Central Insulin Research Articles

Review of Inflammatory Markers in Metabolic Syndrome

The conditions included in the definition of metabolic syndrome typically include central obesity (excessive fat accumulation around the waist), insulin resistance, hyperglycemia (elevated blood sugar levels), dyslipidemia (abnormal levels of lipids in the blood), and hypertension (high blood pressure). Having any three or more of these conditions is considered to be indicative of metabolic syndrome. Metabolic syndrome (MetS) is emerging as a major public health problem with pro-inflammatory changes leading to Insulin Resistance and Cardiovascular Disease (CVD) at a very young age. Metabolic syndrome (MetS) is a global health concern; metabolic syndrome is becoming more common in our country. It is found to be a risk factor for insulin resistance and abnormal adipose tissue . Clinical symptoms of the syndrome could include abdominal obesity, hypertension, diabetes, hypertriglyceridemia, and low HDL cholesterol. So far various studies have been conducted on the effect of inflammatory markers like Serum Uric acid (UA), serum homocysteine, Leptin, Lp(a) etc. Most of them have reported a positive correlation between these inflammatory markers and the various components of (MetS) like abdominal obesity, elevated Blood pressure, Fasting blood Glucose and Lipid profile abnormalities like elevated Triglycerides (TAG) and low High Density Lipoprotein-Cholesterol (HDL-C). Various studies have reported a positive correlation between serum uric acid and Serum Homocysteine and Lp(a) in causing endothelial dysfunction and premature Cardiovascular events. Hence a review of the studies pertaining to the various inflammatory markers was done. There was an association of various inflammatory markers like uric acid, homocysteine, MDA, lipoprotein and others. More awareness must be created even at the high school level regarding the ill effects of sedentary lifestyle the likely hood of metabolic syndrome. An early identification of surging biomarker levels in high-risk children may find new cases at an earlier stage to prevent upcoming diabetes mellitus and its complications.

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium.

A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer's disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.

The Correlation between Diabetes Mellitus and Neurodegenerative Diseases.

Today there is no longer any doubt that diabetes mellitus is associated with cognitive impairment and neurodegenerative diseases. The two most common forms of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is characterized by an absolute insulin deficiency that is associated with a large number of metabolic changes. This type of diabetes requires insulin therapy. Without insulin, this disease is fatal. The far more common form of diabetes mellitus nowadays is type 2 diabetes mellitus. It is characterized by insulin resistance. For a number of years drugs have been available that can be used to treat this form of diabetes in a multimodal manner. These therapy options can not only improve metabolic control, but also prevent cardiovascular events. Different cognitive alterations associated with diabetes mellitus can be distinguished. On the one hand, the change in glucose homeostasis itself leads to cognitive alterations, i.e. blood sugar levels that are too high or acutely too low are regularly associated with significant impairments in mental performance, including loss of consciousness. But not only the momentary blood sugar levels, but also long-term changes in glucose metabolism might lead to neurodegeneration and even dementia in a way that has not yet been fully understood. Insulin or insulin-like molecules have important effects in the central nervous system. In the last decades, it has been shown that insulin receptors themselves are expressed in many regions of the brain and e.g. regulate food intake and memory formation in humans and in animal models. In the animal model, disturbances in insulin signal transduction influence the development of pathologies typical of Alzheimer's disease (AD). In humans, central insulin resistance is at least part of the formal pathogenesis of AD. Vascular changes (macroangiopathy) in patients with diabetes mellitus often lead to cerebral insults, microangiopathies and vascular dementia.

Deletion of Androgen Receptor in LepRb Cells Improves Estrous Cycles in Prenatally Androgenized Mice.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

Ocular manifestations of central insulin resistance.

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

Microbiome-metabolomics analysis reveals the potential effect of verbascoside in alleviating cognitive impairment in db/db mice.

