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In high-risk patients with type 2 diabetes and previous stroke, pioglitazone significantly reduced the occurrence of recurrent fatal and nonfatal stroke. Will pioglitazone stabilize carotid artery vulnerable plaque in patients with acute coronary syndromes (ACS) and type 2 diabetes? Prof John Betteridge reviews the impact of various diabetic drugs on glycemic control, vascular prevention and Beta cell function. Prof John Betteridge, London, discusses the evolution of diabetes therapy, the epidemic rise in diabetes, current and emerging diabetes therapies.
Treatment with pioglitazone to improve insulin sensitivity, reduced stroke and MI in patients with insulin resistance but without diabetes and who have experienced ischaemic stroke or TIA. In patients with type 2 diabetes and angiographic coronary artery disease, treatment with pioglitazone resulted in larger LDL particle size and decreasing concentrations, associated with less plaque progression. A 10-year post-marketing study in patients with type 2 diabetes demonstrated no statistically significant increased risk of bladder cancer to patients exposed to pioglitazone. The development of obesity and insulin resistance has been extensively studied in the last decades, but the mechanisms underlying these alterations are still not completely understood. Alteration in gut microbiota composition due to obesity is accompanied by changes in activation of enzymes and pathways, leading to and increased inflammatory state and energy harvest.
Metabolic endotoxemia leads to activation of insulin resistance in muscle, liver, adipose tissue and hypothalamus through activation of Toll-like receptor (TLR)2 and 4.
Although it is generally assumed that insoluble cereal fiber has beneficial effects that arise from chronic intake and its subsequent fermentation in the colon [114,115,116,117,118], the explanation for its consequent reduction of diabetes risk is still unclear. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Obesity and Weight Loss: The Influence of Thyroid Hormone on AdipokinesRenata de Azevedo Melo Luvizotto1, Sandro Jose Conde1, Miriane de Oliveira1, Maria Teresa De Sibio1, Keize Nagamati Jr1 and Celia Regina Nogueira1[1] Department of Internal Medicine, Botucatu School of Medicine, University of Sao Paulo State, Botucatu, SP,, Brazil1. My diabetes prevention adponectin and adiponectin receptors in insulin resistance conference wife’s daily driver is a 2011 VW Jetta TDi. Type 1 diabetes is typically diagnosed in childhood and is sometimes called juvenile-onset diabetes mellitus. You may also have to give yourself insulin injections and to monitor and record your blood glucose levels four or five times a day with the aid of device called a blood glucose meter. Recent studies suggest that the mTor-S6 kinase 1 (S6K1) pathway may play an important role in regulation of insulin sensitivity and adiposity (Figure 4). S6K1 is regulated by an upstream cascade involving the tumor suppressor products Tuberous Sclerosis Complex (TSC) proteins 1 and 2 that control the activity of the upstream kinase mTOR (Hay and Sonenberg, 2004) (Figure 4). Major advances now reveal that the evolutionarily conserved cellular fuel gauge, AMPK, acts as a master regulator of metabolism not only at the cellular level but also at the whole body level. The identification of LKB1 as an upstream kinase in the AMPK cascade is a long-awaited advance in the field. Recent discoveries demonstrating that the AMPK cascade plays a central role in the regulation of body weight, systemic glucose homeostasis, lipid metabolism, mitochondrial biogenesis, and possibly even insulin signaling make it an attractive therapeutic target. IntroductionThe epidemics of obesity and type 2 diabetes mellitus in the past 20 years have led to numerous investigations concerning the mechanisms that are responsible for the development of these diseases. Gut Microbiota in Type 2 Diabetic IndividualsRecently, research has pointed out that the intestinal microbiome might be an important contributor for the development of type 2 diabetes (T2D) [60]. A recent study showed that palmitate treatment of differentiated C2C12 myotubes resulted in a time-dependent inhibition of insulin-activated signal transduction, through TLR2 activation [106].
A study shows that in the first six weeks of high-cereal fiber (HCF) diet administration for overweight patients, an increase in the insulin sensitivity is observed.
IntroductionThe primary function of adipose tissue is storing energy in triacylglycerol (TG) form, neutralizing the excess of circulating lipids and saving non-adipose tissues of a fat overload.
Methods: A total of 167 subjects, 50 newly diagnosed type 2 diabetic subjects and 117 non-diabetic subjects were included in the study. Sincerely John from Ohio PART OF THE AEGIS PATIENT CARE SERIES DIABETES AND DENTAL HEALTH People with diabetes need to take special care of their oral health because diabetes may lower your resistance to gum disease and other mouth infections. Understand that altered kidney function can be a consequence of diabetes independent of any risk associated with Byetta.
Short or rapid-acting insulin (Regular Humalog NovoLog Apidra) and Lantus or Levemir should appear clear.
If your pet requires insulin injections your veterinarian will prescribe the type and dose of insulin that works best for your diabetic dog or cat.
TSC serves as a GTPase activating protein for the small GTPase Rheb (Ras homolog enriched in brain). As the complexity has broadened, concepts that once had almost the status of dogma have now been challenged, such as the idea that AMPK plays a key role in contraction-stimulated glucose transport. Now it will be important to determine the full extent of the role of LKB1 in regulating AMPK. Indeed, an AMPK activator has therapeutic effects in obese and diabetic rodents and in humans, with some side effects (reviewed in Musi and Goodyear, 2002). Bateman, The structure of a domain common to archaebacteria and the homocystinuria disease protein, Trends Biochem. Carling, The AMP-activated protein kinase cascade?Ca unifying system for energy control, Trends Biochem.
Hardie, The AMP-activated protein kinase pathway ?? new players upstream and downstream, J.
It has been shown that obese individuals present different proportions of bacterial phyla compared with lean individuals, with an increase in Firmicutes and Actinobacteria and a decrease in Bacteroidetes.
The general view is that insulin resistance is an early alteration of type 2 diabetes mellitus and obesity, and both diseases are strongly influenced by genetics and environment [1,2,3,4,5]. The use of genome-wide association studies (GWAS) has achieved many elucidations in this matter [61,62]. We have also shown that short-term inhibition of TLR2 expression using TLR2 oligonucletide antisense in diet-induced obese mice leads to increased insulin sensitivity and signaling [107]. However, after 18 weeks, no significant differences are observed compared to control and high-protein diet [119]. In obesity the hypertrophic and hyperactive adipocytes initiate the production of MCP-1, which attract macrophages into the adipose tissue, increasing proinflammatory adipokines production (mainly TNF-?) and decreasing adiponectin production, leading to insulin resistance and inflammation. Leptin can act on TRH or can directly influence T4 – T3 conversion, showing a regulatory role on thyroid axis. Under normal conditions, in the postprandial state, there is lipogenic endocrine system stimulation, allowing that positive energy balance can be stored as TG in adipose tissue, a process called lipogenesis.
Obese and overweight newly diagnosed type 2 diabetic patients were matched for age and BMI with obese and overweight non-diabetic subjects.
Try ring or email the manufacturer of the 3% saline and ask them about their recommendations for it? So I know this book is great because I have ordered it before but I did not get it this time. But I think eventually we will have a much clearer picture of potential research outcomes and their associated costs in advance of carrying them out.
S6K1 phosphorylates IRS proteins on serine residues, which decreases tyrosine phosphorylation and insulin signaling (Harrington et al., 2004). TSC controls the activity of the mTOR-S6Kinase signaling pathway by serving as a GTPase activating protein for the small protein Ras-like GTPase Rheb (Ras homolog enriched in brain).
Once activated, TSC increases Rheb-GDP levels, which decreases mTOR activity and S6K1 activation (Figure 4). The nature of the effects of AMPK on glycogen synthesis is also increasingly complex due to multiple regulatory factors. Similarly, we need to determine what functions of LKB1 are mediated by AMPK and whether these are involved in cell proliferation effects such as those seen in PJS. Carling, Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome, J. Denton, The activation of p38 MAPK by the beta-adrenergic agonist isoproterenol in rat epididymal fat cells, FEBS Lett. Goodyear, Targeting the AMPK-activated protein kinase for the treatment of type 2 diabetes, Curr.
Hardie, Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise, Am.
This alteration seems to interfere with intestinal permeability, increasing the absorption of lipopolysaccharide (LPS), which reaches circulation and initiates activation of Toll-like receptor (TLR) 4 and 2 and LPS receptor CD14, leading to increased activation of inflammatory pathways. Moreover, studies in the past ten years have shown that low-grade inflammation has an important role in the molecular mechanism of insulin resistance in these diseases [6,7,8,9,10] and more recently (within the past five years) a new component that has both genetic and environmental factors is also being studied: the gut microbiota [11,12,13,14,15,16,17]. Other studies [108,109] have reported that TLR2 knockout (KO) mice present decreased body weight and adiposity, are protected against insulin resistance, and gain less weight on a HFD than control mice and are also protected against related comorbidities [55,110] (Figure 2). Moreover, the HCF diet effects observed in whole body insulin sensitivity were not accompanied by changes in the composition of the gut microbiota neither after 6 weeks nor after 18 weeks of diet administration [120]. The weight loss process revert this alterations, improving insulin resistance and inflammation. Despite contradictory data, thyroid hormone also regulates leptin levels increasing or decreasing depending on condition.
