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

FROM FITNESS TO FATNESS
MarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClubMarthaEugeniaRamirez-Dominguez–IFC-UNAM-Hiriart’sJournalClub-060308

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

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.

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

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 :

Metabolic overload in the liver

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.

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.‑

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

ER STRESS

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.

| 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.

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.


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.

Stages of Type 2 Diabetes Mellitus as a Conformational Disease
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.‑

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.‑

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.

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

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