Cognitive impairment is the main central nervous system complication of diabetes, affecting the quality of life of patients. Herba Cistanche is a homologous plant widely used as a health food and therapeutic drug. Verbascoside, a signature component of Herba Cistanche, has anti-diabetic and neuroprotective effects. However, it is quickly metabolized by the gut microbiota, and the mechanism of its neuroprotection and improvement of learning and memory remains unclear. We investigated the effectiveness and potential mechanisms of verbascoside on cognitive dysfunction in db/db mice using a 16S rRNA microbiome and serum metabolomics approach. We found that 12-week treatment with verbascoside significantly inhibited insulin resistance, reduced blood glucose and lipids, and improved cognitive deficits. In addition, verbascoside increased the gut microbiota diversity, improved intestinal dysbiosis, attenuated intestinal barrier disruption, reduced the levels of inflammatory factors, regulated the expression of the metabolites associated with cognitive function, and enhanced the central insulin sensitivity and hippocampal synaptogenesis signaling. We revealed that verbascoside induced the enrichment of Alistipes, Roseburia, and Intestinimonas in the gut, suppressed the abundance of Escherichia-Shigella, increased the serum levels of gamma-aminobutyric acid, L-glutamic acid, and L-lysine, and decreased taurine expression. Finally, a strong association between gut microbes, serum metabolites, and cognitive performance affected by verbascoside was observed. Our research suggests that alterations in gut microbes/metabolites are involved in the development of diabetic cognitive dysfunction, which is alleviated by verbascoside in the db/db mice through restructuring the gut microbiota composition, ameliorating diabetic metabolic disorders, and attenuating pathological brain damage.

Burden of Cardiovascular Disease in South Asians: Risk Factors Prevention and Early Screening is the Key

Cardiovascular diseases (CVD) have declined over the past two decades.1 However, despite improvements in population health, marked racial and ethnic disparities in longevity and CVD management persist. South Asians (SAs), people with ancestors from the Indian subcontinent constitute 1/5 of the world's population. During the late 1980s, the term “double burden of disease” was first used and can be defined as the burden of non-communicable diseases on top of infectious diseases that remain undefeated.2 Coronary artery disease (CAD), also called heart disease, stood out as the most common cause of this increasing double burden of diseases. The first study that was published related to South Asians and CAD risk was in 1991 by McKeigue et al.3 The study assessed the relation of central obesity and insulin resistance with high type 2 diabetes mellitus prevalence and CAD risk in immigrant SAs. A sample of industrial workers and general practitioners in the United Kingdom were shown to have a higher prevalence of diabetes, higher blood pressure, higher fasting and post-glucose serum insulin concentrations, higher plasma triglyceride (TG), and lower high-density lipoprotein (HDL). This study confirms the existence of an insulin resistance syndrome in SAs.

Study of metabolic syndrome indicators in newly diagnosed diabetes mellitus type 2 patients in Pakistani population.

Metabolic syndrome (MetS) being a biological abnormality confers the highest risk of type 2 diabetes mellitus (T2DM). To assess MetS indicators in the newly diagnosed T2DM Pakistani population. A cross-sectional study (N = 123) with newly diagnosed T2DM patients (gender: both, MeanAge: 49.24 ± 6.84 years) was selected from Medical OPD, Pakistan Institute of Medical Sciences, Islamabad. Basic profile, family history, and physical activity were recorded through a predesigned questionnaire, dietary intake through seven days Food Diary and Food Frequency Questionnaire. Blood pressure and selected clinical signs and symptoms were recorded. Anthropometric measurements included mid-upper arm circumference (MUAC), body mass index (BMI), waist circumference (WC), waist-and-hip ratio (WHR), waist-to-height ratio (WHtR), and conicity index. Lab parameters included fasting blood glucose, HbA1c, insulin levels, and lipid profile. Homeostatic model assessment of insulin resistance (HOMA-IR) was computed to assess insulin resistance. Almost all parameters related to MetS were higher than normal. The prevalence of MetS was 59.7%. BMI, MUAC, and WHtR were independently associated with HOMA-IR, but WC, WHR, and the conicity index had no relationship MetS indicators. The prevalence rate of MetS was found to be 59.7% in newly diagnosed T2DM patients. MUAC was found to be a better parameter for the diagnosis of central obesity and insulin resistance in the selected population.

Investigating the effects of antipsychotics on brain insulin action: Study protocol for a multi-modality magnetic resonance imaging (MRI) study in healthy controls.

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2-6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.