In contrast, the mobilization of fat in adipocytes occurs through the hydrolysis of TG by hormone sensitive lipase (HSL), a phenomenon called lipolysis. Diabetes Diet Plan For Indian Food adverse childhood experiences diabetes mellitus diabetes-related distress autonomy support. Best price on the vitamin combination for diabetes educator new york ear health and large enough supply for some time. Taste might seem like an odd way to refer to a disease that involves urine but diabetes mellitus is so-named because the earliest helth-care workers in ancient Greece Of course if intake is excessive output in the form of urine will also be excessive resulting in polyuria.
People with CFRD who receive treatment for diabetes often start to feel better, gain weight and improve their lung function. Other key challenges include (1) identifying the molecules that lie upstream and downstream of AMPK in the hypothalamic regulation of food intake (Figure 3), (2) determining the mechanisms by which the naturally occurring mutations in the ¦A subunits produce alterations in cardiac or skeletal muscle function (Table 2), and (3) determining the physiological significance of the potential effects of AMPK on the insulin signaling cascade (Figure 4). An attractive hypothesis would link nutrient regulation of metabolism with cell proliferation, and the connection between LKB1 and AMPK is an obvious link. Furthermore, a therapeutic agent would ideally activate AMPK in peripheral tissues (to increase fatty acid oxidation and glucose uptake and reduce gluconeogenesis) while inhibiting it in the hypothalamus (to reduce food intake and body weight). Goodyear, 5?a adenosine monophosphate-activated protein kinase, metabolism and exercise, Sports Med.
Carling, The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways, J. Winder, Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase, Am.
With these activations, an impairment of the insulin signaling is observed, with decreased phosphorylation of the insulin receptor, insulin receptor substrate (IRS) and Akt, as well as increased inhibitory serine phosphorylation of IRS-1. This way, a paradigm has been dismantled: microorganisms should no longer be associated with pathogenesis, since both bacteria and their eukaryote hosts benefit from their cooperative relationships [18]. At the center of this interface - lipolysis and lipogenesis - is the insulin hormone, which exerts a potent inhibitory role on the HSL, allowing lower rates of lipolysis and hence, highest fat mass [1]. More than 50 million Americans have metabolic disorders that include insulin resistance according to the American Heart Association. Feline Diabetes is a disease of the endocrine system which includes the pancreas thyroid glands and parathyroid gland. Since AMPK inhibits phosphorylation of S6K1 on Thr389, and, thus, its activation (Kimura et al., 2003), this could provide a molecular mechanism by which AMPK increases insulin sensitivity in addition to its effects on lipid metabolism. Research in this field will undoubtedly continue to elucidate the intricate biology of energy balance and provide critical information to understand the pathogenesis of obesity and type 2 diabetes.
Shepherd, Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status, J. Hudson, Management of cellular energy by the AMP-activated protein kinase system, FEBS Lett. Hardie, The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism, Diabetes 51 (2002), pp.
Gibson, Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme.
Winder, AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle, Am.
Alessi, Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR, Am. Altered proportions of bacterial phyla have also been demonstrated to interfere with host’s biochemical pathways, increasing energy extraction and depot in adipose tissue. In humans, there are at least 100 trillion microbial cells, collectively called microbiota, distributed in complex and site-specific communities. However, they observed decrease in the levels of butyrate biosynthesis, bacterial chemotaxis, flagellar assembly, vitamins and cofactors metabolism. TLR2 KO mice in conventionalized conditions in our breeding center have insulin resistance and glucose intolerance associated with alterations in the composition of the gut microbiota, which displayed an increase in the relative abundance of Firmicutes and Bacteroidetes and decreased relative abundance of Proteobacteria, compared to their controls.
However, adipose tissue is not only a passive stock organ of triacylglycerol, being currently recognized as an endocrine organ with multiple functions [1, 2]. A ground breaking new study in Diabetologia proved that indeed type 2 diabetes can be reversed through diet changes and the study showed this can happen Today one in four Americans over 60 years old has type 2 diabetes. Epidemiologists at the University at Buffalo have found that newly identified risk factors for diabetes found in the blood, such as markers of endothelial dysfunction, chronic sub-acute inflammation and blood clotting factors, are present early on in wome. In contrast, phosphorylation of TSC by AMPK activates TSC, leading to inhibition of the mTOR pathway. Dohm, AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle, Am. Carlson, Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases, Proc. Charron, Acute stimulation of glucose metabolism in mice by leptin treatment, Nature 389 (1997), pp. Birnbaum, A role for AMP-activated protein kinase in contraction- and hypoxia- regulated glucose transport in skeletal muscle, Mol. Coleman, Leptin directly alters lipid partitioning in skeletal muscle, Diabetes 46 (1997), pp. Rossetti, Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production, Nat. Richter, Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle, Diabetes 51 (2002), pp.
Therefore, understanding the mechanisms by which the alteration in the gut microbiota produces different signaling activations and phenotype changes may offer an interesting opportunity for the treatment of obesity and type 2 diabetes.
As the genome of these bacteria—the microbiome—contains hundreds of genes that do not exist in the human genome [19], we can consider our symbionts as an important extra organ.
This study has also shown that the gut environment of T2D individuals is one that stimulates bacterial defense mechanisms against oxidative stress and against drugs [63].Changes in the composition of the gut microbiota of obese individuals also implicate changes in the concentration of short-chain fatty acids in their feces [64].
The insulin resistance of TLR2 KO mice was accompanied by a down-modulation of insulin-induced insulin signaling in the liver, muscle, and adipose tissue, associated with an increase in endoplasmic reticulum stress.
It is also relevant to state that most of the results with administration of diets or drugs are usually obtained from short-term studies, which hampers the transposition of conclusions to humans with dietary habits carried on for most of their lives.
Produces several biologically active substances called adipokines, among them tumor necrosis factor- (TNF-), monocyte chemoattractant protein 1 (MCP-1), interleukin-6 (IL-6), leptin, resistin and adiponectin. Insulin Resistance and Type 2 by Paula Ford-Martin with Ian diabetes weight loss diet type 1 Blumer M. Leverve, Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I, J. Shimazu, Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats, Diabetes 48 (1999), pp. Sul, Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit, Diabetes 53 (2004), pp. Goldstein, Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes, Diabetes 52 (2003), pp.
This complex community—bacteria, eukaryotes, viruses and Archeae—in its majority cannot be cultured. Of the SCFA produced during from microbial fermentation process, butyrate has an important role as an energy substrate for cellular metabolism in the colonic epithelium, while acetate and propionate are taken up by the liver as substrates for lipogenesis and glucogeneogenesis.
For instance, the metabolic effects of guar gum consumption can be completely opposite depending of the duration of its administration [121,122].In addition, it is unclear whether results obtained from studies using animal models can be applies to humans since they present differences regarding the composition of gut microbiota and diet. These substances actively participate in, among others, body energy regulation, mainly, by endocrine, paracrine and autocrine signals, which allow the adipocyte play a metabolic role in other tissues [3-5]. Results: CIMT was greater in newly diagnosed type 2 patients compared to non-diabetic subjects. Thus, we propose that AMPK may affect insulin sensitivity by modulating the mTOR-S6K pathway, which in turn alters phosphorylation and protein levels of IRS (Harrington et al., 2004). Witters, An activating mutation in the gamma1 subunit of the AMP-activated protein kinase, FEBS Lett. Hardie, Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase, J. Kuhajda, Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors, Science 288 (2000), pp.
Kahn, Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase, Nature 415 (2002), pp. Cantley, The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress, Proc.
Hardie, Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex, Curr. Shulman, AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation, Proc. The reasons for this limitation are unknown growth requirements of the bacteria, selectivity of the media that are used, stress imposed by the cultivation procedures, necessity of strictly anoxic conditions, and the difficulties on simulating the interactions of bacteria with other microbes and host cells [20]. These SCFA, especially butyrate, also contribute to modulation of gene expression in mammalian colonic epithelial cells.
However, in obesity there is an imbalance in adipokines production, a fact which, together with the inability to store fat in the adipocytes, results in a process of adipose tissue dysfunction [6], a known risk factor for developing obesity-associated metabolic disorders [1, 2, 6]. When analyzed by BMI, the difference regarding CIMT between diabetic and non-diabetic subjects was significant only in overweight subjects, in both sexes. Insulin shock therapy is distinguished from electroconvulsive therapy, the latter of which is still used in the United States and elsewhere. Hardie, CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations, J.
