM of adult offspring.

Transgenerational Effects of Periconception Heavy Metal Administration on Adipose Weight and Glucose Homeostasis in Mice at Maturity.

We previously demonstrated that periconception maternal administration (2 mg/kg body weight each) of cadmium chloride (CdCl2) plus methylmercury (II) chloride (CH3HgCl) impaired glucose homeostasis and increased body weights and abdominal adipose tissue weight of male offspring in the F1 generation. However, transgenerational effects of this exposure have not been studied. Therefore, the effects of periconception Cd+Hg administration on indices of chronic diseases at adulthood in F2-F4 generations were examined. Male and female progeny of Cd+Hg periconceptionally treated females, and offspring of vehicle control females were bred with naïve CD1 mice to obtain F2 offspring, with additional crosses as above to the F4 generation (F1-F4 animals were not administered Cd+Hg). Birth weights and litter size were similar in all generations. Indices of impaired glucose homeostasis were observed in matrilineally descended F2 male offspring, including reduced glucose tolerance, along with increased basal phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307 suggesting altered insulin signaling. Reduced glucose tolerance was also seen in F4 males. Increased body weight and/or abdominal adiposity were observed through the F4 generation in males descended matrilineally from the treated female progenitors. Patrilineally derived F2 females displayed reduced glucose tolerance. Females (F2) patrilineally and matrilineally derived displayed significant kidney enlargement. Periconception administration of cadmium and mercury caused persistent transgenerational effects in offspring through the F4 generation in the absence of continued toxicant exposure, with persistent transgenerational effects inherited specifically through the matrilineal germline.