中枢胰岛素抵抗与脑血管病的关系 Relationship between Central Insulin Resistance and Cerebrovascular Disease

中枢胰岛素抵抗与脑血管病的关系 Relationship between Central Insulin Resistance and Cerebrovascular Disease

Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate.

Glutamate excitotoxicity is involved in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer’s disease, for which central insulin resistance is a comorbid condition. Neurotoxicity of glutamate (Glu) is primarily associated with hyperactivation of the ionotropic N-methyl-D-aspartate receptors (NMDARs), causing a sustained increase in intracellular free calcium concentration ([Ca2+]i) and synchronous mitochondrial depolarization and an increase in intracellular superoxide anion radical (O2–•) production. Recently, we found that insulin protects neurons against excitotoxicity by decreasing the delayed calcium deregulation (DCD). However, the role of insulin in O2–• production in excitotoxicity still needs to be clarified. The present study aims to investigate insulin’s effects on glutamate-evoked O2–• generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in cortical neurons. We found a linear correlation between [Ca2+]i and [O2–•] in primary cultures of the rat neuron exposed to Glu, with insulin significantly reducing the production of intracellular and mitochondrial O2–• in the primary cultures of the rat neuron. MK 801, an inhibitor of NMDAR-gated Ca2+ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments in sister cultures, insulin diminished neuronal death and O2 consumption rate (OCR).

Kinetic and data-driven modeling of pancreatic β-cell central carbon metabolism and insulin secretion.

Pancreatic β-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic β-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between β-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.

Insulin modulates emotional behavior through a serotonin-dependent mechanism.

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.

Can Leptin/Ghrelin Ratio and Retinol-Binding Protein 4 Predict Improved Insulin Resistance in Patients with Obesity Undergoing Sleeve Gastrectomy?

IntroductionObesity is associated with metabolic syndrome (MBS), a cluster of components including central obesity, insulin resistance (IR), dyslipidemia, and hypertension. IR is the major risk factor in the development and progression of type 2 diabetes mellitus in obesity and MBS. Predicting preoperatively whether a patient with obesity would have improved or non-improved IR after bariatric surgery would improve treatment decisions.MethodsA prospective cohort study was conducted between August 2019 and September 2021. We identified pre- and postoperative metabolic biomarkers in patients who underwent laparoscopic sleeve gastrectomy. Patients were divided into two groups: group A (IR < 2.5), with improved IR, and group B (IR ≥ 2.5), with non-improved IR. A prediction model and receiver operating characteristics (ROC) were used to determine the effect of metabolic biomarkers on IR.ResultsSeventy patients with obesity and MBS were enrolled. At 12-month postoperative a significant improvement in lipid profile, fasting blood glucose, and hormonal biomarkers and a significant reduction in the BMI in all patients (p = 0.008) were visible. HOMA-IR significantly decreased in 57.14% of the patients postoperatively. Significant effects on the change in HOMA-IR ≥ 2.5 were the variables; preoperative BMI, leptin, ghrelin, leptin/ghrelin ratio (LGr), insulin, and triglyceride with an OR of 1.6,1.82, 1.33, 1.69, 1.77, and 1.82, respectively (p = 0.009 towards p = 0.041). Leptin had the best predictive cutoff value on ROC (86% sensitivity and 92% specificity), whereas ghrelin had the lowest (70% sensitivity and 73% specificity).ConclusionPreoperative BMI, leptin, ghrelin, LGr, and increased triglycerides have a predictive value on higher postoperative, non-improved patients with HOMA-IR (≥ 2.5). Therefore, assessing metabolic biomarkers can help decide on treatment/extra therapy and outcome before surgery.Graphical

Effect of pioglitazone on oxidative stress of skeletal muscle in the insulin resistance rat model induced by high sucrose diet

