Since the 1970s, the biological role of vanadium compounds has been discussed as insulin-mimetic or insulin-enhancer agents. The action of vanadium compounds has been investigated to determine how ...they influence the insulin signaling pathway. Khan and coworkers proposed key proteins for the insulin pathway study, introducing the concept “critical nodes”. In this review, we also considered critical kinases and phosphatases that participate in this pathway, which will permit a better comprehension of a critical node, where vanadium can act: a) insulin receptor, insulin receptor substrates, and protein tyrosine phosphatases; b) phosphatidylinositol 3′-kinase, 3-phosphoinositide-dependent protein kinase and mammalian target of rapamycin complex, protein kinase B, and phosphatase and tensin homolog; and c) insulin receptor substrates and mitogen-activated protein kinases, each node having specific negative modulators. Additionally, leptin signaling was considered because together with insulin, it modulates glucose and lipid homeostasis. Even in recent literature, the possibility of vanadium acting against metabolic diseases or cancer is confirmed although the mechanisms of action are not well understood because these critical nodes have not been systematically investigated. Through this review, we establish that vanadium compounds mainly act as phosphatase inhibitors and hypothesize on their capacity to affect kinases, which are critical to other hormones that also act on common parts of the insulin pathway.
Into cell, the vanadium species can act at the same time on different critical nodes of insulin and leptin pathways, modulating phosphatases and kinases activity. Thus, vanadium has multi-target regulation such as glucose and lipid metabolism, protein synthesis, as well as growth, survival, proliferation, and death cell. Display omitted
•The insulin pathway was grouped into critical nodes related to vanadium activity.•Leptin signaling modulates the cell functions linked to the insulin pathway.•Vanadium has activity on leptin and insulin signaling.•V improves insulin/leptin signaling via inhibiting/interfere of phosphatases/kinases.
Diabetes mellitus is a pandemic expected to spread from 422 million patients in 2014 to 592 million patients in 2035. Type 1 diabetes mellitus (T1D) is characterized by both autoimmune destruction of ...beta cells and insulinopaenia, which generates severe oxidative stress in multiple tissues. In this work, we aimed to study both metabolic control and redox balance of the liver and muscle in a model similar to T1D through a temporary treatment with Metformin-decavanadate (MetfDeca). Alloxan (150 mg kg −1 ; i.p.) was administrated orally to male Wistar rats (300–320 g), Then, six working groups were formed: (1) intact control, (2) untreated group, (3) insulin 1 UI/100 mg dL −1 of glucose per day, (4) metformin 350 mg per kg per day, (5) NaVO 3 5 μM/0.1 kg per day, and (6) MetfDeca 3.5 μM/0.1 kg per day. Treatments were administered daily and analysis was performed at 30 and 60 days. In each cohort-time analysis, blood and tissues were collected under experimental conditions ( n = 5). Results at day 0 showed glucose levels greater than 300 mg dL −1 and insulin levels smaller than 5 μUI mL −1 , and these conditions remained constant during the whole experimental time in untreated animals. Hyperglycemia was associated with increased levels of oxidized glutathione, reactive oxygen species, malondialdehyde, and 4-hydroxyalkenal, which were observed in both the liver and muscle. The antioxidant defense was depleted (superoxide dismutase and catalase activities, and reduced glutathione level). Metformin treatment was ineffective ameliorating hyperglycemia and oxidative stress, whereas metavanadate treatment was moderately effective partially diminishing hyperglycemia and improving the oxidative environment in the muscle. Insulin and MetfDeca treatments ameliorate glucose and insulin levels, and reduce the levels of oxidized glutathione, reactive oxygen species, malondialdehyde, and 4-hydroxyalkenal; the superoxide and catalase activities, as well as glutathione levels were regulated. Therefore, it is suggested that the nuclear factor erythroid 2-related factor was involved. These results allow us to conclude that decavanadate and metavanadate regulated hyperglycemia and oxidative stress through different pathways, probably due to MetfDeca stability and its low intracellular biotransformation, which regulate oxidative stress, antioxidant signaling pathways, and metabolic activities, similarly to insulin.
