From Fitness to Fatness Hiriart´s Journal Club MER -060308

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FROM FITNESS TO FATNESS MarthaEugenia Ramirez-Dominguez – IFC-UNAM - Hiriart’s Journal Club MarthaEugenia Ramirez-Dominguez – IFC-UNAM - Hiriart’s Journal Club - 060308

Transcript of From Fitness to Fatness Hiriart´s Journal Club MER -060308

Page 1: From Fitness to Fatness Hiriart´s Journal Club MER -060308

FROM FITNESS TO FATNESS

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Molecular and metabolic mechanisms

of insulin resistance and β‑cell failure in type 2 diabetes

Deborah M. Muoio and Christopher B. Newgard

Mechanisms of disease

Nature Reviews |

Molecular Cell BiologyMolecular Cell Biology volume 9 | march 2008 | 193 © 2008 Nature Publishing Group

MarthaEugenia Ramirez-Dominguez – IFC-UNAM - Hiriart’s Journal ClubMarthaEugenia Ramirez-Dominguez – IFC-UNAM - Hiriart’s Journal Club - 060308

Page 3: From Fitness to Fatness Hiriart´s Journal Club MER -060308

Link between obesity and diabetes : a new word coined :

diabesity. But researchers cannot exactly say how, eating too many calories causes the insulin resistance that often leads to diabetes.

FOCUS OF THIS REVIEW

current understanding of molecular, genetic factors and biochemical factors

loss of metabolic fuel homeostasis in DM2.

Then obesity develops when chronic overnutrition conspires toxicologically with genetic susceptibility

chronic increases in circulating glucose and lipid levels can furtherimpair insulin secretion and action and cause other forms of tissue damage by mechanisms that are discussed

in more detail

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Insulin normally controls fuel homeostasis through the stimulation of glucose uptake

into peripheral tissues and by suppressing the release of stored lipids from adipose tissue.

OVERNUTRITION:

chronic exposure to

LipidsGlucoseAmino acids

+ MetabolitesBy products

Citosol

Mitochondrion

ER -Lumen

Defective insulin secretion and action = to multiple metabolic abnormalities leading to DM2.M

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Adipokines and insulin resistance.Role of inflammatory mediators.

Alterations in metabolic function.Metabolic overload in the liver.Metabolic overload in muscle.

A unifying hypothesis of metabolic overload.

Relating metabolic overload to insulin signalling.

β-cell failure in type 2 diabetesRegulation of insulin secretion in normal islets.Genetic susceptibility to β‑cell failure.

Metabolic overload in β‑cells.The role of ER stress pathways in β‑cell failure.

Role of amyloid fibrils in β‑cell failure.

Mechanisms of insulin resistanceM

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Mechanisms of insulin resistance

However other factors : inter-organ communication networks mediated by :

peptide hormonesand

inflammatory molecules (cytokines)

• And activation of intracellular stress response pathways

insulin resistance as a direct consequence of obesity-associated exposure of tissues to elevated dietary

nutrients =

accumulation of toxic metabolic by-products.

NOTION OF :

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Metabolic overload in the liver

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b | During conditions of overnutrition, fatty acid influx and PPARa/d-mediated activation of target genes (yellow) promote β‑oxidation without a

coordinated increase in TCA cycle flux. As a result, metabolic by-products of incomplete fat oxidation (acylcarnitines, ROS) accumulate in the

mitochondria. These stresses might activate Ser kinases that impede insulin signalling and GLUT4 translocation (blue). Exercise combats lipid stress

by increasing TCA cycle flux and by coupling ligand-induced PPARa/d activity with PGC1α-mediated remodelling of downstream metabolic pathways

