ABSTRACT The millennial generation of human beings is at risk of the epidemic of lifestyle disorders such as obesity

ABSTRACT
The millennial generation of human beings is at risk of the epidemic of lifestyle disorders such as obesity, diabetes and cardiac vascular diseases. With the advancement in science and technology, today’s society has an excess of food supply and machines to lessen their physical burden, resulting in energy imbalance. Obesity and in association with chronic inflammation and dyslipidemia impairs the functioning of the cells, markedly by inducing endoplasmic reticulum (ER) stress, thereby hampering cellular responses of the anabolic hormone insulin. However, the associated underlying mechanisms that regulate the aforesaid disorder are less understood. PHLPP1 is a hydrophobic motif targeted phosphatase that inactivates Akt, the master regulator of insulin-mediated glucose homeostasis. Our knowledge about the role of PHLPP1 in regulating glucose metabolism is very limited warranting deeper studies with mechanistic insights. In the current study, we show that PHLPP1 expression was augmented in the insulin-responsive tissues like skeletal muscle, liver, and adipose of insulin-resistant rodents which also displayed ER stress, a key cellular driver of insulin resistance. As 70% of glucose uptake is mediated by the skeletal muscle, we further examined the effect of PHLPP1 on skeletal muscle insulin resistance (IR). Using chemical and molecular biology tools in both cell-based and in vivo studies, we identified that PHLPP1 promotes the development of ER stress in skeletal muscle. Importantly, ablation of PHLPP1 improved glucose clearance from systemic circulation along with heightened expression of skeletal muscle insulin responsive glucose transporter, GLUT-4. Upon further investigation, we observed that the endogenous interaction of PHLPP1, but not PP2Ac or PP2C?, with AMPK, was enhanced under ER stress. Furthermore, we show that PHLPP1 directly dephosphorylates AMPK at Thr172 in myoblasts without influencing its upstream kinase, LKB1. Importantly, the association between endogenous PHLPP1 and AMPK was enriched in soleus muscle of high-fat diet fed mice, while a minimal change was detected in the basal association of PP2Ac and AMPK highlighting the pathophysiological in vivo relevance of PHLPP1. Moreover, through biochemical studies, we demonstrate that PHLPP1? is phosphorylated by ERK1/2 at Ser932 under ER stress response which enhanced its ability to interact with and dephosphorylate its substrates (AMPK/Akt). We here show that ERK1/2 mediated phosphorylation of PHLPP1 inactivated AMPK to facilitate ER stress and inhibit GLUT4 expression resulting in insulin resistance (IR). Collectively, our data position PHLPP1 as a key regulator of ER stress-mediated IR, regulating not only insulin-stimulated Akt signaling but also AMPK mediated insulin independent pathway.

GRAPHICAL ABSTRACT:

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PHLPP1 promotes ER stress-mediated IR in skeletal muscle. ER stress augments the expression as well as ERK1/2 mediated activating phosphorylation of PHLPP1 which by inactivation of AMPK facilitates ER stress and restrict glucose uptake both in response to insulin and independent of insulin by direct dephosphorylation of Akt and AMPK respectively. In addition, PHLPP1 also limits the expression of GLUT4 expression upon induction of ER stress. (Figure adapted from Behera et al. 2018 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWhlcmE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 1)

TABLE OF CONTENTS
TOC o “1-4” h z u Chapter 1: Introduction and review of literature PAGEREF _Toc432143167 h 11.1Insulin and insulin secretions PAGEREF _Toc432143168 h 41.1.1The Discovery of Insulin PAGEREF _Toc432143169 h 61.1.2Structure and Chemical Properties of Insulin PAGEREF _Toc432143170 h 201.1.3Biosynthesis PAGEREF _Toc432143171 h 27 1.1.4 Biphasic Mode of insulin secretion……………………………………
1.1.5 Factors influencing Insulin Secretion………………………………….
1.2Insulin Signalling PAGEREF _Toc432143172 h 321.2.1Insulin signalling through Akt PAGEREF _Toc432143173 h 341.3Negative regulators of insulin signalling PAGEREF _Toc432143178 h 801.3.1Phosphoprotein Phosphatases PAGEREF _Toc432143179 h 811.3.2Lipid Phosphatases PAGEREF _Toc432143180 h 891.3.3Adaptor Proteins PAGEREF _Toc432143181 h 921.3.4Inhibitory Ser/Thr phosphorylation PAGEREF _Toc432143182 h 98 1.4 Insulin resistance and its drivers………………………………………..
1.4.1Genetic causes PAGEREF _Toc432143183 h 991.4.2Environmental causes PAGEREF _Toc432143184 h 1071.4.3 Molecular causes
1.4.3.a Lipotoxicity/dyslipidemia…………………………………………

1.4.3.b Inflammation……………………………………………………..

