Mecanismos de resistencia a la insulina en obesidad

7.376 visualizaciones

Publicado el

Memorias Conferencia Científica Anual sobre Síndrome Metabólico 2015 - Programa Científico - Dra. Roopa Mehta - Investigadora, Servicio de Endocrinología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán»

Publicado en: Salud y medicina
0 comentarios
10 recomendaciones
Estadísticas
Notas
  • Sé el primero en comentar

Sin descargas
Visualizaciones
Visualizaciones totales
7.376
En SlideShare
0
De insertados
0
Número de insertados
42
Acciones
Compartido
0
Descargas
0
Comentarios
0
Recomendaciones
10
Insertados 0
No insertados

No hay notas en la diapositiva.
  • In the fed state, dietary carbohydrate (CHO) increases plasma glucose and promotes insulin secretion from the pancreatic b cells. Insulin has numerous actions to promote storage of dietary calories, but only some are illustrated here.
    In the skeletal muscle, insulin increases glucose transport, permitting glucose entry and glycogen synthesis.
    In the liver, insulin promotes glycogen synthesis and de novo lipogenesis while also inhibiting gluconeogenesis.
    In the adipose tissue, insulin suppresses lipolysis and promotes lipogenesis.
    In the fasted state, insulin secretion is decreased. The drop in insulin (as well as the action of other hormones that are not depicted) serves to increase hepatic gluconeogenesis and promote glycogenolysis. Hepatic lipid production diminishes while adipose lipolysis increases.

    La insulina mantiene la homeostasis de glucosa en estado post-absortivo y postprandial. En forma general la insulina suprime la producción hepática de glucosa y estimula utilización de glucosa en tejidos sensibles a insulina: músculo, grasa e hígado
  • In the fed state, dietary carbohydrate (CHO) increases plasma glucose and promotes insulin secretion from the pancreatic b cells. Insulin has numerous actions to promote storage of dietary calories, but only some are illustrated here.
    In the skeletal muscle, insulin increases glucose transport, permitting glucose entry and glycogen synthesis.
    In the liver, insulin promotes glycogen synthesis and de novo lipogenesis while also inhibiting gluconeogenesis.
    In the adipose tissue, insulin suppresses lipolysis and promotes lipogenesis.
    In the fasted state, insulin secretion is decreased. The drop in insulin (as well as the action of other hormones that are not depicted) serves to increase hepatic gluconeogenesis and promote glycogenolysis. Hepatic lipid production diminishes while adipose lipolysis increases.

    La insulina mantiene la homeostasis de glucosa en estado post-absortivo y postprandial. En forma general la insulina suprime la producción hepática de glucosa y estimula utilización de glucosa en tejidos sensibles a insulina: músculo, grasa e hígado
  • In skeletal muscle, insulin binds and activates the insulin receptor tyrosine kinase, with subsequent phosphorylation of insulin receptor substrate 1 (IRS-1). When phosphorylated, IRS-1 binds and activates phosphatidylinositol 3-kinase (PI3K), which in turn, through signaling intermediaries, promotes translocation of glucose transporter type 4 (GLUT4) to the plasma membrane, resulting in glucose uptake into the skeletal muscle.

    In muscle, insulin binding to its receptor leads to tyrosine phosphorylation of IRS-1, which mediates insulin’s effect on glucose metabolism. In liver, IRS-2 phosphorylation mediates the actions of insulin. IRS-1 activates phosphatidylinositol (PI)-3 kinase [80], which catalyses 3′ phosphorylation of PI, PI-4 phosphate and PI- 4,5 diphosphate, and augments glucose transport and glycogen synthase
    The increased influx of glucose provides a substrate for glycogen synthesis in skeletal muscle and
    TAG synthesis in adipocytes.

    Phosphorylation of IRS is important in eliciting IRS binding to Src-homology (SH)-2 domain of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K). This binding in turn activates the catalytic subunit of PI3K, which subsequently catalyzes the formation of lipid second messenger PIP3. Binding of this lipid moiety to proteins with pleckstrin-homology (PH) domains leads to their activation. Further, activation of 3-phosphoinositide-dependent protein kinase (PDK) 1, leads to activation of Akt/protein kinase B (PKB). This is a serine/ threonine kinase, which targets several downstream proteins. Akt phosphorylates Rab small GTPases and inactivates AS160.
    This initiates cytoskeletal reorganization and leads to translocation of the insulin sensitive glucose transporter (Glut)-4 into
    the cell membrane, thus facilitating glucose entry into cells.
  • Phosphorylation of IRS is important in eliciting IRS binding to Src-homology (SH)-2 domain of the regulatory subunit of phosphatidylinositol 3-kinase (PI3K). This binding in turn activates the catalytic subunit of PI3K, which subsequently catalyzes the formation of lipid second messenger PIP3. Binding of this lipid moiety to proteins with pleckstrin-homology (PH) domains leads to their activation. Further, activation of 3-phosphoinositide-dependent protein kinase (PDK) 1, leads to activation of Akt/protein kinase B (PKB). This is a serine/ threonine kinase, which targets several downstream proteins. Akt phosphorylates Rab small GTPases and inactivates AS160.
    This initiates cytoskeletal reorganization and leads to translocation of the insulin sensitive glucose transporter (Glut)-4 into
    the cell membrane, thus facilitating glucose entry into cells.
  • In skeletal muscle, insulin resistance is manifested as a decrease in glucose transport and a decline in muscle glycogen synthesis in response to circulating insulin
    In the liver, insulin resistance is selective in that insulin fails to suppress gluconeogenesis, but continues to stimulate fatty acid synthesis
    In adipose tissue, insulin resistance is manifested as impaired insulin-stimulated glucose transport, as well as impaired inhibition of lipolysis.