Richter, Regulation of 5?aAMP-activated protein kinase activity and substrate utilization in exercising human skeletal muscle, Am. Tian, Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase, J.
Thus, a new approach was introduced, culture-independent sequencing [21,22,23], which made detection of microbial genes and disease-associated patterns in our gut microbiota possible.
As butyrate acts as histone deacetylase inhibitor, it may regulate around 2% of the mammalian transcriptome [65]. In spite of the fact that our knockout mice and those used in the other studies mentioned above had the same genetic background, they were bred in different rooms and fed with food from different sources, which can certainly have a role in the establishment and maintenance of gut microbiota [111]. This fact occurs because the adipocytes (hypertrophic and hyperactive) initiates the production of adipokines and chemotactic factors (such as MCP-1), which attract macrophages into the adipose tissue [7].
In univariate analysis in men with newly diagnosed type 2 diabetes, CIMT was positively correlated with age, SBP, triglycerides, leptin and negatively correlated with HDL-cholesterol and in women CIMT was positively correlated with SBP and leptin.
I have been telling for for years she should try to get some exercise and that I would help her learn how to cook healthy food but it falls on deaf ears. Regulation of the mTOR-S6K1 pathway by AMPK may affect insulin sensitivity by modulating the phosphorylation and amount of IRS. AMPK may function on both TSC and mTor directly to prevent impaired insulin signaling and obviate the metabolic changes that increase the risk for obesity and diabetes (Figure 4).
Seidman, Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy, J. Hardie, A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias, Curr. Zimmer, Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase, Nat.
Wojtaszewski, Knockout of the alpha2 but not alpha1 5?a-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle, J.
Ronnett, C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase, J.
Ebina, AMP-Activated protein kinase is activated by the stimulations of G(q)-coupled receptors, Biochem. The bacterial component of the microbiota has been intensively studied in the past few years, including high-investment studies such as the Human Microbiome Project [24,25] and MetaHIT [26].
For example, glucagon-like peptide (GLP)-1, a hormone with antidiabetic effects secreted by L-cells of the distal small intestine and colon, may have its secretion modulated by SCFA [66,67].
This way, gut microbiota per se can subvert a genetically predetermined condition previously described as being protective towards obesity and insulin resistance into a phenotype associated with weight gain and its complications, such as glucose intolerance and diabetes [46].Although the molecular origin of the state of low-grade inflammation found in obese individuals is unknown, LPS has been associated as the responsible one for the onset of metabolic diseases [97], since a continuous low-rate infusion of LPS induced most of the features of metabolic diseases, which did not occur in LPS receptor CD14 knockout mice [12].

Other Bacterial Factors may Contribute to Insulin ResistanceOther bacterial factors may play a role in the development of the insulin resistance. Consequently there is a synergistic interaction on proinflammatory adipokines production - mainly TNF-? - and antagonistic on adiponectin. My desk is oak wood with a gloss finish and it works very well except in one spot (it and every other mouse). Maguire et al., Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy, Circulation 107 (2003), pp. Galuska et al., The 5?a-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle, J.
Shepherd et al., The TSC1?C2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins, J.
Park et al., Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase, Nat. Yonezawa, A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway, Genes Cells 8 (2003), pp. Rask et al., A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle, Science 288 (2000), pp. Birnbaum et al., AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus, Nature 428 (2004), pp. Young, AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury, J. Bennoun et al., The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity, J.
Ueki et al., Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase, Nat.
Using this new approach made it possible to detect three dominating bacterial phyla in the human gastrointestinal tract: the gram-positive Firmicutes and Actinobacteria, and the gram-negative Bacteroidetes. Therefore, diabetic individuals might also have differential secretion of hormones due to fermentation products of their altered gut microbiota. Thus, we have found that the insulin resistance presented by TLR2 KO mice could be explained by the increased LPS serum levels, which led to increased activation of TLR4 in muscle, liver and adipose tissue, and increased phosphorylation of JNK, but not of IKK.
Like TLRs, nucleotide oligomerization domain (NOD)-1 and -2 proteins are intracellular pattern recognition receptors that sense bacterial cell wall peptidoglycan (PGN) moieties, which induce stress and inflammation pathways.
These substances lead to insulin resistance, reducing the lipogenic action of insulin in adipocytes, which results in higher rates of lipolysis in the adipose tissue [8, 9]. Conclusions: Subclinical atherosclerosis is present in newly diagnosed type 2 diabetic subjects. Furnsinn, Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions?, Diabetes 53 (2004), pp. Ruderman, AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise, Biochem.
Thomas, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity, Nature 431 (2004), pp.
Firmicutes is known as the largest bacterial phylum, comprehending 200 genera, which includes Lactobacillus, Mycoplasma, Bacillus, and Clostridium. Likewise, these mice presented reduced serum levels of proinflammatory citokynes IL-6 and TNF-? [46] (Figure 3).The absence of increased IKK pathway activation in our model was very intriguing and can be explained by the cooperation between TLR4 and TLR2 signaling, as demonstrated by Laflamme and colleagues. NOD1 detects PGN structures found in gram-negative bacteria, whereas NOD2 detects PGN segments typically found in gram-positive strains [123]. Body fat accumulation in men and hypertension in postmenopausal women have a primary role in increase carotid intima-media thickness.1. These changes may reduce downstream insulin signaling and the metabolic and transcriptional effects of insulin.
In spite of Actinobacteria being also a dominant phylum, it is usually missed by RNA gene sequencing and can only be detected by fluorescent in situ hybridization [20,27].Although gut microbiota has been described as relatively stable concerning its composition until old age [28,29,30,31], this temporal consistency considers that numerous variables are being held constant [32].
Recent studies have associated NOD1- and NOD2-activating bacterial motifs with insulin resistance. Alterations in the downstream biologic effects modulate the risk for obesity and type 2 diabetes. For example, dietary changes have been shown to have significant effects on the microbiota.
After the first bolus of LPS, TLR2 KO mice show a robust signal for genes encoding innate immune proteins in the brain. Administering PGN-based NOD1 activator to adipocytes leads to activation of inflammatory programs, impairing insulin signaling and decreasing insulin-stimulated glucose uptake [124]. An increase in the carotid intima-media thickness (CIMT), examined by B-mode ultrasonography, is generally considered an early marker of atherosclerosis [2-6]. Shifting mice to a high-fat, high-sugar “Western” diet, from a low-fat, plant polysaccharide-rich diet, changed the microbiota within 24 h [33]. Likewise, PGN motifs that act on NOD2 induce muscle cell-autonomous insulin resistance [125]. Previous studies have shown an association of increased CIMT with cardiovascular risk factors [7,8] and future cerebrovascular and cardiovascular events [9,10]. These results indicate that TLR2 is involved in the second wave of TNF-? expression after LPS and that there is an elegant cooperation between TLR2 and TLR4 [112]. NOD1-activating bacterial PGN motifs can also cause acute systemic insulin resistance in mice [126]. Also will be discussed the physiological role of adipokines as well as the effect of obesity and weight loss on the adipokines.2. This NOD1 activation suppressed insulin action in the liver and in isolated hepatocytes, and decreased insulin-mediated glucose uptake in adipocytes [126]. Adipokines physiological role The adipose tissue is considered an endocrine organ and shows great dynamism. In subjects with established diabetes, traditional risk factors such as hypertension, dyslipidemia (high LDL-cholesterol, triglycerides and apoB levels and low HDL-cholesterol levels), obesity as well as lower plasma adiponectin, inflammation markers and insulin resistance are associated with CIMT [15-21].
These findings also support the thought that intestinal microbiota could be responsible for changes in metabolic state, leading to endotoxemia and metabolic diseases. Therefore, NOD1 ligand-mediated insulin resistance seems to involve crosstalk between cells from different tissues, likely adipose and hepatic, with indirect manifestation in skeletal muscle [123].It is possible that many levels of regulation for NOD1-mediated sensing of PGN take place during obesity, since NOD1 transcripts were increased in epididymal adipose tissue of mice fed with high-fat diet [124].
Since 1940 there is a hypothesis that adipose tissue has signals to communicate with other tissues [11], but only later was shown that this tissue is able to synthesize and secrete a large number of protein factors (which also act as cytokines) collectively called adipokines. We noticed large differences between the studies which evaluated the correlation of cardiovascular risk factors with measures of subclinical atherosclerosis, both in diabetic and non-diabetic subjects, mainly because of the wide variations of the populations included. Treating high-fat diet-fed mice with antibiotics reduced normal plasma LPS values, reducing the occurrence of adipose tissue inflammation, oxidative stress and macrophage markers, as well as preventing adipocyte hypertrophy and improving metabolic parameters of diabetes and obesity in high-fat diet-fed mice [11].