Metabolic syndrome (MetS) is a public health problem and a risk of developing cardiometabolic and neurodegenerative diseases. The biochemical-inflammatory impairment in brain areas related to ...learning and memory has not been differentiated between MetS models. We aimed to compare the effect of the MetS generated by consuming high-fat (HFD) or -carbohydrate diets (HCD) on the hippocampus and frontal cortex, related to astrocyte-neuron metabolism and neuroinflammation origin. Sixty male Wistar rats were separated into three groups: 1) control group, 2) HCD group, and 3) HFD group. After 3 months, we evaluated zoometry, a serum bioclinical profile, and in the hippocampus and frontal cortex, we performed biochemical assays (concentration of lactate, glutamate, fatty acids, and ASAT, ALAT, and LDH activity), immunoreactivity tests (GFAP, COX2, CD36, and BDNF), and immunoassays (TNF-α, IL-1β, IL-6, and PGE2). The bioclinical parameters showed that both diets induce MetS. At the brain level, it is noteworthy that the HCD group had an increase in lactate and glutamate concentration, reactive astrogliosis, immunoreactive COX2 neurons in the CA1 subfield hippocampus and frontal cortex, and high levels of PGE2, TNF-α, IL-1β, and IL-6, and low BDNF immunoreactivity. Meanwhile, the HFD is highlighted by increased fatty acid levels and CD36 expression in the hippocampus and frontal cortex, strong reactive astrogliosis and COX2 immunoreactivity, and the greatest inflammation with the lowest BDNF immunoreactivity. In conclusion, MetS induction by an HFD or HCD generates different biochemical, cellular, and inflammatory patterns in the hippocampus and frontal cortex.
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•High-fat or -carbohydrate diets consumption modified transaminases and LDH activity in Hp and FC.•HCD consumption increases glutamate and lactate in Hp and lactate in FC.•At the frontal cortex and hippocampus level, inflammatory patterns differ among inducer diets.•A high-fat diet induces high CD36 expression and storage of fatty acids in Hp and FC.•Hypercaloric diet consumption diminishes BDNF levels in Hp and CF but increases proBDNF in Hp.
Cadmium, a hazardous environmental contaminant, is associated with metabolic disease development. The dose with the lowest observable adverse effect level (LOAEL) has not been studied, focusing on ...its effect on the pancreas. We aimed to evaluate the pancreatic redox balance and heat shock protein (HSP) expression in islets of Langerhans of male Wistar rats chronically exposed to Cd LOAEL doses, linked to their survival. Male Wistar rats were separated into control and cadmium groups (drinking water with 32.5 ppm CdCl
2
). At 2, 3, and 4 months, glucose, insulin, and cadmium were measured in serum; cadmium and insulin were quantified in isolated islets of Langerhans; and redox balance was analyzed in the pancreas. Immunoreactivity analysis of p-HSF1, HSP70, HSP90, caspase 3 and 9, and cell survival was performed. The results showed that cadmium exposure causes a serum increase and accumulation of the metal in the pancreas and islets of Langerhans, hyperglycemia, and hyperinsulinemia, associated with high insulin production. Cd-exposed groups presented high levels of reactive oxygen species and lipid peroxidation. An augment in MT and GSH concentrations with the increased enzymatic activity of the glutathione system, catalase, and superoxide dismutase maintained a favorable redox environment. Additionally, islets of Langerhans showed a high immunoreactivity of HSPs and minimal immunoreactivity to caspase associated with a high survival rate of Langerhans islet cells. In conclusion, antioxidative and HSP pancreatic defense avoids cell death associated with Cd accumulation in chronic conditions; however, this could provoke oversynthesis and insulin release, which is a sign of insulin resistance.