  • Para cuantificar la liberación de AGL a la circulación sistémica proveniente de diferentes almacenes de tejido adiposo Jensen utilizó infusión de AG marcados y canulación regional del tejido adiposo midiendo el flujo regional antes y después de alimento estandarizado.
    Un 20 a 50% de los AGL en plasma se originan del tejido adiposo visceral y el resto del hígado (arteria hepática).
    La pequeña contribución de la grasa de la porción inferior del cuerpo a la concentración sistémica de AGL fue corroborada en un estudio en el cual se cuantificaron AGL de las venas que drenan la grasa glútea y el tejido abdominal SC adiposo. La lipólisis mediada por la lipasa hormono sensible en la grasa glútea fue solo 1/8 de la de la región abdominal.
    En un estudio se obtuvieron muestras de venas que drenaban la grasa del omento durante cirugía abdominal y las concentraciones de AGL en estas venas (que drenan exclusivamente tejido adiposo visceral) fueron semejantes a las obtenidas en venas que drenan el tejido adiposo SC.
  • It has been more than 30 years that insulin resistance is considered as a result of hyperinsulinemia, which represents a body’s effort to prevent hyperglycemia. However, hyperinsulinemia also induces insulin resistance. The insulin signaling pathway has a negative feedback loop to control the pathway activity precisely in response to insulin stimulation [1]. This loop is activated by insulin signal to avoid activation insulin-induced stress responses
    Hyperinsulinemia is derived from either over production or decreased clearance of insulin in obesity (Fig. 2). The mechanism is inhibition of IRS-1/2 function after activation of the negative feedback loop in the insulin signaling pathway
  • Thus, a defect in insulin signalling, not only impairs glucose utilisation, but causes hypertension and accelerated atherosclerosis.
    In diabetic and obese patients, continued MAP kinase pathway stimulation causes vascular smooth muscle proliferation, increased collagen formation and excessive production of growth factors/inflammatory cytokines, contributing to accelerated atherosclerosis.
  • IKKb= la cinasa del factor nuclear KB
  • La explicación para el desarrollo de RI en estados de inflamación converge en la activación de la cinasa n-terminal c-Jun (JNK1). Su activación también tiene un papel en el mecanismo por el cual la respuesta de proteínas desacopladoras (UPR) causa RI. Sin embargo, al parecer se han identificado diferentes efectos en diferentes tejidos de la activación de JNK1. Así, la activación de JNK1 altera la respuesta a la insulina pero su papel parece ser relacionado a su capacidad para alterar los lípidos intracelulares
    La deleción de JNK1 protege de RI inducida por dieta y se asocia con menor ganancia de peso y aumento de temperatura (mayor gasto energético) así como con disminución de depósito ectópico de lípidos.
    Sin embargo, la deleción específica de JNK1 en hígado aumenta esteatosis con aumento de expresión de enzimas lipogénicas, disminución de señalización de insulina y RI a nivel hepático. A diferencia de estos hallazgos, la deleción en tejido adiposo protege de esteatosis y RI asociándose con disminución de liberación de IL-6 que impide señalización de insulina a través de SOCS3. La deleción en músculo mejora captación de glucosa y señalización de la insulina.
  • Insulin’s presence at the cell surface is transduced to cytoplasmic and nuclear responses by tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and -2. Serine phosphorylation of these same proteins by Jun N-terminal kinases (JNK) and inhibitor of nuclear factor κB (NF-κB) kinases (IKK), however, potently inhibits insulin signaling.
    Many diverse cell-intrinsic and -extrinsic sequelae of chronic nutrient excess activate these signaling pathways, directly linking overfeeding to insulin resistance. Furthermore, JNK and IKK activation triggers inflammatory cytokine production, further activating JNK/IKK in an autocrine and paracrine manner and reinforcing insulin resistance.

    First, each pathway converges upon and inhibits insulin signaling pathways, primarily through serine phosphorylation of IRS (insulin receptor substrate) proteins, which blunts insulin action in stressed target tissues and stems the influx of
    nutrients into already overwhelmed cells (Fig. 1). Second, these signals converge on two main inflammatory signaling pathways, JNK and IKKβ, to initiate, support, and augment an inflammatory response within metabolic tissues
  • These studies and subsequent studies have led to an alternative hypothesis in which a transient increase in
    myocellular diacylglycerol (DAG) content results in activation of the theta isoform of protein kinase C (PKCθ). This transient increase in DAG content can be attributed to an imbalance of intracellular fluxes in which rates of DAG synthesis, owing to increased fatty acid delivery and uptake into the myocyte, exceed rates of mitochondrial long-chain CoA oxidation and incorporation of DAG into neutral lipid (triacylglycerol [TAG]). Activation of PKCθ leads to increased serine phosphorylation of insulin receptor substrate 1 (IRS-1) on critical sites (e.g., Ser 1101), which in turn blocks insulin-stimulated tyrosine phosphorylation of IRS-1 and subsequent binding and activation of PI3K. This leads to decreased insulin-stimulated glucose-transport activity, resulting in decreased insulin-stimulated glycogen synthesis and glucose oxidation.
    Two intermediate metabolites of FFAs (DAG and ceramide) are involved in the inhibition of insulin sensitivity. Reduction of DAG and Ceramide in the skeletal muscle by physical exercise is able to improve insulin sensitivity.