It remains to be elucidated whether these NOD1 ligands, possibly derived from the gut microbiota, are altered during obesity and the extent of their contribution for the development of insulin resistance. These adipokines, in most part, are related, directly or indirectly, in processes involving atherosclerosis, hypertension, insulin resistance (IR) and type 2 diabetes (DM2), dyslipidemia, ie, represent the link between adiposity, metabolic syndrome and cardiovascular diseases [12-15]. Few studies showed that early atherosclerosis, evaluated by CIMT or arterial stiffness, is present in newly diagnosed type 2 diabetic subjects [22-25]. This way, dietary fats can be associated with increased absorption of LPS, which might be related to changes in the gut microbiota, characterized by reduction in Gram-negative Bacteroides-like bacteria, in the Eubacterium rectale-Clostridium coccoides group, and in Bifidobacteria [113,114]. Amar and colleagues have shown that after only one week of high-fat diet, bacterial translocation occurs towards adipose tissue and blood where inflammation is induced.
In the present study we evaluated CIMT in newly diagnosed type 2 diabetic patients, in comparison with nondiabetic subjects, matched for age and sex. This translocation is prevented in mice lacking the microbial recognition receptors NOD1 or CD14 [127], suggesting that these receptors have important roles in the development of the low-grade inflammatory state that characterizes insulin resistance.Activation of TLR9 is another possible route by which bacterial components may contribute to development of other metabolic diseases. LeptinWith its gene identified in 1994 [16] leptin is the adipokine most studied and thenceforth it has been identified more than 30 biochemical products secreted by adipocytes. In addition we analyzed the influence of traditional cardiovascular risk factors, adipokines (adiponectin and leptin), inflammation markers (fibrinogen and hs-CRP), insulin resistance and albuminuria on CIMT in patients with newly diagnosed type 2 diabetes without cardiovascular disease.2.
TLR9 recognizes bacteria-derived cytosine phosphate guanine (CpG)-containing DNA, activating innate immunity.
Leptin is a peptidic hormone with 167 amino acids and 16kDa of molecular weight and synthesized from the “ob” gene in adipocytes, being more common in subcutaneous adipose tissue than in visceral fat [17]. Studies using TLR9 knockout mice have stated the relevance of this receptor in the development of non-alcoholic fatty liver disease, steatohepatitis and fibrosis.
Besides to be considered an important lipostate, or energy balance regulator according to body fat mass in long-term [18, 19] has been implicated in the regulation of immune, respiratory and reproductive systems [20]. SubjectsA total of 167 subjects were included in this study: 50 newly diagnosed type 2 diabetes (25 men and 25 women) and 117 control, non-diabetc (64 men and 53 women). When its expression is ablated, suppression of IL-1? secretion and reduced steatohepatitis and fibrosis are observed. Subjects were recruited at the Department of Diabetes, Nutrition and Metabolic Diseases, Clinical Hospital Colentina, from February 2009 to January 2010. Together with TLR4, TLR9 leads to enhanced hepatic TNF-? expression and to the development of non-alcoholic steatohepatitis progression [128,129]. Reaching these tissues after crossing the blood-brain barrier, leptin acts in the arcuate nucleus where there is a large concentration of leptin receptors, when binding to reduce the action of neurons that use neuropeptide Y (NPY) signaling and agouti-related protein (ARGP). NPY is a peptide of 36 amino acids, synthesized mainly in the arcuate nucleus, which projects to the paraventricular nucleus, ventromedial, perifornical and lateral, also involved in energy balance regulation.
The ARGP also synthesized in the arcuate nucleus, also is projected to paratentricular nucleus, ventromedial and lateral, acting as a melanocortin system analogue on receptors MC-3 and MC-4, stimulating food intake. Leptin acts by decreasing the activity of these orexigenics signals, inhibiting food intake and increasing energy expenditure by activating the sympathetic nervous system [24, 25]. Also in the hypothalamus, leptin activates neurons pro-opiomelanocortin (POMC) producing alpha-melanocyte stimulating hormone (alpha-MHS). Carotid Artery UltrasoundCIMT was determined using a B-mode ultrasound scanner (Siemens Sonoline Sienna) and a 7.5 MHz linear probe with subjects in the supine position, by a trained specialist with no knowledge of the subjects clinical characteristics. All substances expressed in this system are anorexigenics, ie, act on reducing food intake [14]. This product acts on malanocortin-4 receptors and also on neurons that express cocaine and amphetamine-regulated transcript (CART). Measurement of IMT was made on the near (anterior) and far (posterior) wall of the common carotid artery at 1 cm proximal to the bifurcation, in segments that were free of plaque, plaque being defined as the presence of wall thickening at least 50% greater than the adjacent thickness. The nucleus tractus solitarius (NTS) participates in the satiety control, involved in the end of food intake process. Total adiponectin, leptin, hs-CRP, insulin and proinsulin were measured by ELISA (DRG International, Inc.) on a Dynex analyzer. Afferent inputs related satiety signals include neurological vagus nerve and sympathetic system associated with chemical signals such as endocrine factors of gut cholecystokinin. The Development of Obesity is Influenced by Gut Microbiota CompositionObesity has also been correlated with reduced bacterial diversity, altered expression of bacterial genes, and metabolic pathways [36].
Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and glucose were measured using standard techniques. Obese individuals have a differential proportion of particular phyla in their gut microbiota: fewer Bacteroidetes and more Firmicutes, compared with lean controls [36,53]. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as the product of the fasting plasma insulin value (in microunits per liter) and the fasting plasma glucose value (in mg per deciliter) divided by 405. Some studies, however, point that the decrease in Bacteroidetes is accompanied by an increase in Actinobacteria rather than Firmicutes [47].
In perifornical nucleus, there is production of peptides termed orexins A and B, which act in the ventromedial nucleus and inhibits satiety and increase food intake.
We have shown that Toll-like Receptor (TLR)2 knockout (KO) mice present increased relative proportion of Firmicutes and, slightly, of Bacteroidetes. However, these mice presented increased weight gain after 12 weeks of age compared with their controls and were obese after 20 weeks [46], suggesting that different proportions of bacterial phyla may lead to alterations that culminate in obesity.The Bacteroidetes bins were shown to be enriched in phosphotransferase systems involved in microbial processing of carbohydrates, whereas the Firmicutes bins were shown to be enriched in transport systems.
The leptin role in the CNS as a regulator is thus triggering mechanism (cascading effect), in order to stimulate or inhibit substances that act directly or indirectly in the hypothalamic areas involved in energy balance control.In addition to their central effects, leptin also interacts with numerous peripheral tissues.
Seventy-five percent of the obesity-enriched genes were from Actinobacteria and twenty-five percent from Firmicutes, while forty-two percent of lean enriched genes were from Bacteroidetes. Essentially, there are two major isoforms of leptin receptor, a long isoform which is required for full stimulation of the janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, and the short isoforms which result in the activation of JAK2 but not STAT.
Functional analyses suggest that many of them were involved in carbohydrate, lipid, and amino acid metabolism [47,54].
In skeletal muscle, for example, there are the two isoforms but the expression of short isoform is greater than the long one, making the leptin signalization in skeletal muscle activate various kinases including PI3-kinase, Akt (or PKB), PKC, MAP kinase kinase and Jun ERK [27, 28].In the immune system the leptin receptor are expressed in hematopoietic cells, where leptin produced by adipocytes stimulates the normal growth of myeloid and erythroid [14]. These findings suggest that a core gut microbiome exists as shared genes, with important alterations in metabolic functions rather than alterations simply in the relative abundance of bacterial taxa [47]. In addition, leptin synergistically acts with other cytokines by increasing the proliferation of leukocytes, specifically T4 cells.Leptin effects on reproduction are varied and the target organs range of hypothalamus, ovary and endometrial.
This shift in the relative abundance of phyla is associated with increased capacity for harvesting energy from food and with increased low-grade inflammation.
Continuous variables were tested for normality of distribution with the use of the Wilk-Shapiro test.
The increased capacity to harvest energy from nutrients observed in mice with increased proportion of Firmicutes and decreased proportion of Bacteroidetes seems to be related to the presence of genes encoding enzymes that break down polysaccharides that cannot be digested by the host, consequently with increased production of more fermentation end-products, mainly short-chain fatty acids, and their conversion to triglycerides in the liver. Its levels have a circadian and ultradian cycle, and these variations are associated with varying levels of luteinizing hormone (LH) and estradiol, informing to the brain about the critical fat stores necessary for secretion of luteinizing releasing hormone and activation of hypothalamic-pituitary-gonadal axis [30]. Data normally distributed were expressed as mean ± standard deviation (SD) and data skewed distributed were expressed as median (interquartile range). Moreover, regulation of host genes that promote deposition of lipids in adipocytes has been related to altered gut microbiota composition.