1.4.3.c Hyperglycemia……………………………………………………
1.4.3.d Mitochondrial Dysfunction and ROS Formation………………..

1.4.3.b ER Stress………………………………………………………..

1.5 Endoplasmic Reticulum Stress and Unfolded Protein response
1.5.1Adaptation Phase
1.5.1.a Recognition of unfolded proteins
1.5.1.b Transduction of the unfolded protein signal
1.5.2Alarm Phase
1.5.3Apoptotic Phase
1.5.3.a Intrinsic pathways
1.5.3.b Extrinsic pathways
1.6 ER stress and Type 2 diabetes
1.6.1ER stress-mediated insulin resistance in various tissues
1.6.1.a Hypothalamus
1.6.1.a Adipose tissue
1.6.1.a Liver
1.6.1.a Pancreatic ? cells
1.6.1.a Skeletal muscle
1.7PHLPP: Emerging target for therapeutics PAGEREF _Toc432143178 h 801.7.1Domain composition and function PAGEREF _Toc432143179 h 811.7.2Substrates of PHLPP PAGEREF _Toc432143180 h 891.7.3Multifaceted Regulation of PHLPP PAGEREF _Toc432143181 h 921.7.4PHLPP in physiology and pathology PAGEREF _Toc432143182 h 98Chapter 2: ER stress ; inflammation augments PHLPP1 PAGEREF _Toc432143185 h 1102.1.Modulation of PHLPP1 expression alters glucose metabolism PAGEREF _Toc432143186 h 1122.2.PHLPP1 expression is enhanced in animals displaying insulin resistance PAGEREF _Toc432143187 h 1192.3.PHLPP1 expression is enhanced under inflammation in skeletal muscle PAGEREF _Toc432143188 h 1232.4.PHLPP1 expression is enhanced upon ER stress in skeletal muscle PAGEREF _Toc432143189 h 1272.5.Summary PAGEREF _Toc432143194 h 146Chapter 3: AMPK? a novel substrate of PHLPP1 PAGEREF _Toc432143195 h 1473.1.PHLPP1 regulates the activity of AMPK? PAGEREF _Toc432143196 h 1503.2.PHLPP1 interacts with AMPK? PAGEREF _Toc432143197 h 1533.3.In vitro dephosphorylation of AMPK? by PHLPP1 PAGEREF _Toc432143200 h 1673.4.PHLPP1 facilitates ER stress by inhibition of AMPK activity PAGEREF _Toc432143201 h 169 3.5. PHLPP1 suppresses GLUT4 expression PAGEREF _Toc432143202 h 174 3.6. Summary………………………………………………………………….

Chapter 4: PHLPP1 is phosphorylated by ERK1/2 upon ER stress PAGEREF _Toc432143203 h 1754.1.In silico analysis of PHLPP1 phosphorylation sites PAGEREF _Toc432143204 h 177 4.2. PHLPP1 is a substrate of ERK1/2……………………………………….. PAGEREF _Toc432143205 h 1794.3.Confirmation of Ser932 as the site of ERK1/2 phosphorylation PAGEREF _Toc432143206 h 1834.4.PHLPP1 is phosphorylated by ERK1/2 in intact cells PAGEREF _Toc432143207 h 1874.5.ER stress induces ERK1/2 mediated PHLPP1 phosphorylation PAGEREF _Toc432143208 h 1924.6.Summary PAGEREF _Toc432143209 h 196Chapter 5: Consequences of ERK1/2-mediated PHLPP phosphorylation PAGEREF _Toc432143203 h 1755.1.Impact of PHLPP1 phosphorylation on its cellular functions PAGEREF _Toc432143204 h 1775.1.1Effect of p-PHLPP1 on induction of ER stress……………………
5.1.2Effect of p-PHLPP1 on skeletal muscle insulin resistance………..