    DAG leads to activation of a serine/threonine kinase cascade (possibly initiated by protein kinase C) leading to phosphorylation of serine/threonine sites on insulin receptor substrates, which in turn reduces the ability of the insulin receptor substrates to associate and activate PI 3-kinase, resulting in decreased activation of glucose transport activity and other downstream events
  • In the liver, a transient increase in DAG, due to an imbalance of intrahepatocellular fluxes, results in activation of
    the epsilon isoform of protein kinase C (PKCε). Specifically, this transient increase in hepatocellular DAG occurs
    when rates of DAG synthesis, from both fatty acid re-esterification and de novo lipogenesis, exceed rates of mitochondrial
    long-chain CoA (fat) oxidation, rates of DAG incorporation into neutral lipid (TAG), or both. Activated
    PKCε binds to and inhibits the insulin receptor tyrosine kinase, leading to decreased insulin-stimulated glycogen
    synthesis in the liver through increased glycogen synthase kinase 3 (GSK3) phosphorylation. This results in inhibition
    of glycogen synthase activity and decreased insulin suppression of hepatic gluconeogenesis through decreased
    phosphorylation of forkhead box subgroup O (FOXO), leading to increased FOXO translocation to the nucleus, where
    it promotes increased gene transcription of the gluconeogenic enzymes (e.g., phosphoenolpyruvate carboxykinase
    [PEP-CK] and G6P).
  • FFA was considered to induce insulin resistance through induction of inflammation. FFA, such as palmitate (saturated
    FFA) and linoleic acids, was reported to induce activation of IKK/NF-κB pathway through an interaction with Toll-like
    receptor 4 (TLR4) [93–95]. TLR4 is a cell membrane receptor for endotoxin (LPS) in macrophages and adipocytes. When palmitate signals via TLR4, inhibitor of κB-kinase (IKK) is activated, which phosphorylates and degrades IκBα enabling nuclear translocation and expression of NF-κβ, a “master regulator” of inflammation
    Alternatively, FFA was proposed to induce inflammation after conversion into DAG or ceramide, which are intracellular
    signaling molecules [96,97]. DAG is an endogenous activator for PKC (protein kinase C), which activates IKKs and JNKs. DAG is generated as an intermediate product in cells during triglyceride biosynthesis. However, a consensus about relative significance of this inflammatory pathway remains to be established in vivo for FFA. The major challenge is the disassociation of FFA level with inflammation in the fasting condition, where plasma FFA is high and inflammation is low. In addition, inflammation is observed without FFA elevation in plasma in diet-induced obese mice.
  • Saturated free fatty acids (FFAs) such as palmitate not only represent the substrate for de novo ceramide biosynthesis, but also signal via the toll-like receptor 4 (TLR4) to activate inhibitor of kB-kinase (IKKβ) which stimulates transcript levels of enzymes involved in ceramide biosynthesis e.g., serine palmitoyl transferase long chain base 1 (Sptlc1) and 2
    (Sptlc2) and dihydroceramide desaturase (des1). The dashed line indicates that ceramide disrupts the association between inhibitor 2 of protein phosphatase 2A (I2PP2A) and protein phosphatase 2A (PP2A) by binding to I2PP2A. PP2A translocates to the cell membrane and associates with endothelial nitric oxide synthase (eNOS). PP2A association with eNOS decreases the association between eNOS and protein kinase B (Akt) and between eNOS and heat shock protein 90 (Hsp90). PP2A promotes the dephosphorylation of Akt that colocalizes with eNOS and /or decreases eNOS phosphorylation at serine (S) 1177 and S617 directly. This impairs NO bioavailability and leads to vascular dysfunction. Adiponectin might modify the effects of ceramide accumulation by binding to adiponectin (Adipo) R1and Adipo R2 receptors and increasing ceramidase activity. Ceramidases hydrolyze ceramide to form sphingosine leading to an increase sphingosine-1-phosphate (SIP) to
    ceramide ratio. Evidence exists that signaling via this pathway increases NO production. Neither this pathway, nor the potential metabolism of ceramide via adiponectin, have been evaluated in vivo in the context of obesity and endothelial dysfunction
  • Inflammation and insulin resistance are central to obesity-induced metabolic disease
    Under conditions of acute intake-expenditure imbalance, metabolic tissues store excess
    nutrients for future use. With chronic imbalance, physiologic storage capacity is exceeded,
    activating cellular stress signaling pathways that attempt to stem further nutrient influx by
    inhibiting insulin signaling and promoting inflammation. In adaptive obesity, such as is seen
    in hibernators, nutrient excess is time-limited with eventual resumption of physiologic
    normality before tissue damage can occur. In obesity-induced metabolic disease, however,
    continued nutrient imbalance drives this process forward, leading to chronic inflammation
    and insulin resistance and, ultimately, to diabetes, cardiovascular disease, and other overtly
    pathologic consequences.
  • Excess energy leads to adipose expansion with hypertrophic adipocytes that secrete chemoattractants suchasMCP-1,drawing immune cellsintothe tissue. Secretion of pro-inflammatory mediatorssuchasTNF-a, IL-1b, and IL-6by adipocytes,pre-adipocytes,and infiltrating immunecells results in polarization of macrophages to a pro-inflammatory M1 phenotype, and drive an inflammatory T cell population. Augmented lipolysis leads to increased levels of FFAs. This environment negatively impacts on the insulin signaling pathway and a state of insulin resistance results. Additionally hypertrophic adipocytes are also linked with hypoxia.
    The stimuli for macrophage recruitment include adipocyte hypertrophy and necrosis, tissue hypoxia, lipid spillover, metabolic endotoxemia, and endoplasmatic reticulum (ER) stress to the effects of other subtypes of AT immune cells. Obesity alters not only the number of ATMs (adipose tissue macrophages) but also their function and tissue distribution.