Cadmium is a nonessential transition metal considered one of the more hazardous environmental contaminants. The population is chronically exposed to this metal at low concentrations, designated as ...the LOAEL (lowest observable adverse effect level) dose. We aimed to investigate whether oral subacute exposure to cadmium LOAEL disrupts hormonal and metabolic effects of the liver-adipose axis in Wistar rats. Fifty male Wistar rats were separated into two groups: control (standard normocalorie diet + water free of cadmium) and cadmium (standard normocalorie diet + drinking water with 32.5 ppm CdCl
2
). After 1 month, zoometry, a serum lipid panel, adipokines, and proinflammatory cytokines were evaluated. Tests of glucose and insulin tolerance (ITT) and insulin resistance were performed. Histological studies on structure, triglyceride distribution, and protein expression of the insulin pathway were performed in the liver and retroperitoneal adipose tissue. In both tissues, the cadmium, triglyceride, glycogen, and proinflammatory cytokine contents were also quantified. The cadmium group developed dyslipidemia, glucose intolerance, hyperinsulinemia, hyperleptinemia, inflammation, and selective insulin resistance in the liver and adipose tissue. In the liver, glycogen synthesis was diminished, while de novo lipogenesis increased, which was associated with low GSK3β-pS9 and strong expression of SREBP-1c. Dysfunctional adipose tissue was observed with hypertrophy and lipolysis, without changes in SREBP-1c expression and low glycogen synthesis. Both tissues accumulated cadmium and developed inflammation. In conclusion, oral subacute cadmium LOAEL dose exposure induces inflammation, insulin signaling modifications, an early insulin resistance stage (insensibility), and impairment of the hormonal and metabolic liver-adipose axis in Wistar rats.
Cadmium is a critical toxic agent in occupational and non-occupational settings and acute and chronic environmental exposure situations that have recently been associated with metabolic disease ...development. Until now, the no observed adverse effect level (NOAEL) of cadmium has not been studied regarding insulin resistance development. Therefore, we aimed to monitor whether chronic oral exposure to cadmium NOAEL dose induces insulin resistance in Wistar rats and investigate if oxidative stress and/or inflammation are related. Male Wistar rats were separated into control (standard normocalorie diet + water free of cadmium) and cadmium groups (standard normocalorie diet + drinking water with 15 ppm CdCl
2
). At 15, 30, and 60 days, oral glucose tolerance, insulin response, and insulin resistance were analyzed using mathematical models. In the liver glycogen, triglyceride, pro- and anti-inflammatory cytokines, cadmium, zinc, metallothioneins, and redox balance were quantified. Immunoreactivity analysis of proteins involved in metabolic and mitogenic insulin signaling was performed. The results showed that a cadmium NOAEL dose after 15 days of exposure causes ROS and mitogenic arm of insulin signaling to increase while hepatic glycogen diminishes. At 30 days, Cd accumulation accentuated ROS production, hepatic triglyceride overaccumulation, and mitogenic signals that develop insulin resistance. Finally, inflammation and lipid peroxidation appear after 60 days of Cd exposure, while lipids and carbohydrate homeostasis deteriorate. In conclusion, environmental exposure to cadmium NAOEL dose causes hepatic Cd accumulation and ROS overproduction that chronically declines the antioxidant defense, deteriorates metabolic homeostasis associated with the mitogenic pathway of insulin signaling, and induces insulin resistance.
An increase in intracellular Ca2+ concentration (Ca2+i) plays a key role in controlling endothelial functions; however, it is still unclear whether endothelial Ca2+ handling is altered by type 2 ...diabetes mellitus, which results in severe endothelial dysfunction. Herein, we analyzed for the first time the Ca2+ response to the physiological autacoid ATP in native aortic endothelium of obese Zucker diabetic fatty (OZDF) rats and their lean controls, which are termed LZDF rats. By loading the endothelial monolayer with the Ca2+-sensitive fluorophore, Fura-2/AM, we found that the endothelial Ca2+ response to 20 µM and 300 µM ATP exhibited a higher plateau, a larger area under the curve and prolonged duration in OZDF rats. The “Ca2+ add-back” protocol revealed no difference in the inositol-1,4,5-trisphosphate-releasable endoplasmic reticulum (ER) Ca2+ pool, while store-operated Ca2+ entry was surprisingly down-regulated in OZDF aortae. Pharmacological manipulation disclosed that sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity was down-regulated by reactive oxygen species in native aortic endothelium of OZDF rats, thereby exaggerating the Ca2+ response to high agonist concentrations. These findings shed new light on the mechanisms by which type 2 diabetes mellitus may cause endothelial dysfunction by remodeling the intracellular Ca2+ toolkit.