(orange). Enhanced mitochondrial performance then restores insulin sensitivity. ACC, acetyl CoA carboxylase; AKT2, Ser/Thr protein kinase; CPT1,

carnitine palmitoyltransferase‑1; DAG, diacylglycerol; DGAT1, diacylglycerol acyltransferase-1; ER, endoplasmic reticulum; ETC, electron transport

chain; FAS, fatty acid synthase; GLUT4, glucose transporter‑4; GPAT1, glycerol‑3-phosphate acyltransferase-1; IL‑6, interleukin‑6; IRE1, inositol

requiring kinase‑1; LC‑CoAs, long-chain acyl CoAs; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, PPARγ co-activator‑1α; PPARγ,

peroxisome proliferator-activated receptor-γ; ROS, reactive oxygen species; RXR, retinoid X receptor; SPT1, serine palmitoyltransferase‑1; TCA,

tricarboxylic acid cycle; TF, transcription factor; TGs, triglycerides; TNFα, tumour necrosis factor-α.

Metabolic overload in skeletal muscle.M

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Biochemical mechanisms of glucose-stimulated insulin secretion, Biochemical mechanisms of glucose-stimulated insulin secretion, including roles of the pyrvuate cycling pathways of the including roles of the pyrvuate cycling pathways of the ββ‑cell.‑cell.

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Cellular Stress Appears to Link Obesity to Diabetes

Diagnosing the source of insulin resistance in the ER. The overloaded endoplasmic reticula (ERs) inside fat and liver

cells of overweight mice cope with stress by sending out the molecule XBP-1, a transcriptional regulator. This molecule

temporarily reduces the number of proteins entering the ER for processing and increases the number of ER helper

molecules that fold client proteins and degrade misfolded proteins. If this is not enough for the ER to catch up with its

metabolic duties, the stress-induced IRE1 activates JNK, which impairs insulin signaling via IRS-1. (Image by Jeff Cleary)

How does obesity distress the ER exactly

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ER STRESSM

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 Activation of PERK and eventually the

GADD34-PP1 phosphatase complex results

in dephosphorylation of eIF2  , thereby

promoting apoptosis. ER stress also

activates IRE1-TRAF2– mediated JNK

signaling, which leads to translocation of Bax

to the mitochondrial membrane—the result is

cytochrome c release and collapse of the

mitochondrial membrane potential. Salubrinal

is a small-molecule inhibitor of the

endoplasmic reticulum stress response, that

prevents dephosphorylation of eIF2  , and

prevents apoptosis through a pathway

upstream from JNK activation. The

nonreceptor tyrosine kinase c-Abl may act to

suppress the endoplasmic reticulum stress

response indirectly by preventing

mitochondrial collapse, or directly through an

as yet unidentified mechanism. Kerkelä et al.

provide evidence that the anticancer drug

imatinib mesylate promotes apoptosis and

heart damage by inhibiting c-Abl. ROS,

reactive oxygen species.

Sustained endoplasmic reticulum stress can lead to apoptosis through several pathways.

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| a | Proteins of the secretory pathway are translocated into the endoplasmic reticulum (ER) lumen co-translationally through proteinaceous channels in the ER membrane called translocons.

b | In the extremely crowded, calcium-rich, oxidizing environment of the ER lumen, resident chaperones like BiP, calnexin and protein disulphide isomerase (PDI) serve to facilitate the proper folding of the nascent protein by preventing its aggregation, monitoring the processing of the highly branched glycans, and forming disulphide bonds to stabilize the folded protein.

c | Once correctly folded and modified, the protein will exit the ER through theformation of transport vesicles and move on through the secretory pathway.

d | If the ER quality-control system deems that the protein is malfolded or unable to fold, it will be targeted for retrotranslocation to the cytosol and degraded by the 26S proteasome.

e | Changes in the ER environment shift the balance from normal folding to improper folding (thicker arrow), leading to the accumulation of unfolded proteins in the ER. This activates three ER-stress sensors — IRE1, PKR-like ER kinase (PERK) and ATF6 — which initiate the unfolded protein response. SRP, signal-recognition particle.