    Lean individuals have M2 ATMs- fulfill a number of homeostatic functions including clearing cellular debris, regulating proliferation, and differentiation of adipocyte precursors as well as angiogenesis and thermogenesis and remodeling extracellular matrix. The most important cytokines for M2 maintenance are IL4 originating mostly from AT eosinophils and IL13 originating from innate lymphoid type 2 cells and invariant natural killer T (iNKT) cells.
    Obesity leads to decreased expression of these factors while simultaneously increasing the expression of proinflammatory antigens and cytokines including TNFa, IL6, and nitric oxide synthase 2 (NOS2) resulting in a shift from the antiinflammatory M2 to proinflammatory M1 phenotype. This shift is not induced by the transformation of resident M2 macrophages, but rather by increased recruitment of circulating monocytes and their differentiation into M1 cells as more than 90% of recruited monocytes become CD11cC ATMs. These macrophages cluster to form crown like structures
  • The roles of AT immune cells in the development of obesity-induced inflammation. This diagram is based on the current published findings that are discussed in this review.
    The blue fonts represent cells that suppress inflammation, while the red fonts represent cells that induce inflammation
  • Lean and obese adipose tissues are associated with distinct macrophage phenotypes
    In lean adipose tissue (a), eosinophil-derived interleukin (IL)-4 supports alternatively activated M2 macrophages characterized by production of tolerogenic cytokines such as IL-10 and minimal production of inflammatory mediators. This phenotype establishes a tolerogenic immune environment and directly promotes adipocyte insulin sensitivity. In turn, lean adipocytes produce adiponectin, which collaborates with IL-4 signaling to enhance alternative M2 macrophage activation. In obese adipose tissue (b), inflammatory M1 macrophages, activated by the stigmata of chronic nutrient excess, produce proinflammatory cytokines and chemokines that exacerbate adipocyte insulin resistance, enhance cellular stress, and recruit additional leukocytes. Adipocytes, in turn, also secrete inflammatory cytokines and saturated fatty acids that, along with signals from necrotic cells, reinforce the inflammatory environment.
  • Anti-inflammatory actions of AMPK in adipose tissue
    In lean adipose tissue, small adipocytes and alternatively activated macrophages secrete adipocytokines such as IL-10
    and adiponectin, which maintain an anti-inflammatory environment. Production of these adipocytokines is promoted by
    activated AMPK. Excess calorie intake leads to the development of a pro-inflammatory environment within obese adipose
    tissue. Adipocytes enlarge, becoming hypertrophic and often necrotic, and there is an increased infiltration of macrophages.
    The pro-inflammatory environment drives macrophage polarization towards the classically activated M1 state, and they
    tend to accumulate around necrotic adipocytes, forming crown-like structures. The secretory products of the macrophages
    and hypertrophic adipocytes further exacerbate this inflammation. Adipose tissue inflammation is linked to obesity-related
    insulin resistance and Type 2 diabetes. Activation of AMPK can inhibit production of pro-inflammatory cytokines and
    chemokines, increase adiponectin secretion and inhibit macrophage recruitment and M1 polarization, thereby potentially
    reducing insulin resistance.
  • Obesity results in chronic ER stress in adipose tissue. Indeed, increased activation of inositol-requiring enzyme 1 alpha (IRE-1a) and c-Jun N-terminal kinase (JNK), and upregulation of X-box binding protein 1 (XBP1s) expres-sion is observed in adipose tissue from obese patients. Interestingly, the loss of fat in obese patients following gastric bypass surgery reduces XBP1s and immunoglobu-lin binding protein (BiP) expression in white adipose tis-sue, as well as the phosphorylation levels of alpha subunit of eukaryotic initiation factor 2 (eIF2a) and JNK [8]; whereas exercise training decreases ER stress and IR in white adipose tissue of obese rodents
  • During obesity, the release of NEFAs from visceral adipose tissue is an important factor that triggers ER stress, which induces inflammation through a PERK–eIF2a-dependent mechanism. The resultant increase in proinflammatory cytokine expression and secretion (e.g. TNF-a and IL-6) may induce ER stress in a loop manner perpetuating this process and the development of IR. Exposure of human adipocytes to LPS or high glucose levels potentiates the ATF6- and IRE-1a-dependent chaperone expression. In addition, Perilipin A is inhibited by ER stress, resulting in the activation of TG lipolysis in adipocytes and subsequent intracellular FA increase. Finally, ER stress induces TXNIP expression, which acts as a key negative feedback regulatory mechanism of the unfolded protein response to decrease XBP1s levels via direct PDI activation.
  • It was therefore hypothesized in what is known as the ‘portal theory’ that the exaggerated release of FFAs and proinflammatory cytokines from visceral fat are directly delivered to the liver via portal vein, promoting the development
    of hepatic insulin resistance and hepatic steatosis in obese individuals.
    Consequently, the ‘portal theory’ has initially been explained by a relative high lipolysis rate specifically in visceral adipose tissue, which increases the portal concentration of FFAs in obesity, leading to hepatic insulin resistance and metabolic abnormalities.
    However, we recently compared lipolysis rate in mesenteric adipocytes isolated from mice fed either a standard or fat-enriched diet, and we unexpectedly found that basal lipolysis was not increased in mesenteric adipocytes isolated from high-fat diet-fed mice.