The amount of leptin released in the brain is greater in women than in men, suggesting that women may be more resistant to the leptin action and require higher levels to achieve an appropriate response [31].
Normally distributed variables were compared by unpaired t-test and not normally distributed variables were compared by Mann-Whitney test. The microbiota suppresses the expression of fasting-induced adipose factor, Fiaf, a secreted lipoprotein lipase (LPL) inhibitor. It is known that leptin, in ovaries, may affect the menstrual cycle by a direct inhibitory effect on the follicles development [29]. Variables not normally distributed (insulin, proinsulin, proinsulin to insulin ratio, HOMA-IR, adiponectin, leptin, leptin to adiponectin ratio, hs-CRP, UACR) were log transformed before evaluating the correlations. By suppressing Fiaf, colonization enhances LPL activity, increasing storage of liver-derived triglycerides [55]. Leptin may still have an important role in the early stages of cleavage and embryonic development [32], in the fetal growth regulation and development, hematopoiesis and angiogenesis, as leptin receptors were found in syncytiotrophoblast, suggesting that leptin may play an important role in fetal endocrine function of feto-placental unit [33].
Associations between CIMT and the variables evaluated, in subjects with newly diagnosed type 2 diabetes, were examined using linear regression analysis.
In addition, leptin may play a central role in other target organs for reproduction, such as endometrial and mammary gland, influencing important functions including lactation and prevention of misbirth [34].In the respiratory system leptin acts as a growth factor in the lung and as a modulator in the mechanisms of breathing central control. Leptin levels are elevated in patients with sleep apnea, independent of body fat, being associated with leptin resistance [14].For hypothalamic-pituitary-thyroid axis leptin acts on the expression of thyrotropin-releasing hormone (TRH). Mice in vitro and in vivo study has demonstrated that leptin stimulates neurons directly in the paraventricular nucleus, which express TRH, increasing proTRH expression [35]. Characteristics of Study SubjectsThe clinical and biochemical characteristics of the subjects included in this study are presented in Table 1. During fasting, the prohormone convertases 1 and 2 (PC1 and PC2) are decreased and leptin showed to restore PC1 and PC2 to pre-fasting levels [36]. Obese and overweight newly diagnosed type 2 diabetic patients were matched for age, sex and BMI with obese and overweight non-diabetic subjects.
Another possible mechanism suggested by this group would be the increased activation of AMP-activated protein kinase (AMPK) in the skeletal muscle and liver, increasing fatty acid oxidation and glucose uptake in the muscle.
Studies in rodents have shown that calorie restriction rapidly suppresses TRH expression in the paraventricular nucleus, leading to decreased thyroxine (T4) and triiodothyronine (T3) levels [37], and leptin can reverse these changes [38].Both partial and complete deficiency of leptin is associated with hypothyroidism. Phosphorylated AMPK stimulates fatty acid oxidation in peripheral tissues by phosphorylating acetylCoA carboxylase (Acc). Clinical and biochemical characteristics of diabetic patients and control subjects.lin, proinsulin, leptin and UACR were significantly higher and adiponectin and HDL-cholesterol were significantly lower in obese subjects, both newly diagnosed diabetic and non diabetic, compared to non diabetic, lean subjects. Phosphorylation of Acc leads to inhibition of its activity, decreasing malonylCoA levels, which releases carnitine:palmitoyl transferase-1 (Cpt1). Individuals with congenital leptin deficiency have a disorganized TSH secretion, suggesting that leptin may regulate the pulsatile characteristics of TSH and the circadian cycle [40]. This enzyme catalyzes the rate limiting step for entry of long-chain fatty acylCoA into mitochondria, therefore increasing fatty acid oxidation [57].This way, results from experiments performed in germ-free and Bacillus-associated wild-type (WT) mice also support an active role of microbiota in modulating fat oxidation and accumulation, suggesting that, different from early beliefs, dietary fats alone might not be enough to cause overweight and obesity. In women with hypothalamic amenorrhea leptin treatment significantly increased free T3 and free T4, however did not affect TSH levels [41]. It has been demonstrated that transplantation of gut microbiota from mice with obese phenotype to germ-free or Bacillus-monoassociated lean WT mice leads to increased body weight gain [27,46,58].
Fasting glucose and HBA1c were higher in newly diagnosed type 2 diabetic, both in obese and overweight, compared to non-diabetic subjects. ResistinResistin is a polypeptide at approximately 12kDa and belongs to proteins family with cysteine-rich C-terminal domain call resistin-like molecules, which are identical to those found in inflammatory zone family, giving to resistin the alias FIZZ3 [44].
Fasting insulin, proinsulin and HOMA-R were significantly higher in obese type 2 newly diagnosed diabetic vs.obese non-diabetic. Likewise, Vijay-Kumar and colleagues have shown that transplantation of gut microbiota from mice genetically deficient in Toll-like Receptor (TLR)5 to germ-free WT lean mice leads to weight gain and other signs of metabolic syndrome in the recipients [58]. Its expression is 15 fold higher in visceral adipose tissue when compared to subcutaneous adipose tissue, in rodents [44], but it is also expressed in human macrophages [45]. Its name is due to the resistin presents a significant role in obesity-associated insulin resistance [46] and its molecular structure is very similar to adiponectin.
However, UniFrac analysis indicated that TLR5 deficient mice and WT littermate mice were different in their species composition. Resistin production increases with food intake and obesity, and decreases in the presence of PPAR-gamma ligands [47].Resistin promotes insulin resistance by increasing hepatic gluconeogenesis, and presenting rapid effect on this tissue [47]. In newly diagnosed type 2 diabetic patients BMI, waist, insulin, HOMA-R and proinsulin were higher in obese vs. Moreover, the knockout mice presented increased or decreased phylotypes from various phyla. Other in vivo study also found effects of administration and neutralization of resistin on glucose tolerance in skeletal muscle and adipose tissue, indicating resistin action also in these tissues by negative modulation of insulin signaling on glucose uptake [46].Regarding the specific body fat deposits, resistin expressions 2-3 fold higher is found in visceral adipose tissue, followed by subcutaneous, abdominal and gluteal-femoral subcutaneous.
We have shown that transplantation of gut microbiota from mice genetically deficient in TLR2 to Bacillus-monoassociated WT lean mice leads to weight gain, insulin resistance and impaired insulin signaling, resembling the phenotype found in TLR2 deficient mice [46]. Its expression is 3 fold higher in preadipocytes compared with mature adipocytes, also functioning as a potential regulator of adipogenesis [48].Resistin deficient mice have weight and fat mass similar to wild-type mice, even when high-fat fed.
None of the subjects had macroalbuminuria, 7 subjects (5 subjects from the non-diabetic group and 2 subjects from the diabetic group) had microalbuminuria and the rest of the participants had low grade albuminuria.CIMT was greater in obese and overweight, both in newly diagnosed type 2 diabetic (obese vs.
These metabolic characteristics were also similar to what was found in TLR5 deficient mice, except for the fact that TLR2 knockout mice did not present hyperphagia. However, resistin deficient mice significantly improved fasting glucose levels in control diet and improved glucose tolerance in high-fat diet. However, regarding the gut microbiota composition, TLR2 knockout mice were different from TLR5 knockout mice, presenting increased relative abundance of Firmicutes compared with WT mice.It has also been suggested that obese individuals might be able to extract more energy from nutrients due to hydrogen transfer between taxa, as a concurrent increase in both hydrogen-producing Prevotellaceae and hydrogen-utilizing methanogenic Archaea has been associated with obesity [59]. There was no significant difference between CIMT in obese, newly diagnosed diabetic patients and CIMT in obese, nondiabetic subjects. Another study corroborates these data, showing that germ-free mice colonized with Bacteroides thetaiotaomicron, a saccharolytic member of the normal human colonic microbiota, together with the dominant human colonic methanogen, Methanobrevibacter smithii, have increased polysaccharide fermentation, increased de novo lipogenesis and enhanced host adiposity compared with animals with either organism alone [35] (Figure 1).
The improvement in glucose homeostasis in resistin deficient mice is associated with decreased hepatic gluconeogenesis.
Unlike other factors secreted by adipose tissue, adiponectin acts as a protective factor for cardiovascular disease and increases insulin sensitivity. It is an approximately 30 kDa polypeptide that shows high homology with collagen VIII and X, and complement component C1q. DISCUSSIONIn this study we show that patients with newly diagnosed type 2 diabetes have an increase CIMT compared to non-diabetic, lean subjects matched for age.