Cadmium, one of the more hazardous environmental contaminants, has been proposed as a metabolic disruptor. Vanadium has emerged as a possible treatment for metabolic diseases. Both metals are ...important in public health. We aimed to investigate whether vanadium treatment is effective against metabolic disturbances caused by chronic exposure to the lowest-observable adverse effect level of cadmium. Male Wistar rats were exposed to cadmium (32.5 ppm) in drinking water for 3 months. Metabolic complications such as overweight, visceral adipose gain, hyperglycemia, impaired glucose tolerance, and dyslipidemia were detected, and low glycogen levels and steatosis were observed in the tissues. Then, the control and treated animals were subdivided and treated with a solution of 5 μM NaVO
3
/kg/twice a week for 2 months. The control-NaVO
3
group did not show zoometric or metabolic changes. A strong interaction of NaVO
3
treatment over cadmium metabolic disruption was observed. The vanadium accumulation diminished cadmium concentration in tissues. Also, vanadium interaction improved glucose homeostasis. The major effect was observed on glycogen synthesis, which was fully recovered in all tissues analyzed. Additionally, vanadium treatment prevented overweight and visceral fat accumulation, improving BMI and the percentage of fat. However, NaVO
3
treatment did not have an effect on dyslipidemia or steatosis. In conclusion, this work shows that vanadium administration has a strong effect against metabolic disturbances caused by chronic cadmium exposure, observing powerful interaction on glucose homeostasis.
Cadmium has been well recognized as a critical toxic agent in acute and chronic poisoning cases in occupational and nonoccupational settings and environmental exposure situations. Cadmium is released ...into the environment after natural and anthropogenic activities, particularly in contaminated and industrial areas, causing food pollution. In the body, cadmium has no biological activity, but it accumulates primarily in the liver and kidney, which are considered the main targets of its toxicity, through oxidative stress and inflammation. However, in the last few years, this metal has been linked to metabolic diseases. The pancreas-liver-adipose axis is largely affected by cadmium accumulation. Therefore, this review aims to collect bibliographic information that establishes the basis for understanding the molecular and cellular mechanisms linked to cadmium with carbohydrate, lipids, and endocrine impairments that contribute to developing insulin resistance, metabolic syndrome, prediabetes, and diabetes.
Population growth, poorly planned industrial development and uncontrolled production processes have left a significant footprint of environmental deterioration in the Alto Atoyac watershed. In this ...study, we propose using the integrated pollution index (PI) to characterize the temporary variations in surface water quality during the rapid urbanization process in the municipalities of San Martín Texmelucán (SMT) and Tepetitla de Lardizabal (TL), in the states of Puebla and Tlaxcala, between 1985 and 2020. We assessed the correlation between the population growth rate and the water quality parameters according to the Water Quality Index (ICA). The contribution of each polluting substance to the PI was determined. The industry database was created and the increase in population and industry, and their densities, were estimated. The results indicated that the temporal pattern of surface water quality is determined by the level of urbanization. The water integrated pollution index (WPI) increased with the passage of time in all the localities: SLG 0.0 to 25.0; SMTL 25.0 to 29.0; SRT 4.0 to 29.0; VA 6.0 to 30.0; T 3.5 to 24.0 and SMA 4.0 to 27.0 from 2010 to 2020, respectively. The correlation coefficients between the five parameters (BOD5, COD, CF, TU and TSS) in the six localities were positive with the population. The values that showed a higher correlation with the population were: SLG (FC 0.86), SMTL (BOD5 0.61, COD 0.89, TSS 0.64) and SRT (TU 0.83), corresponding to highly polluted localities, which generates complex and severe environmental implications due to the unsustainable management of water resources. Achieving the sustainability of water in the watershed is a challenge that should be shared between society and state. This type of research can be a useful tool in making environmental management decisions.
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