    We observed an increased release of pro-inflammatory cytokines such as IL-6 from mesenteric adipocytes of high-fat compared with standard diet-fed mice Increased production and release of proinflammatory cytokines such as IL-6 and/or IL-1b from omental and mesenteric adipocytes into the portal vein may contribute to the development of hepatic insulin resistance.
    Thus, the ‘portal theory’ may be explained as an increased release of both FFAs and/or pro-inflammatory cytokines into the portal circulation
    Moreover, it is conceivable that obesity-associated changes in the composition of the gut microbiota and the resulting release of gut-derived pro-inflammatory and bacterial factors such as endotoxin may contribute to the ‘portal theory’ as large parts of the small bowel are also drained into the portal vein
    The lipopolysaccharides (LPS) produced in the intestine due to the lysis of Gram-negative bacteria triggers proinflammatory cytokines that result in insulin resistance both in mice [5] and humans [29]. A more causal role was defined when germfree
    mice were colonized with E. coli, as this promoted macrophage accumulation and up-regulation of proinflammatory cytokines resulting in low-grade inflammation [30]. The mechanism via which LPS is translocated into the plasma might be either indirectly via indirect transport via dietary chylomicrons [31] or directly via leakage due to a
    decreased intestinal barrier function [5]. Taken together with the MGWAS studies, these data suggest that altered (less SCFA-producing) gut microbiota composition may affect the host metabolism via impaired intestinal barrier
    function resulting in low-grade endotoxaemia.
  • Proposed mechanisms for visceral obesity-induced insulin resistance (‘portal theory’). Individuals with central obesity accumulate fat mainly in intra-abdominal deposits, i.e. in mesenteric and/or omental adipose tissue. The concomitant increased release of free fatty acids and/or pro-inflammatory factors from these depots are drained via the portal vein directly to the liver. Additionally, increased release of gut-derived pro-inflammatory and bacterial factors such as endotoxin might contribute to the ‘portal theory’ as large parts of the small bowel are also drained into the portal vein. Hepatic exposure to these factors will result in the development of hepatic insulin resistance, steatosis and inflammation
  • In this study, we demonstrated that MHO and MHNO
    subjects presented with lower C3 concentrations and, depending
    on metabolic health definition, also lower levels
    of CRP, IL-6, TNF-, PAI-1, and WBCs and higher adiponectin
    concentrations
  • CVD-free survival curves in normal-weight and obese
    individuals with normal and abnormal metabolic status. MHO (solid
    curve), MUH-NW (dashed curve), and metabolically unhealthy obese
    (dotted curve) individuals had a higher risk of developing CVD than
    metabolically healthy normal-weight individuals
  • Studies with 10 year follow up
    First, compared with metabolically healthy normal-weight persons, metabolically healthy obese individuals are at increased risk for all-cause mortality and CV events over the long term (10 years). Second, all phenotypes with unhealthy metabolic status present increased risk, regardless of normal weight, overweight, or obesity. Third, blood pressure, waist circumference, and insulin resistance increased, and HDL cholesterol decreased, across the BMI categories in both
    metabolically healthy and unhealthy subgroups.
    It is essential that the reference group in studies evaluating BMI phenotypes should be metabolically healthy and of normal weight. It is also important to recognize that duration of follow-up is a critical element in evaluating low-risk populations
    for future events.
  • In fact, when the follow-up examinations were grouped into those carried out within 10 days (n=8), between 11 days and 18 months (n=10), or longer than 18 months (n=14) after surgery, insulin sensitivity was already within the normal range at the earliest time post-surgery, when weight change was negligible, and was above normal when body weight was still above the normal range
    This early improvement could not be explained by changes in fasting plasma NEFA, leptin or adiponectin concentrations, which were minimal in the first 10 days
  • Mecanismos de resistencia a la insulina en obesidad

    1. 1. La resistencia a la insulina en el contexto de la obesidad Dra Roopa Mehta
    2. 2. Plan • Acción de insulina y la señalización de insulina • La resistencia a la insulina y mecanismos para la RI en obesidad • El obeso metabólicamente sano • La resistencia a la insulina post cirugía bariatrica
    3. 3. Acciones de insulina: Post-prandial Cell 148, March 2, 2012 Durante post-prandio, la glucosa aumenta y promueve secreción insulina de las células β. La insulina tiene numerosas acciones para promover almacenamiento de calorías.  En músculo esquelético, insulina incrementa transporte de glucosa, permitiendo entrada de glucosa y síntesis de glucógeno.  En hígado, insulina promueve síntesis de glucógeno y lipogénesis de novo, también inhibe gluconeogénesis.  En tejido adiposo, insulina suprime lipólisis y promueve lipogénesis.
    4. 4. Acciones de insulina: ayuno Cell 148, March 2, 2012 Durante ayuno, secreción de insulina disminuye. Incrementar gluconeogénesis hepática y glucogenólisis. Producción hepática de lípidos disminuye mientras el lipólisis en tejido adiposo aumenta.
    5. 5. Vía de señalización normal de la insulina • La unión de insulina a su receptor desencadena la autofosforilación así como la fosforilación del sustrato del receptor de insulina (IRS). • IRS se una al dominio Src-homology (SH)-2 de la fosfatidilinositol 3-kinasa (PI3K)- asi activando PI3K Diabetologia (2010) 53:1270–1287
    6. 6. Vía de señalización normal de la insulina• PI3K, cataliza la formación del segundo mensajero PIP3. • Después existe activación de proteína cinasa 1 dependiente de fosfo-inositide-3 (PDK) , la cual lleva a la activación de Akt/PKB. • Akt /PKB inactiva AS160. Esto inicia la reorganización del citoesqueleto y lleva a traslocación de GLUT-4 a la membrana celular, facilitando la entrada de glucosa al interior de la célula.
