FROM FITNESS TO FATNESS
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNA...
Molecular and metabolic mechanisms
of insulin resistance and β cell failure‑
in type 2 diabetes
Deborah M. Muoio and Chris...
Link between obesity and diabetes :
a new word coined :
diabesity.
But researchers cannot exactly say how, eating too many...
Insulin normally controls fuel homeostasis
through the stimulation of glucose uptake
into peripheral tissues and
by suppre...
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-0...
Adipokines and insulin resistance.
Role of inflammatory mediators.
Alterations in metabolic function.
Metabolic overload i...
Mechanisms of insulin resistance
However other factors :
inter-organ communication networks mediated by :
peptide hormones...
Metabolic overload in the liver
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez...
b | During conditions of overnutrition, fatty acid influx and PPARa/d-mediated activation of target genes (yellow) promote...
Biochemical mechanisms of glucose-stimulated insulin secretion,Biochemical mechanisms of glucose-stimulated insulin secret...
Cellular Stress Appears to Link Obesity to Diabetes
Diagnosing the source of insulin resistance in the ER. The overloaded ...
ER STRESS
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJou...
 Activation of PERK and eventually the 
GADD34-PP1 phosphatase complex results 
in dephosphorylation of eIF2   , thereby 
...
| a | Proteins of the secretory pathway are 
translocated into the endoplasmic reticulum 
(ER) lumen co-translationally th...
Type 2 Diabetes Mellitus as a Conformational Disease
JOP. J Pancreas (Online) 2005; 6(4):287-302.
Human islet amyloid poly...
Metformin mediates its action by stimulating adenosine monophosphate-activated protein kinase (AMPK), a critical enzyme. I...
Stages of Type 2 Diabetes Mellitus as a Conformational Disease
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClu...
Insulin resistance develops as a consequence of the effects of
inflammatory and hormonal factors, endoplasmic reticulum (E...
Recent works have been shown that :
 Insulin resistance develops as a consequence of the effects of
inflammatory factors,...
Adipocytes have a regulatory role in the development of insulin resistance because they
can produce adipokines (a group of...
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-0...
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From Fitness to Fatness Hiriart´s Journal Club MER -060308

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

  1. 1. FROM FITNESS TO FATNESS MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  2. 2. 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
  3. 3. 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 MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  4. 4. 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 Lipids Glucose Amino acids + Metabolites By products Citosol Mitochondrion ER -Lumen Defective insulin secretion and action = to multiple metabolic abnormalities leading to DM2. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  5. 5. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  6. 6. 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 diabetes Regulation 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 resistance MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  7. 7. Mechanisms of insulin resistance However other factors : inter-organ communication networks mediated by : peptide hormones and 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 : MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  8. 8. Metabolic overload in the liver MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  9. 9. 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. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  10. 10. Biochemical mechanisms of glucose-stimulated insulin secretion,Biochemical mechanisms of glucose-stimulated insulin secretion, including roles of the pyrvuate cycling pathways of theincluding roles of the pyrvuate cycling pathways of the ββ cell.‑cell.‑ MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  11. 11. 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 MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  12. 12. ER STRESS MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  13. 13.  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. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  14. 14. | 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 the formation 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 Conditions.Schematic of Endoplasmic Reticulum Functions Under Non-Stress Conditions. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  15. 15. 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.   MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  16. 16. 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- Metformin activates AMPK in liver and muscle to improve glucose and lipid metabolism. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  17. 17. Stages of Type 2 Diabetes Mellitus as a Conformational Disease MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308 Conformational Diseases.
  18. 18. 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.‑ MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  19. 19. 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.‑ MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  20. 20. 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 exhibits hyperphagia, 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. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308
  21. 21. MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308

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