5.2.Impact of PHLPP1 phosphorylation on catalytic activity PAGEREF _Toc432143205 h 1795.3.Impact of PHLPP1 phosphorylation upon substrate interaction PAGEREF _Toc432143206 h 1835.4.Impact of PHLPP1 phosphorylation on its protein stability PAGEREF _Toc432143207 h 1875.5.Summary PAGEREF _Toc432143208 h 192Chapter 6: Discussion and Future Perspectives PAGEREF _Toc432143211 h 202Chapter 7: Materials and Methods PAGEREF _Toc432143212 h 222References PAGEREF _Toc432143213 h 234Appendix PAGEREF _Toc432143214 h 276
ABBREVIATIONS
2-NBDG 2-(N-7-nitrobenz-2-oxa-1,3-diazol-4-ylamino)-2-deoxyglucose)
4E-BP1 4E-binding protein 1
4-PBA 4-phenyl butyric acid
ACC Acetyl-CoA carboxylase
ADP Adenosine diphosphate
AGEs Advanced glycation end products
AMP Adenosine monophosphate
AMPK AMP-activated protein kinase
AICAR 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside
AP-1 Activator protein-1
APAF1 Apoptotic protease activating factor 1
ARE Antioxidant response element
AS160 Akt Substrate of 160 KDa
ASK1 Apoptosis signal-regulating kinase 1
ATF Activating Transcription Factor
ATP Adenosine triphosphate
AUC Area under the curve
Bak Bcl-2-like protein 7
Bax Bcl-2-like protein 4
Bcl-2 B-cell lymphoma 2
?-TrCP BetaTransducin repeats-Containing Proteins
Bim Bcl-2-like protein 11
BiP Binding immunoglobulin protein
bZIP Basic Leucine Zipper
cAMP 3?,5?-cyclic adenosine monophosphate
CBP CBP (CREB-binding protein)
CCR C-C chemokine receptor
CD Cluster of differentiation
CDS Coding sequence
CHOP C/EBP Homologous Protein
CK1 Casein kinase 1
CREB cAMP response element binding protein
CRP C-reactive protein
DAG Diacylglycerol
DIO Diet induced obesity
DEPTOR DEP domain-containing mTOR-interacting protein
DHet Double Heterozygous deficiency of insulin receptor and IRS-1 alleles
DMEM Dulbecco’s modified Eagle’s medium
DNA Deoxyribonucleic acid
DTT 1,4-dithiothreitol
EDTA Ethylenediaminetetraacetic acid
EGFR Epidermal growth factor receptor
eIF Eukaryotic translation initiation factor
ER Endoplasmic reticulum
ERAD ER-associated degradation
ERSE ER stress response elements
ER stress Endoplasmic reticulum stress
ERK Extracellular signal-regulated kinase
FAS Fatty acid synthase
FBS Fetal bovine serum
FFA Free fatty acids
FKBP51 FK506-binding protein of 51 kDa
FGF Fibroblast growth factor
FoxO Forkhead box O
G6Pase glucose 6-phosphatase
GADD Growth Arrest and DNA Damage-Inducible Protein
GIP glucose-dependent insulinotropic polypeptide
GLP-1 glucagon-like peptide-1
GLS1 Golgi localization sequences 1
GLUT4 Glucose transporter type 4
Grb Growth factor receptor-bound protein
GRP78 78 kDa glucose-regulated protein
GSIS glucose-stimulated insulin secretion
GSK-3beta Glycogen synthase kinase-3beta
GST Glutathione STransferase
HA Hemagglutinin
HDAC Histone deacetylases
HFD High fat diet
hIAPP Human islet amyloid polypeptide
HIF Hypoxia-inducible factor
HSD High sucrose diet
HSP Heat shock protein
IFN Interferon
IGF1 Insulin-like growth factor 1
IKK Ikappa B kinase
IL Interleukin
iNOS Inducible nitric oxide synthase
IP7 inositol pyrophosphate (diphosphoinositol pentakisphosphate 5-PP-1(1,2,3,4,6)IP5).