    7. 7. Resistencia a la insulina. • Se define como respuesta inadecuada por tejidos sensibles a la insulin (hígado, músculo esquelético y tejido adipose) a los niveles normales de insulin. • En músculo esquelético, existe una disminución en transporte y síntesis de glucógeno muscular. • En hígado, la supresión mediada por insulina de la producción de glucosa (gluconeogenesis) es alterada, pero la síntesis de ácidos grasos persiste. • En tejido adiposo, hay disminución en transporte de glucosa e inhibición alterada de lipólisis. • Esto lleva a hiperglucemia relativa y elevación de ácidos grasos no esterificados.
    8. 8. Resistencia a la insulina (IR) Frontiers in Endocrinology May 2013 | Volume 4 | Article 52, Los mecanismos involucrados en IR relacionados a obesidad comprende defectos pre-receptor, receptor y post-receptor:  Pre-receptor: disminución del acceso de insulina a músculo, secundario a exceso de FFA.  Receptor: regulación a la baja de receptor de insulina secundario a hiperinsulinemia.  Post-receptor: inhibición vías intracelulares.
    9. 9. Resistencia a la insulina (IR) y Obesidad • En obesidad hay elevación de AGL en ayuno y período postprandial • La contribución de las diferentes regiones del cuerpo a los AGL circulantes varía: – Tejido adiposo visceral: 20-50% – Tejido adiposo de la parte inferior del cuerpo sólo contribuye con una pequeña cantidad • Tejido adiposa: Síntesis de TNF-α, Leptina y más de 50 adipocitocinas.
    10. 10. Adipocitocinas Journal of Diabetes Research, Volume 2013
    11. 11. Resistencia a la insulina y obesidad • La obesidad esta asociado con factores que genera resistencia a la insulina 1. Inflamación metabolica y lipotoxicidad 2. Disfunción Mitocondrial 3. Estrés reticulo endotelial 4. Estrés Oxidativa (ROS) 5. Hiperinsulinemia 6. Envejecimiento 7. Genetica (altos niveles de ATP en asiaticos)
    12. 12. Señalización de insulina en obesidad. En obesidad, la señalización de insulina esta alterada a nivel de IRS-1, llevando a disminución de transporte de glucosa, alteración de activación de sintasa óxido nítrico/ función endotelial. La vía MAP cinasa permanece sensible a insulina- hay estimulación excesiva de ésta vía. Causa inflamación, proliferación celular y aterogénesis- activación de vías inflamatorias SHC, Src homology collagen Diabetologia (2010) 53:1270–1287
    13. 13. Inflamación metabólica • La obesidad esta asociado con inflamación de bajo grado crónica. Esto afecta las vías de señalización y provoca resistencia a la insulina • Estudios en 1990 mostraron que cuando se expone adipocitos a TNF alfa, se alteró la señalización de insulina produciendo RI • Unos años después, se confirmo que la presencia de obesidad puede activar la vía de inflamación IKKb/NFkB. Biochimica et Biophysica Acta 1842 (2014) 446–462 Molecular Aspects of Medicine 33 (2012) 26–34
    14. 14. IKKβ/NFκB y resistencia a la insulina • NFκB tiene papel fundamental en regular inflamación. • Durante inactividad, NFκB se encuentra en citoplasma por su union a IκBα; esta union enmascara su secuencia de localización nuclear (NLS). • Cuando las células son estimuladas con citocinas, el complejo enzimático IKK se activa, IKKβ fosforila a IκBα. Esta fosforilación induce la degradación de IκBα, que expone el NLS de NFκB y causa que NFκB se trasloque al interior del núcleo, donde inicia la expression de genes de mediadores inflamatorioas. TNFα, IL-6 Y MCP-1, están implicados en el desarrollo de resistencia a la insulina inducida por obesidad. • Esta vía se activa por muchos factores asociados a la obesidad como inflamación, hipoxia, estrés del RE, diacilglicerol y ceramida. Biochimica et Biophysica Acta 1842 (2014) 446–462
    15. 15. JNK (Jun-N terminal Kinase) 1 y resistencia a la insulina La cinasa N-terminal Jun está involucradas en vías de estrés. JNK fosforila a IRS-1- que inhibe esta molécula. Su activación permite la respuesta de proteinas desacopladoras (UPR) causando RI. La deleción de JNKs (musculo y tejido adiposa) mejora la RI mediada por obesidad. Tejido adiposa: reduce IL-6 Musculo: captacion de glucosa y senalización de la insulina Higado: aumenta esteatosis
    16. 16. Inflamación y resistencia a la insulina. Science. 2013 January 11; 339(6116): 172–177
    17. 17. Vias de señalización: Inflamación y RI International Journal of Endocrinology Volume 2015,
    18. 18. Lipotoxicidad: musculo • Durante una infusión de lípidos, se mostraron inhibición de la fosforilación de tirosina inducido por insulina en IRS-1 y la activación subsecuente de PI3K- así se produce una reducción en el transporte de glucosa estimulado por insulina • La señal para este proceso es un aumento en el contenido de DAG, inducido por los ácidos grasos libres • Un proceso similar en el hígado- DAG–PKCε Musculo N Engl J Med 2014;371:1131-41.
    19. 19. Lipotoxicidad: hígado N Engl J Med 2014;371:1131-41.