This receptors present seven transmembrane domains but are functionally different of receptors coupled to G protein. In obese subjects we found no difference in CIMT between newly diagnosed type 2 diabetes and non-diabetic, in both sexes and in overweight subjects CIMT was significantly greater in newly diagnosed type 2 diabetes compared to non-diabetic, in both sexes.Temelkova et al.
AdipoR1 is expressed mainly in muscle tissue and has high affinity for globular adiponectin, and low affinity for full-length adiponectin. AdipoR2 has high expression in liver and has intermediate affinity for both isoforms of circulating adiponectin.
Carotid intima-media thickness (CIMT) in newly diagnosed type 2 diabetic patients and non-diabetic subjects.Table 3.
It increases insulin sensitivity via increased fatty acid oxidation and glucose uptake and utilization in skeletal muscle and adipose tissue; reduction of hepatic glucose release, leading to better control of glucose serum levels, free fatty acids and triglycerides [59]. In rat adipocytes, in vitro, the 60% reduction in adiponectin expression increased significantly insulin resistance. The presence of nucleotide polymorphisms in adiponectin caused by genetic or environmental factors (diet rich in fat, for example), can be a determining factor in reducing their insulin sensitizing action [60].In the liver, adiponectin increases insulin sensitivity by reducing nonesterified fatty acids uptake, increasing fatty acid oxidation and decreasing glucose output. In the endothelium, it inhibits monocyte adherence by reducing adhesion molecules; inhibits macrophages transformation and reduces migrating smooth muscle cells proliferation in response to growth factors.

Multiple regression analysis with CIMT as the dependent variable in women with newly diagnosed type 2 diabetes.female, diabetic vs.
Adiponectin also increases nitric oxide production by endothelial cells and stimulates angiogenesis.
Others adipokinesTumor Necrose Factor - alpha (TNF-?) – TNF-? is a cytokine expressed by adipocytes and stromovascular cells, with higher expression in subcutaneous adipose tissue compared to visceral adipose tissue, acting directly on adipocytes, promoting apoptosis induction, lipogenesis inhibition, by inhibiting lipoprotein lipase (LLP), GLUT-4 and the acetyl CoA synthetase expressions, as well as increased lipolysis, therefore exerting an important regulatory role in fat accumulation in adipose tissue [61, 62]. Also, the authors showed that in diabetic patients triglycerides and the total-to-HDL cholesterol ratio were significantly correlated to IMT after adjustment for age and sex, but in multivariate analysis no independent determinants of carotid IMT were found. TNF-? is a transmembrane protein of 26 kDa, which, after being cleaved generates a portion of 17-kDa, which is biologically active and exerts its effects through TNF- receptor type I and II.
It is a cytokine initially described as an endotoxin-induced factor causing necrosis in tumors. The ability of TNF to induce cachexia in vivo led to an extensive evaluation of its role in energy homeostasis [3]. In this study waist-to-hip ratio, diabetes onset status (newly diagnosed versus established) and triglycerides were independent correlates of carotid IMT in men with diabetes.We found that in patients with newly diagnosed type 2 diabetes, without cardiovascular diseases and treatment for hypertension or dyslipidemia, there are sex differences in the risk of subclinical atherosclerosis. TNF-? alters gene expression of metabolically important tissues such as adipose tissue and liver [63] and impairs the insulin signaling by activation of serine kinases that increase the insulin receptor substrate-1 and -2 phosphorylation, increasing its degradation [64].
In men, in univariate analysis age, SBP, triglycerides and leptin correlated positively with CIMT and HDL-cholesterol correlated negatively with CIMT and in multivariate analysis, age and leptin were independent predictors of CIMT and in women, in univariate analysis SBP and leptin correlated positively with CIMT and in multivariate analysis, SBP was an independent predictor of CIMT. Both TNF-? and triiodothyronine are involved in the tissue homeostasis maintenance of the anterior pituitary gland, however, triiodothyronine inhibit the signaling cascade that TNF-? promotes on this tissue in signaling pathways affecting MAPK p38 and nuclear factor kappaB [65].Interleukin-6 (IL-6) – IL-6 is also a cytokine with pro-inflammatory effect in acute responses and action on carbohydrates and lipids metabolism [66, 67]. Leptin, a hormone produce by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Plasma leptin concentration is increased in obese subjects and reflects increased adiposity and leptin resistance [26-28].
Its receptor (IL-6R) is homologous to the leptin receptor and exists in two isoforms, a membrane-bound and soluble. In vitro and in vivo assays demonstrated that leptin has multiple atherogenic effects such as induction of endothelial dysfunction [29,30], stimulation of migration and proliferation of vascular smooth cells [31], production of reactive oxygen species (ROS) [32] stimulation of inflammatory reaction [33], platelet aggregation [34], sympathetic activation [35]. The infusion of IL-6 near physiological doses, in healthy humans, increase lipolysis independently of catecholamines, glucagon and insulin modulation [68], indicating IL-6 as an important factor in lipid metabolism. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects.
According to the concept of selective leptin resistance, there is resistance to the effects of leptin on appetite and thermogenic metabolism, whereas its other actions are maintained [36]. Furthermore, the increased expression may be related to leptin suppression and stimulation of C-reactive protein production, as well as in reducing IRS-1 and GLUT-4 expression in the liver and muscle [66]. There are studies which have shown that serum leptin is lower in subjects with established diabetes mellitus [37,38].In recent years many studies evaluated the cardiovascular effects of leptin [39-41].
IL-6 is secreted by adipocytes and macrophages, which are responsible for 30% of its secretion [67]. Catecholamines can stimulate IL-6 expression via ?2-and ?3-adrenoceptors in adipose tissue, when in high concentrations [69]. The IL-6 central administration increases energy expenditure and decreases body fat in rodents. Also, transgenic mice with IL-6 overexpressed showed generalized growth deficiency and reduced body mass, however, IL-6 deficient mice develop obesity and metabolic abnormalities, suggesting that IL-6 may prevent, rather than cause these conditions [70].Monocyte chemotactic protein-1 (MCP-1) – MCP-1 is a chemokine and a member of the small inducible cytokine family, which plays a role in the recruitment of monocytes and T lymphocytes to sites of injury and infection.
Its main receptor is the chemokine CC motif receptor (CCR) 2 that is expressed in various cell types including adipocytes, skeletal muscle cells and macrophages. MCP-1 was first described as a secretory product of monocytes and endothelial cells with a role in atherosclerosis. MCP-1, acting through its receptor CCR2, is now thought to play a central role in the recruitment of monocytes to atherosclerotic lesions and in the development of intimal hyperplasia after arterial injury.
Owing to their crucial roles in monocyte recruitment in vascular and nonvascular diseases, MCP-1 and CCR2 have become important therapeutic targets in cardiovascular research. As for skeletal muscle, MCP-1 is increased during myopathies and can be induced by interferon-gamma.
Recently, MCP-1 has been attributed an additional role in the pathophysiology of obesity [71].Plasminogen activator inhibitor (PAI)-1 – Adipocytes can secrete many proteins in hemostasis and fibrinolytic system as PAI-1 [72]. PAI-1 is a member of the serine protease inhibitor family and is the primary inhibitor of fibrinolysis by inactivating urokinase-type and tissue-type plasminogen activator. PAI-1 has also been implicated in a variety of other biological processes including angiogenesis and atherogenesis.
PAI-1 expression and secretion are greater in visceral adipose tissue relative to subcutaneous adipose tissue [54]. The authors found no association for leptin.In the present study we show that SBP, triglycerides, fibrinogen, hs-CRP, insulin, proinsulin, leptin and UACR were significantly higher and adiponectin and HDL-cholesterol were significantly lower in obese subjects, both newly diagnosed diabetic and non-diabetic, compared to non-diabetic, lean subjects. PAI-1 promotes thrombi formation and unstable atherogenic plaque rupture, and change the fibrinolytic balance by inhibition of plasmin production, contributing to vascular architecture remodeling and atherosclerotic process [66, 73]. We found no difference in the plasma concentration of total cholesterol, LDL-cholesterol, HDL-cholesterol, fibrinogen, hsCRP, leptin and adiponectin, systolic blood pressure and diastolic blood pressure between the diabetic and nondiabetic subjects, irrespective of BMI (obese or overweight).
Adipsin and acylation stimulating protein (ASP) – Also secreted by adipose tissue it has an important effect on lipogenesis [59].