IR Insulin resistance
IRE1 Inositol Requiring Enzyme 1
IRS insulin receptor substrate
JAK Janus tyrosine kinase
JNK C-Jun N-terminal kinase
LAR Leukocyte common antigen-related protein tyrosine phosphatase
LIF Leukemia inhibitory factor
LKB1 Liver Kinase B1
lncRNAs long noncoding RNAs
LPS Lipopolysaccharide
MAPK Mitogen activated protein kinase
MBTPS2 Membrane-bound transcription factor protease site 2
MCP-1 Monocyte chemoattractant protein-1
MEFs Mouse embryo fibroblasts
MEK1 MAPK/ERK kinase 1
MIDY Mutant INS-gene-induced Diabetes of Youth
miR/miRNAs MicroRNAs
mLST8 mammalian lethal with SEC13 protein 8
Mst1 Mammalian sterile 20-like kinase
mTORC1 mammalian target of rapamycin complex 1
mTORC2 mammalian target of rapamycin complex 2
NAD Nicotinamide adenine dinucleotide
NADPH Nicotinamide adenine dinucleotide phosphate hydrogen
NEFAs Nonesterified fatty acids
NF-Y Nuclear transcription factor Y
NFAT Nuclear factor of activated T cells
NF?B Nuclear factor ?B
NLR NOD (nucleotide-binding oligomerization-domain protein)-like receptor
NLRC NOD-LRR (leucine-rich repeat) family with CARD (caspase recruitment domain)
NO Nitric oxide
Nrf2 Nuclear factor erythroid 2–related factor 2
p300/Ep300 E1A-associated protein p300
PAK1 p21- activated kinase 1
PACAP pituitary adenylate cyclase-activating polypeptide
PCR Polymerase chain reaction
PDE3B Phosphodiesterase 3B
PDK-1 3-phosphoinositide-dependent protein kinase 1
PEPCK Phosphoenolpyruvate carboxykinase
PERK Protein kinase-like endoplasmic reticulum kinase
PGC-1? Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
PHLPP PH (pleckstrin homology) domain Leucine-rich repeat Protein Phosphatase
PI3K Phosphatidylinositol 3 kinase
PIMT PRIP interacting protein with methyl transferase domain
PIP2 phosphorylates phosphatidylinositol 4,5-bisphosphate
PIP3 phosphatidylinositol (3,4,5)-triphosphate
PKA protein kinase A
PKC Protein kinase C
pNPP p-nitrophenyl phosphate
PPAR? Peroxisome Proliferator-activated Receptor ?
PP1 Protein phosphatase 1
PP2A Protein phosphatase 2A
PP2B Protein phosphatase 2B
PP2C Protein phosphatase 2C
PRAS40 40kDa Proline-rich Akt substrate
PSP Protein serine/threonine phosphatase
PTEN Inositol 3-phosphatase and tensin homologue deleted on chromosome 10
PTP Protein tyrosine phosphatase
PTP1B protein-tyrosine phosphatase 1B
RHEB Ras homolog enriched in brain
RNA Ribonucleic acid
ROS Reactive oxygen species
RP reserve pools
RRP readily releasable pools
RTKs Receptor tyrosine kinases
S6K p70 ribosomal protein S6 kinases
SCD Stearoyl-CoA desaturase
SCOP Scn circadian oscillatory protein
SFB Streptavidin Flag Biotin
SGT1 Suppressor of G2 allele of SKP1 homolog
SHIP (SH2)-containing inositol phosphatase
SH2 Src-homology2
shRNA Small hairpin RNA
siRNA Small interfering RNA
SKIP Skeletal muscle kidney-enriched inositol polyphosphate phosphatase
SNP Single nucleotide polymorphism
SOCS Suppressor of cytokine signaling
SP1 Specificity protein-1
SR Sarcoplasmic reticulum
SREBP Sterol regulatory element binding protein
ss RNA Single stranded RNA
STAT Signal transducer and activator of transcription
sTWEAK Soluble tumour necrosis factor-like weak inducer of apoptosis
T2D Type 2 diabetic
TBC1D4 TBC1 Domain Family Member 4
TCPTP T-cell protein tyrosine phosphatase
TGF-? Transforming growth factor-?
TLR Toll-like receptor
TRAF TNF receptor associated factor
Trb3 Tribbles homolog 3
Treg Regulatory T cell
TSC Tuberous sclerosis proteins
TUDCA Taurine-conjugated ursodeoxycholic acid
TXNIP Thioredoxin-interacting protein
UDP Uridine 5′-diphospho
UPR Unfolded protein response
USP Ubiquitin specific protease
UTR Untranslated region
VLDLs Very low-density lipoproteins
WFS Wolfram syndrome
WT Wild type
XBP1 X-box-binding protein
LIST OF FIGURES
Figure Page
Chapter 1
1.1 Factors influencing Insulin Secretion at the cellular level 5