    20. 20. Lipotoxicidad • AGL inducen inflamación después de conversion a DAG o ceramidas. DAG es activador endógeno de PKC, que activa IKKs y JNKs. Diabetologia (2010) 53:1270–1287
    21. 21. Ceramida • AGL saturados, a través de TLR4 provoca biosíntesis de ceramida. • Ceramida interfiere con la asociación entre I2PP2A and PP2A (proteina fosfatasa 2A.) • PP2A se asocia con NO sintetasa (eNOS) en la membrana celular, preveniendo la asociación entre Akt y eNOS/hsp90– altera disponibilidad de NO y disfunción vascular. Rev Endocr Metab Disord. 2013 March ; 14(1): 59–68
    22. 22. Inflamación y la resistencia a la insulina Science. 2013 January 11; 339(6116): 172–177
    23. 23. Inflamación y la resistencia a la insulina: tejido adiposo The stimuli for macrophage recruitment include adipocyte hypertrophy and necrosis, tissue hypoxia, lipid spillover, metabolic endotoxemia, and ER stress
    24. 24. Células en el tejido adiposa involucradas en inflamación: no solo macrófagos ATM= adipose tissue macrophages
    25. 25. Inflamación y la resistencia a la insulina: IL-6 y TNFα Science. 2013 339(6116): 172–177 IL-6: producido por WAT, el higado y musculo (MO e adipocitos) Estimula lipolisis y acidos grasos libres Reduce adiponectina Reduce differenciación de adipocitos Aumenta RI- fosforilación de IRS1 TNF-a: Activacion de MAPK y NF-kB. Fosforilacion de IRS-1, activa JNK1 Aumenta IL-1B, IL-6, y reduce mRNA de adiponectina
    26. 26. Citocinas inflamatorias International Journal of Endocrinology Volume 2015,
    27. 27. Activación mitocondrial y la resistencia a la insulina • En la obesidad, los lipidos inducen sobre- activación de mitocondria por un aumento en la oxidación beta de los acidos grasos- permitiendo la depuración de energia por el musculo, higado y grasa parda (brown fat). • El proceso genera ATP (catabolismo de acidos grasos). • El exceso de ATP, inactiva AMPK, reduciendo la captación de glucosa insulino-dependiente. • En este modelo, la resistencia a la insulina es un mecanismo celular protectivo- para controlar la respuesta de ATP a estrés en el higado y musculo. Front. Med. 2013, 7(1): 14–24 Lipotoxicity Mitochondrial overactivation ATP increases AMPK decreases Glucose uptake and oxidation decrease Insulin sensitivity decrease
    28. 28. AMPK y adipocitos Clinical Science (2013) 124, 491–507
    29. 29. El estrés retículo endoplásmico • El estrés reticulo endoplasmico (RE) puede inducir inflamación cronica en la obesidad por activación de JNK • El RE es un red membranosa que funciona en la síntesis y procesamiento de proteínas. • La acumulación de proteinas no doblados (UPR- unfolded protein respose) es asociado con estrés RE • El estrés RE es inducido por factores que inhiben el doblado de proteinas- hipoxia, infección viral, hiperlipidemia y malnutrición.
    30. 30. El estrés retículo endoplásmico: tej. adiposo Trends in Endocrinology and Metabolism, August 2015, Vol. 26, No. 8
    31. 31. Inflammación metabolica: Portal Theory • Tejido graso abdominal aumenta liberación de AGL al hígado a través del drenaje portal- Resistencia a la insulin hepatica/esteatosis. • Citocinas inflamatorias, liberadas por tejido visceral dentro de porta también causa Resistencia a la insulin hepatica/sistémica. • Cambios asociados a obesidad en la composición de la microbiota intestinal-liberación de factores proinflamatorias derivados del intestino y factores bacterianos como endotoxinas, contribuyen a “teoría portal”, ya que partes importantes del intestine delgado drenan a la vena porta. obesity reviews (2012) 13 (Suppl. 2), 30–39
    32. 32. Teoría Portal obesity reviews (2012) 13 (Suppl. 2), 30–39 Produce un aumento en la sintesis de lipidos, gluconeogenesis y resistencia a la insulina .