Plasma triglycerides were higher in both obese and overweight newly diagnosed type 2 diabetes, compared to obese and overweight non-diabetic subjects. APS inhibits the lipolysis by inhibition of hormone sensitive lipase (HSL), and stimulating lipogenesis by increasing GLUT4 translocation from cytosol to membrane; increases glycerol-3-phosphate production and increases diacylglycerol acyltransferase activity, an catalyst enzyme in triglycerides synthesis [74]. Insulin, HOMA-R and proinsulin were higher in obese type 2 diabetic subjects compared to obese non-diabetic subjects. Insulin, proinsulin and HOMA-R were higher in obese type 2 diabetic subjects compared to overweight type 2 diabetic subjects. Proteins of the renin angiotensin system (RAS) – Pathogenic models have been proposed to explain the association between adiposity and the renin angiotensin system [75].
These data sustained our view[49] that the main pathogenic link of type 2 diabetes with vascular disease is close related with obesity.
This seems to be related to fat accumulation in adipose tissue, as well as its involvement in inflammatory and atherogenic process.
Adipose tissue secretes many proteins related to the RAS as renin, angiotensinogen (AGT), angiotensin I, angiotensin II, angiotensin type I receptors (AT1) and type 2 (AT2) angiotensin-converting enzyme (ACE), and other proteases capable of producing angiotensin II (chymase, cathepsins D and G) [76, 77]. CONCLUSIONSubclinical atherosclerosis is present in patients with newly diagnosed type 2 diabetes. The angiotensin I receptor is secretion inductor of series 2 prostaglandins which participates in preadipocytes cell differentiation, and the angiotensin II stimulates adipocytes differentiation and lipogenesis in time of angiotensin I to II conversion, indicating their involvement in the accumulation of fat mass process [78]. Body fat accumulation in men and hypertension in women have primary roles in development of subclinical atherosclerosis in newly diagnosed type 2 diabetic patients. Adipokines and thyroid hormonesThe thyroid gland mainly produces the thyroid hormones T3 and T4.
However, also produces small amounts of other iodothyronines as reverse T3 and 3,5-diiodo-L-thyronine. Thyroid hormones secretion is regulated by the classical mechanism of negative feedback; briefly, thyroid releasing hormone (TRH), produced predominantly by neurons of the paraventricular nucleus in the hypothalamus, stimulates the release of thyroid stimulating hormone (TSH) in pituitary and this in turn, stimulates the synthesis and release of thyroid hormones.
The increase in thyroid hormones serum concentrations inhibit the production of both TRH and TSH, leading to decreased thyroid function. The subsequent decrease in thyroid hormones serum levels, in turn, stimulates TRH and TSH, again increasing the concentration of hormones [79].
The thyroid hormone receptors (TRs), members of the superfamily of nuclear receptors interact with a specific DNA sequence, called responsive element in the promoter region of target gene and regulates gene transcription [80].
Generally, TRs are repressors in the absence of binding T3 and transcriptional activators in its presence [81].Although the thyroid hormones are essential for the survival [37], thyroid function disorder leads to changes in metabolic parameters, for example, thyroid hormone excess is associated with weight loss and reduced muscle and fat mass [82], showing that thyroid hormones play a central role in regulating the adipose tissue metabolism [83].
These modulated genes give rise to proteins involved in transduction signal, lipid metabolism, apoptosis and inflammatory responses. LeptinA potential interaction between leptin and thyroid hormones has been suggested since both hormones are associated with body weight and energy expenditure regulation.Leptin deficiency leads to severe obesity, however, in humans it’s usually find high levels of leptin associated with leptin-resistance state [86-91]. Although thyroid function is usually normal in obese subjects, many studies have demonstrated that TSH levels are slightly increased in obese subjects [92-94].
Several studies have suggested that leptin influences TSH release, suggesting a regulatory role by leptin on thyroid axis at least in some conditions [35, 40, 95-101]. Thyroid hormones regulate the expression of several genes in human adipocyte [84], however, the role of thyroid hormones in leptin modulation remains controversial (Figure 3). Obese human subjects have high serum leptin levels as leptin concentrations are directly proportional to body fat mass, more specifically to adipocyte volume [110, 111]. Regarding to thyroid hormones, there is indications that human obesity is usually associated with increased TSH and T3 levels [92, 112]. As in rats, studies with humans reached to controversial results about the effect of thyroid hormones over leptin concentrations. In fact, human studies present more difficulties in terms of controlling variables as patient characteristics, treatments and method for measuring leptin levels and body composition. In hypothyroid subjects serum leptin was found to be increased [83, 113], decreased [114, 115] or unchanged [116, 117] when compared with euthyroid subjects.
ResistinResistin is strongly related to insulin resistance, showing increased resistin concentrations in obese and diabetic animals [46], and additionally it has been associated with inflammatory condition [119]. There is evidence that the hyperlipidic diet-induced obesity as well as leptin gene mutations are associated with high resistin circulating levels [120].
Resistin administered intraperitoneally increases plasma glucose and induces a hepatic insulin resistance. Other studies involving administration of resistin-recombinant promoted insulin resistance and reduced glucose transport stimulated by insulin, whereas administration of anti-resistin antibodies produced the opposite effect in rats [46]. Moreover, anti-resistin antibodies decrease blood glucose levels and improve the insulin sensitivity in obese rats [121, 122]. In contrast, high resistin levels are related to obesity and insulin resistance [46], and since body mass index has a possible association with thyroid hormones during periods of weight gain [125], could be establish a relationship between thyroid hormones and resistin in obesity.
Thyroid hormones appear to regulate resistin, at least in rats, however, in humans, studies on resistin levels and thyroid status have produced conflicting results. Some studies report that patients with hyperthyroidism have elevated resistin concentrations when compared with euthyroid control subjects [126].
Normalization of circulating thyroid hormones was accompanied by a significant decrease in resistin concentrations [126]. Others showed that hyperthyroid patients exhibit a significant decrease in resistin levels compared with euthyroid individuals. Normalization of circulating thyroid hormones levels was not accompanied by any significant change in resistin levels [127].
After adjusting the weight by the body mass index, the resistin levels of hyperthyroid patients were similar to euthyroid individuals [128].Azza et al.
These data may help to explain previous findings showing a marked improvement in insulin resistance observed in obese rats after treatment with exogenous thyroid hormones [106].
AdiponectinThe main target tissue and the precise mechanism of adiponectin action are not fully understood.
The adiponectin activity is probably regulated at several levels, including gene expression, post-transcriptional modifications, oligomeric complexes formation, and proteolytic cleavage into smaller and perhaps more active fragments [131]. Some experimental models suggest that reduced adiponectin expression is associated with obesity and insulin resistance. Adiponectin expression may be activated during adipogenesis, but the feedback inhibition on its production may be involved in obesity development.
It has been shown that adipogenic genes expression was suppressed during obesity and diabetes development in mice [132]. A negative correlation between obesity and circulating adiponectin has been well accepted.Studies of a possible relationship between adiponectin and lipid metabolism changes associated with thyroid dysfunction are scarce.
Hyperthyroid patients showed an increase in body weight, body mass index and cholesterol serum levels after controlling for thyrotoxicosis.
The lack of correlation between these parameters and serum adiponectin suggests that changes in body composition and lipid profile observed in hyperthyroidism are independent of adiponectin.
In contrast, patients with hypothyroidism showed elevated cholesterol and triglycerides levels when compared to normal subjects.
Thyroid function control was followed by a significant decrease in serum cholesterol and triglyceride concentrations. However no relationship between adiponectin and lipid profile before and after therapy was evidenced.
Furthermore, after adjusting adiponectin levels for body mass index, no significant change was observed in patients with hyper- and hypothyroidism, suggesting that thyroid hormones play a small role in adiponectin levels modulation [128].An experimental study of rats with hyperthyroidism showed an important rise in serum adiponectin [133].
High-fat fed rodents showed significantly increased TNF-? expression and alteration in insulin signaling pathway in vivo [136]. Anti-TNF-? antibodies improves insulin sensitivity in obese rats, whereas TNF-? deficient animals, even when subjected to high-fat diet, present themselves "protected" from obesity development and insulin resistance.
TNF-? is a cytokine that may be involved in autoimmune thyroid disease development [137, 138]. Jiskra & Telicka [138] examined the relationship between thyroid function and cytokines, using patients with Graves' disease (characterized by hyperthyroidism), and patients with Hashimoto thyroiditis (disease characterized by hypothyroidism). The cytokine profile was assessed and patients with Hashimoto's thyroiditis present body mass index above the ideal level and TNF-? serum levels smaller than in patients with Graves' disease, who had body mass index within normal limits. However TNF-? reduction was not observed in patients with hypothyroidism who have had the thyroid function normalized, despite a positive correlation between the TNF-? post-treatment levels and weight loss. IL-6 - IL-6 levels are increased in obesity [140], and is also a marker of insulin resistance [141, 142]. According Nonogaki et al [143], metabolic impact produced by increased expression of IL-6 in the body fat deposits can be very importante in the obesity pathogenesis. The increase in IL-6 plasmatic could stimulate the hepatic synthesis of triacylglycerol, contributing to hypertriglyceridemia associated with visceral obesity.