Schematic of Endoplasmic Reticulum Functions Under Non-Stress Schematic of Endoplasmic Reticulum Functions Under Non-Stress Conditions.Conditions.

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Type 2 Diabetes Mellitus as a Conformational Disease JOP. J Pancreas (Online) 2005; 6(4):287-302.

Human islet amyloid polypeptide (IAPP). The amyloidogenic

region of IAPP is responsible for providing a toxic

conformational structure within islets. Note disulfide bond at

position C2 and C7.

Improper folding of islet amyloid polypeptide

(IAPP) results in insoluble fibrils.

 

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Metformin mediates its action by stimulating adenosine monophosphate-activated protein kinase (AMPK), a critical enzyme. It

also reduces enzymatic pathways involved in incraesing fatty acid production by the liver. (ACC = acteyl-CoA carboxylase;

SREPB-1 = sterol-regulatory-element-binding-protein-1) In this manner it reduces storage of fat in the liver and in the blood

carrier protein (VLDL or very low density lipoprotein) that shuttles triglycerides (trigs) and the body.

'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal 172(2),2005 pp213-

226.

Metformin activates AMPK in liver and muscle to improve glucose and lipid metabolism.

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Stages of Type 2 Diabetes Mellitus as a Conformational Disease

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Conformational Diseases.

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Insulin resistance develops as a consequence of the effects of inflammatory and hormonal factors, endoplasmic reticulum (ER) stress, and accumulation of by-products of nutritional ‘overload’ in insulin-sensing tissues.

both animals and humans, the triggering factor for the transition from an obese, insulin-resistant state to fullblown type 2 diabetes is β‑cell failure, which involves both a partial loss of β‑cell mass and a deterioration of β‑cell function. Some of the mechanisms that are involved in β‑cell failure are similar to the mechanisms of insulin resistance.

Obese and insulin-resistant humans can remain in a state of β‑cell compensation that protects them from diabetes for long periods of time before a subset of such individuals ultimately succumb to β‑cell failure.M

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Recent works have been shown that : Insulin resistance develops as a consequence of the effects of

inflammatory factors, hormonal factors, endoplasmic reticulum (ER) stress, and accumulation of by-products of nutritional ‘overload’ in insulin-sensing tissues.

Although several of the damaging mechanisms are common across organs and tissues, others may be more specific, which highlights the significant challenges in designing pharmacological interventions for this condition.

Meanwhile, in both animals and humans, the triggering factor for transition from an obese, insulin-resistant state to fullblown type 2 diabetes is β‑cell failure, which involves both a partial loss of β‑cell mass and a deterioration of β‑cell function.

Some of the mechanisms that are involved in β‑cell failure are similar to the mechanisms of insulin resistance.

However, it should be noted that obese and insulin-resistant humans can remain in a state of β‑cell compensation that protects them from diabetes for long periods of time before a subset of such individuals ultimately succumb to β‑cell failure.

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Adipocytes have a regulatory role in the development of insulin resistance because they can produce adipokines (a group of hormones and cytokines) and because their capacity to store excess lipids can become saturated in obesity,

resulting in abnormal redistribution of lipids to other organs and tissues. A new appreciation of endocrine functions of adipose tissue began with the

discovery that the mutated gene in the ob/ob mouse, which exhibitshyperphagia, hyperlipidaemia and insulin resistance, is the cytokine-related

molecule leptin3,4. The ensuing decade of research has revealed that adipose cells also produce other peptide hormones, including adiponectin (ACRP30),

retinol-binding protein‑4 (RBP4) and resistin, and proinflammatory cytokines such as interleukin (IL)‑6 and tumour necrosis factor‑α (TNFα)5,6. Leptin and

adiponectin have been categorized as ‘anti-diabetogenic’ based on their common capacity to decrease triglyceride (TG) synthesis, stimulate β‑oxidation and

enhance insulin action in both skeletal muscle and liver.

Adipokines and Insulin Resistance.M

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