Background: Metabolic syndrome is associated with some medical disorders such as central obesity, being overweight, insulin resistance and hypertension. This study was designed to determine the effect of pioglitazone on oxidative stress in the insulin resistance rat model.Methods: In this study, the model was induced by high sucrose (935 mm) diet for 20 weeks. Three groups were used in the experiment. Control group received standard laboratory diet and drinking water. Metabolic syndrome induced group received 32% sucrose containing drinking water for 20 weeks. Pioglitazone-treated metabolic syndrome group has received pioglitazone treatment (30 mg/kg/day, via oral gavage) for two weeks at the end of the 18th week of metabolic syndrome group. After experimental period, skeletal muscle tissues were homogenized to measure important enzymes such as aspartate aminotransferase, lactate dehydrogenase and as the marker of oxidative stress; total-antioxidant-status, total-oxidant-status and malondialdehyde. Western blot technique was used to determine protein level of thioredoxin1.Results: Aspartate aminotransferase and lactate dehydrogenase levels increased in metabolic syndrome group but pioglitazone treatment decreased these levels. In metabolic syndrome group the oxidative stress status increased but the treatment of pioglitazone decreased the level of oxidative stress in the skeletal muscle. In addition, thioredoxin1 decreased in metabolic syndrome group but administration of pioglitazone increased this level.Conclusions: There was an elevated effect of oxidative stress in high sucrose fed rats but the treatment of pioglitazone improved glucose tolerance and insulin sensitivity.

Insulin sensitivity in mesolimbic pathways predicts and improves with weight loss in older dieters.

Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain. How this relates to effective weight management is unclear, especially in older people, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, 50 overweight, non-diabetic older adults participated in a double-blind, placebo-controlled, pharmacological functional magnetic resonance imaging study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and peripheral insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.

An examination of the prevalence of metabolic syndrome in older adults in Ireland: Findings from The Irish Longitudinal Study on Ageing (TILDA)

Metabolic syndrome (MetS) consists of the cluster of central obesity, insulin resistance, hypertension and atherogenic dyslipidaemia. It is a risk factor for cardiovascular disease, diabetes, and mortality. The prevalence of MetS has not been described in older adults from a population-representative sample in a European country before. This study aimed to determine the prevalence of MetS in older adults in Ireland and examine the association between MetS and socio-demographic, health, and lifestyle factors. This study used data from a population aged ≥50 years from waves 1 and 3 of the Irish Longitudinal Study on Ageing. The prevalence of MetS using the National Cholesterol Education Program Third Adult Treatment Panel (ATPIII) and the International Diabetes Foundation (IDF) criteria were determined. Weighted logistic regression examined the association between MetS and age, sex, education, and physical activity. MetS status was determined at both waves with transitions examined. 5340 participants had complete data for MetS criteria at wave 1. 33% had MetS according to the ATPIII criteria (32.5%; 95% CI: 31.1, 34.0), with 39% according to the IDF criteria (39.3%; 95% CI: 37.8, 40.8). MetS was more prevalent with advancing age, among males, those with lower educational attainment and lower physical activity. 3609 participants had complete data for both waves- 25% of those with MetS at wave 1 did not have MetS at wave 3 but the overall number of participants with MetS increased by 19.8% (ATPIII) and 14.7% (IDF). MetS is highly prevalent in older adults in Ireland. 40% of the 1.2 million population aged ≥50 years in Ireland meet either the ATPIII or IDF criteria. Increasing age, male sex, lower educational attainment, and lower physical activity were all associated with an increased likelihood of MetS.

Behavioral and Molecular Effects of Thapsigargin-Induced Brain ER- Stress: Encompassing Inflammation, MAPK, and Insulin Signaling Pathway.

Accumulation of misfolded proteins, known as endoplasmic reticulum (ER) stress, is known to participate in Alzheimer’s disease (AD). AD is also correlated with impaired central insulin signaling. However, few studies have probed the relationship between memory, central ER stress, inflammation, hippocampal mitogen-activated protein kinase (MAPK) activity and insulin resistance. The present study aimed to investigate the causative role and underlying mechanisms of brain ER stress in memory impairment and develop a reliable animal model for ER-mediated memory loss. Thapsigargin (TG), a known ER stress activator, was centrally administered. The cognitive function of animals was evaluated by the Morris Water Maze (MWM). To verify the induction of central ER stress, we investigated the mRNA expression of UPR markers in the hippocampus. In addition, the activation of ER stress markers, including Bip, CHOP, and some related apoptosis and pro-inflammatory proteins, such as caspase-3, Bax, Bcl-2, TNF-α, MAPK, and insulin signaling markers, were assessed by Western-blots. The results demonstrated that TG impairs spatial cognition and hippocampal insulin signaling. Meanwhile, molecular results showed a concurrent increment of hippocampal UPR markers, apoptosis, P38 activity, and TNF-α. This study introduced TG-induced ER stress as a pharmacological model for memory impairment in rats and revealed some underlying mechanisms.