Data on relationship of thyroid hormones and IL-6 in obesity are scarce, but the association between reduction of T3 circulating levels and increasing pro-inflammatory cytokines, particularly IL-6, is described in the literature in both animals’ models and human studies - septic patients and in patients with systemic inflammatory response [144, 145]. Changes in serum thyroid hormone concentrations could effectively be ascribed to IL-6, since they could be prevented by IL-6 preincubation with its neutralizing antibody [144].
In latter study, pro-TRH mRNA hypothalamic and pituitary TSH-b mRNA were unaffected by IL-6, suggesting that the effects of IL-6 on TSH might not necessarily be associated with a decreased synthesis of thyrotropin [145].
On the other hand, the observation that the intracerebroventricular IL-6 administration to rats was followed by a decrease in serum TSH and an increase in serum adrenocorticotropin (ACTH) concentrations, while these changes could be reproduced in hemipituitaries only for ACTH, but not for TSH, suggested that the action of IL-6 on TSH might be exerted predominantly at the hypothalamic levels [146].
Increased concentrations of cytokines, especially IL-6, are often found in nonthyroidal illness patients and correlate with changes in thyroid hormone concentrations [144].MCP-1 - Expression in adipose tissue and plasma MCP-1 levels have been found to correlate positively with the degree of obesity [7, 147-149]. Elevated circulating levels of MCP-1 as well as MCP-1 mRNA have been reported in obese mice [149, 150]. The possibility that MCP-1 formation in adipose tissue is due to macrophage infiltration must be considered since obesity is associated with various degrees of macrophage accumulation in adipose tissue [7, 147]. No data on this adipokines and thyroid hormone have been published.PAI-1 - Adipose tissue PAI-1 gene expression and serum concentration have been reported in several pathological conditions, such as obesity, hyperinsulinemia, and hyperglycemia [151, 152].
The thyroid hormones T4 and T3 also have cardiovascular effects, probably through the regulation of circulating clotting proteins and fibrinolytic activity [153]; however, the mechanisms leading to cardiovascular and thromboembolytic diseases in thyroid dysfunction are controversial.
Some reports have described an increase in serum PAI-1 concentration in hyperthyroidism, whereas others did not detect any differences [154, 155]. Additionally, the effects of T3 and T4 on PAI-1 gene expression in 3T3-L1 adipocytes were also evaluated. The results demonstrated that adipocytes present different responses to thyroid hormones when considering in vivo and in vitro experiments. The diverse in vivo and in vitro effects of thyroid hormones on PAI-1 gene expression regulation are not related to the inhibitory effect of T4 on thyroid-stimulating hormone (TSH) secretion, since the literature has not shown any relationship between TSH and PAI-1 serum concentration [157]. However, it could be suggested that the lower amount of thyroid hormone receptors and deiodinase present in white adipose tissue than in brain, liver, brown adipose tissue, and kidney may be involved in this process. In addition, the low blood flow in white adipose tissue in comparison to other tissue types [158] could contribute to hormone distribution in vivo, suggesting that lower amounts of T4 and T3 were achieved in adipocytes in vivo in comparison to the in vitro study. Thyroid hormones have different effects in relation to PAI-1 gene expression in adipocytes in the intact rat (in vivo study) and in cultured adipocytes (in vitro study).
Further studies are required to better elucidate the diverse in vivo and in vitro effects of thyroid hormone on adipocytes PAI-1 gene expression [156].ASP - In a number of studies, ASP has been demonstrated to be increased in obesity, diabetes and cardiovascular disease [159-161].
Plasma ASP levels correlate positively with body mass index, as well as with plasma lipids. Study using culture of human adipocytes revealed increased secretion of chylomicrons induced by ASP [162]. There is evidence that circulating lipids also stimulate the expression of ASP after drinking large quantities of these nutrients [163]. There is no data available regarding the effect of thyroid hormones on ASP levels in obesity.RAS- Adipose tissue synthesizes and secretes the major components of RAS [164].
There is evidence for overactivation of adipose tissue RAS in obesity in rodents [165], and for a positive correlation between adipose tissue angiotensinogen levels and BMI in humans [166]. Also Ang II secretion from adipose tissue is increased in obese, but not lean, individuals [167].
Increased production of angiotensinogen with excess gain in white adipose tissue contributes to glucose intolerance development, insulin resistance, cardiovascular and renal diseases [76, 168, 169]. The interaction of RAS with other adipokines also contributes to the development of metabolic syndrome.
Ang II appears to stimulate leptin production by adipocytes [76]; which in turn, hyperleptinemia may further hyperactivity of RAS by stimulating renin release by the kidney.
Ang II may also regulate negatively adipocyte production of adiponectin in both rodents and humans [171, 172].
Thyroid hormones are important regulators of cardiac and renal functions while RAS components act systemically and locally in individual organs also to control cardiovascular and renal functions. Several studies have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels [173, 174].
Thyroid hormones also appear to stimulate expression and synthesis of RAS components [175-177].5. LeptinAfter weight loss, leptin levels decrease [178-180], as well TSH and T3 reduces to normal levels [92, 93, 112]. In starvation conditions, serum leptin levels decrease and thyroid hormones levels are quickly supressed, leading to a consequent reduction in energy expenditure [83].
Not only a minimal weight loss is required but a maximal weigh loss beyond which further improvements in circulating adipokine levels are no longer observed has been suggested [179, 182].
The method or diet content by which weigh loss is achieved seems to be less important than the overall weight loss [179, 183].As mentioned before, studies investigating the correlation between thyroid hormones and leptin levels present conflicting results. ResistinSince obesity is considered a global epidemic and one of majors public health problem, affecting developed and developing countries [185, 186], and obese subjects may presente increased resistin levels [46], which can worse insulin resistance and inflammation [119], one of the most used strategies is the weight loss by reduction of caloric intake [187]. Caloric restriction affects the regulation of adipose tissue gene expression, normalizing the adipokines changes caused by obesity [10], while thyroid hormones play a central role in regulating adipose tissue metabolism [83], being related to body weight changes, thyroid hormones may therefore play a key role in the normalization of resistin in weight loss.Nogueiras et al.
T3 had no effect on resistin mRNA levels in adipose tissue of obese animals submitted to calorie restriction [189].Normalization of circulating thyroid hormones was accompanied by a significant decrease in resistin concentrations [126]. Others showed that hyperthyroid patients exhibit a significant decrease in resistin levels compared with euthyroid individuals, and the normalization of circulating thyroid hormones was not accompanied by any significant change in resistin levels [127].
AdiponectinNegative correlation between obesity and circulanting adiponectin has been well accept, and adiponectin concentration increases concomitantly to weight loss [190]. Experimental study on caloric restriction showed increased levels of circulating adiponectin [191]. Thyroid hormones perform a central role in adipose tissue metabolism regulation [83], which produces the biologically active substances adipocytokines, or adipokines, that include adiponectin [127, 194], indeed thyroid hormones share some physiological actions with adiponectin, such as reduction of body fat by increased thermogenesis and lipid oxidation [194].
In humans, hyperthyroidism has been associated with both similar [128, 195] and elevated adiponectin concentrations [196], while experimental study with hyperthyroid rats found an increase in adiponectin serum concentration [133]. In agreement, some data shown that therapy to normalize hyperthyroidism significantly reduced circulating adiponectin levels [197]. Others adipokinesTNF-? - The first information about the TNF-? biological effects indicated an involvement in insulin resistance, weight loss and anorexia.
The increase in lipolysis result from TNF-? stimulus in hormone-sensitive lipase expression, leading to decreased activity of lipoprotein lipase. However, more recent investigations have revealed a molecular mechanism of weight loss on TNF-? levels, showing TNF-? expression is increased in obesity and decreases with weight loss, thereby improving insulin sensitivity [135, 198]. After weight loss there is a decrease of macrophages number in adipose tissue [199], this can lead to decreased TNF-? levels, since both adipose tissue and macrophages produce this cytokine. Patients with HIV tend to lose weight and in some cases it is observed a decrease in T3 levels accompanied by increased TNF-? levels, when these individuals are compared to patients with HIV with normal T3 levels. These results corroborate to other study linking the sick euthyroid syndrome to high TNF-? levels in cachectic patients with HIV [200].
The exact influence of thyroid hormone on adipokines remains unclear.IL-6 - IL-6 levels decrease with weight loss [140-142]. Association studies between thyroid hormones and IL-6 in weight loss are scarce, but studies in critically patients demonstrated a direct association between decreased T3 levels and high IL-6 plasma levels, demonstrating that approximately 28% of T3 fall could be directly related to increased IL-6 [202].

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