    33. 33. La microbiota intestinal y la inflamación • La microbiota intestinal puede afectar el metabolismo : - Metabolismo de los ácidos grasos de cadena corta (SCFA- short chain fatty acid) - Composición de la microbiota intestinal – Los sujetos con resistencia a la insulina (RI) recibieron soluciones de heces fecales de donadores delgados- hubo una mejoría significativo de la resistencia a la insulina periférica y una alteración pequeña en la composición de la microbiota intestinal: Un aumento en las bacterias intestinales que producen SCFA –butirato. – En ratones – Menor cantidad de bacterias anaeróbicas que producen SCFA butirato. Aumentan endotoxinas y como consecuencia inflamación cronica y resistencia a la insulina Clinical and Experimental Immunology, 2014, 177: 24–29
    34. 34. El obeso metabólicamente sano (MHO): Definiciones Rev Endocr Metab Disord (2013) 14:219–227 MHO- Se define como IMC≥30 kg/m2 sin sindrome metabolico – sin un aumento en el riesgo para aterosclerosis, HTA o DM2 - 25-30% de la población obeso La concordancia entre las clasificaciónes es pobre. - 6.8 % por Aguilar-Salinas, 14.2 % por Karelis, 23.7 % por Wildman, 30.2 % por Meigs J Clin Endocrinol Metab 98: E1610–E1619, 2013
    35. 35. El obeso metabólicamente sano (MHO) • No se sabe si los individuos MHO estan geneticamente predispuesta a mantener la sensibilidad a la insulina con la edad o si es un fenotipo inestable que puede convertir en el estado de RI • Los luchadores Sumo convierten de MHO a un estado no saludable de RI cuando de jubilan • Todavia, la biologia de MHO esta asociado a piedras en la vesicula, osteoartritis y otros co-morbilidades incluyendo cardiomiopatia
    36. 36. El obeso metabolicamente sano (MHO): Inflamación • La inflammación puede determinar si un individuo con obesidad es metabolicamente saludable o no. • Un estudio reciente examinó los niveles de citocinas pro- inflamatorias, adipocitocinas, proteinas de respuesta aguda, factores de coagulación y cuenta de leucocitos por un rango de perfiles de la salud metabolica. Querian ver si las diferencias entre el MHO, el obeso no sano y el no-obeso puede ser explicado por el estatus inflamatoria • Los sujetos MHO y no-obesos tuvieron bajos niveles de complemento C3, PCR, TNF alfa, IL-6, PAI-1 y leucocitos y concentraciones altos de adiponectina que el obeso no sano. J Clin Endocrinol Metab 98: E1610–E1619, 2013
    37. 37. El obeso metabólicamente sano (MHO) M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 3 ( 2 0 1 4 ) 1 0 8 4 – 1 0 9 2 En algunos sujetos MHO tienen niveles de adiponectina mayores que sujetos con IMC normal
    38. 38. MHO y DM2 / enfermedad CV • En el SAHS, de los sujetos obesos, 44.4% fueron MHO. • Algunos estudios reportan que en los sujetos MHO, no existe un riesgo CV aumentado • Los sujetos MHO mostraron un riesgo aumentado de DM2 y enfermedad CV Enfermedad CV MHO (solid curve) Metabolically unhealthy obese (dotted curve) MHO fue definido como IMC 30 con no mas de un anormalidad metabolica J Clin Endocrinol Metab 98: 0000–0000, 2013
    39. 39. Pronostico en el MHO Ann Intern Med. 2013;159:758-769. Meta-analisis de estudios con 10 años de seguimiento. • Comparado con personas saludables de peso normal, MHO tuvieron un riesgo aumentado de mortalidad de todas las causas y eventos CV durante un seguimiento largo (10 años) • Todos los fenotipos de estatus metabolica no saludable mostraron un riesgo aumentado- no importaba si fueron de peso normal, sobrepeso o obesidad • No existe un patron “saludable” de obesidad
    40. 40. Manejo de MHO • No existe opciones de tratamiento diferentes para obesidad de grados distintos. • Puede ser que los pacientes con MHO no beneficiarian de cambios en el estilo de vida- como los pacientes con obesidad con cambios metabolicos. Puede ser que el manejo tiene que ser diferente • Sesti et al., examinaron si la perdida de peso inducida por cirugia bariatrica fue asociado con mejoria en el perfil cardiometabolico de pacientes MHO y pacientes obesos con RI (ORI) • Ambos, MHO y ORI mostraron mejoria significativo en el perfil metabolico: sensibilidad a la insulina, reducciones en la glucosa y insulina en ayuno y un perfil de lipidos y hepatico mas favorable. PLoS ONE. 2011;6:e17
    41. 41. Post- cirugía bariatrico • Los cambios metabolicos despues de la cirugia bariatrica, como mejoria en la resistencia ala insulina ocurren antes de perdida de peso significativa • El tipo de intervención quirurgica determina la mejoria en las caracteristicas metabolicas– (bypass gastico y derivación biliopancreatico) • Los niveles de adiponectina aumentan con perdida de peso- este cambio predice mejoria en la resistencia a la insulina
    42. 42. Cambios en la sensibilidad de insulina después de la derivación bilio-pancreatico Diabetologia (2006) 49:2136–2143 La sensibilidad a la insulina fue normal imediatamente post- quirurgico, cuando el cambio en peso fue pequeña. Cambios en conjunto en la sensibilidad de insulina y la producción de insulina. La producción de insulina reduce como la sensibilidad reduce (NGT, IGT and DM2)
    43. 43. Post- cirugia baratrico: trigliceridos intramiocelulares • Hubo una reducción en tinción a los 9 meses (trigliceridos intramiocelular): se correlaciono la reducción en tinción entre mes 3 y 9 con una reducción en peso, grasa y niveles de acidos grasos libres • The decrease in intramyocellular triglycerides is likely a result of decreased FFA supply, increased rates of triglyceride hydrolysis, and increased rates of FFA oxidation. Oil-red-O stain of muscle biopsies Curr Diab Rep. 2013 April ; 13(2): 245–251
    44. 44. Post- cirugía bariatrico • La manga gastrica y el bypass gastrico (Roux-en-Y gastric bypass (RYGB)) se asocia con un aumento en la sensibilidad de insulina en el higado y tejido periferica, independiente de la perdida de peso. • Hay cambios en el patron de secreción de GLP-1 que tal vez explica una mejoria en la función de la celula beta- pero este cambio no contribuye a la mejoria en la acción de insulina • Investigación reciente sugiere que cambios en la concentración de los acidos biliares y alteraciones en la microbiota intestinal puede contribuir a los cambios metabolicos post- quirurgicos- no se conoce los mecanismos
    45. 45. Conclusiones • La resistencia a la insulina en el contexto de la obesidad es complejo • Varios vías de señalización endocrinas, inflamatorias y celulares están disfuncionales. Un exceso de los ácidos grasos libres y la inflamación son los mecanismos mas importantes- pero no hay un factor que predomina. • Opciones de tratamiento que corrige estas anormalidades son faltantes. • Se necesita estudios en los diferentes fenotipos de obesidad y estudios para investigar los cambios metabólicos post cirugía bariatrico

    ×