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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
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.
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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