Brain Insulin Receptor Antagonism Augments The Blood Pressure Response To Activation Of The Exercise Pressor Reflex

Type 2 diabetes mellitus (T2DM) results in abnormal control of blood pressure (BP). However, the underlying mechanisms remain to be elucidated. The transport of insulin into the central nervous system is decreased in T2DM. The resultant central hypoinsulinemia reduces neuronal excitability. The nucleus tractus solitarius (NTS) is a key central integration site for incoming signals from peripheral sensory neurons including input from working skeletal muscle and arterial baroreceptors. Working skeletal muscle activates primary sensory fibers and evokes the exercise pressor reflex (EPR) to reflexively increase BP, a response modulated by the baroreflex. Central hypoinsulinemia in T2DM may influence how neurons in the NTS process this sensory information during exercise affecting BP responsiveness. PURPOSE: To determine whether acute antagonism of insulin receptors in the NTS alters EPR function in baro-intact and barodenervated rats. METHODS: L4 and L5 ventral roots were electrically stimulated in healthy decerebrated male Sprague-Dawley rats to evoke hindlimb muscle contraction and EPR activation in intact and sino-aortic barodenervated rats. Mean arterial pressure (MAP) responses to activation of the EPR were assessed before and 30 min following NTS microinjections of the insulin receptor antagonist, GSK1838705 (100uM), or vehicle, dimethyl sulfoxide (DMSO). RESULTS: In baro-intact rats, contraction-induced changes in MAP were significantly greater following GSK1838705 (Pre, 16 ± 10 mmHg vs. Post, 23 + 13 mmHg, n = 11, p < 0.01) but not DMSO (Pre, 15 ± 8 mmHg vs. Post, 15 + 8 mmHg, n = 9). In barodenervated rats, neither GSK1838705 (Pre, 27 ± 16 mmHg vs. Post, 28 ± 21 mmHg, n = 8) nor DMSO (Pre, 34 ± 17 mmHg vs. Post, 30 ± 27 mmHg, n = 9) affected the MAP response to contraction. CONCLUSIONS: The findings demonstrate that central insulin receptor antagonism augments the BP response to EPR activation, which is abolished by barodenervation. The findings also suggest that insulin in the NTS maintains the capacity to buffer EPR-mediated increases in BP via baroreflex-mediated mechanisms. Alterations in this buffering capacity due to the central hypoinsulinemia in T2DM could account, in part, for the exaggerated pressor response to exercise in this disease. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund.

Hypothalamic Hnscr regulates glucose balance by mediating central inflammation and insulin signal.

Hypothalamic dysfunction leads to glucose metabolic imbalance; however, the mechanisms still need clarification. Our current study was to explore the role of hypothalamic Hnscr in glucose metabolism. Using Hnscr knockout or htNSC-specific Hnscr overexpression mice, we evaluated the effects of Hnscr on glucose metabolism through GTTs, ITTs, serum indicator measurements, etc. Immunofluorescence staining and Western blotting were performed to test inflammation levels and insulin signalling in hypothalamus. Conditioned medium intervene were used to investigate the effects of htNSCs on neuronal cell line. We also detected the glucose metabolism of mice with htNSCs implantation. Hnscr expression decreased in the hypothalamus after high-fat diet feed. Hnscr-null mice displayed aggravated systematic insulin resistance, while mice with htNSC-specific Hnscr overexpression had the opposite phenotype. Notably, Hnscr-null mice had increased NF-κB signal in htNSCs, along with enhanced inflammation and damaged insulin signal in neurons located in arcuate nucleus of hypothalamus. The secretions, including sEVs, of Hnscr-deficient htNSCs mediated the detrimental effects on the CNS cell line. Locally implantation with Hnscr-depleted htNSCs disrupted glucose homeostasis. This study demonstrated that decreased Hnscr in htNSCs led to systematic glucose imbalance through activating NF-κB signal and dampening insulin signal in hypothalamic neurons.