1.2 Schematic representation of Insulin signalling 12
1.3 Negative regulators of insulin signalling 14
1.4 Insulin resistance and its drivers 16
1.5 Schematic representation of Endoplasmic Reticulum Stress 19
1.7 Domain architecture of PHLPP isoforms. 21
1.7 Role of PHLPP in physiology and pathology. 24
Chapter 2
2.1 PHLPP1 alters glucose sensing machinery in skeletal muscle 113
2.2 PHLPP1 expression is elevated in insulin-resistant animals 114
2.3 TNF-? enhances the expression of PHLPP1 and ER stress markers 116
2.4 PHLPP1 expression is enhanced by ER stress 118
2.5 PHLPP1 promotes ER stress 120
Chapter 3
3.1 PHLPP1 decreases AMPK? activity. 152
3.2 Interaction of PHLPP1 with AMPK? is enhanced upon ER stress. 154
3.3 AMPK is a novel target of PHLPP1. 156
3.4 PHLPP1 facilitates ER stress by inhibiting AMPK. 158
3.5 PHLPP1 suppresses GLUT4 expression. 160
Chapter 4
4.1 Schematic representation of PHLPP1? protein. 178
4.2 PHLPP1 is phosphorylated by ERK1/2 180
4.3 PHLPP1 is phosphorylated at Ser932 residue by ERK1/2 in vitro. 182
4.4 PHLPP1 is a substrate of ERK1/2 in intact cells. 184
4.5 Phosphorylation of PHLPP1 at Ser932 is enhanced upon ER stress. 186
Chapter 5
5.1 Ser932 PHLPP1? phosphorylation is required for ER stress induction and inhibition of
insulin-stimulated glucose uptake. 178
5.2 ERK1/2 mediated PHLPP1 phosphorylation augments its catalytic activity 180
5.3 Ser932 phosphorylation of PHLPP1? promotes substrate interaction. 182
5.4 Enhanced expression of PHLPP1 is independent of phosphorylation at Ser932. 184
LIST OF TABLES
Table Page
Chapter 1
1.1 List of miRNAs regulating the expression of PHLPP 9
Chapter 4
4.1 Predicted kinase sites of PHLPP1? (Scansite prediction) 172
4.2 Conserved putative ERK1 phosphorylation site on PHLPP1? 172
4.3 Predicted ERK D-domains of PHLPP1? (Scansite motif analysis) 172
4.4 ELISA results for phospho-specific antibody after the 3rd immunization 172
Insulin and insulin signalling:
The Discovery of Insulin:
History of insulin discovery starts way back in 1921 when a Canadian physician Frederick Banting and medical student Charles H. Best isolated insulin from the pancreatic extracts of dogs and administered its chilled saline extracts intravenously in dogs to lower the blood glucose levels in dogs with pancreatectomy induced diabetes. Later, biochemist Collip in collaboration with Banting and Best demonstrated that the enriched and purified extract of insulin was responsible for the restoration of hepatic glycogen and peripheral clearance of ketones. In January 1922 the first human trial of insulin was performed on a 14-year-old diabetic boy and a noted improvement in clinical symptoms and biochemical abnormalities upon administration of pancreatic extract was observed. Subsequently, early in 1923, Eli Lilly started production of porcine insulin by enhancing purification through iso-electric precipitation and in the same year the Nobel Prize for the discovery of insulin was awarded to Banting and McLeod in 1923 ADDIN EN.CITE <EndNote><Cite><Author>Bliss</Author><Year>1993</Year><RecNum>192</RecNum><DisplayText>2</DisplayText><record><rec-number>192</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>192</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bliss, M.</author></authors></contributors><auth-address>Department of History, University of Toronto, Canada.</auth-address><titles><title>The history of insulin</title><secondary-title>Diabetes Care</secondary-title><alt-title>Diabetes care</alt-title></titles><periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></periodical><alt-periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></alt-periodical><pages>4-7</pages><volume>16 Suppl 3</volume><keywords><keyword>Adolescent</keyword><keyword>Diabetes Mellitus, Type 1/blood/*drug therapy</keyword><keyword>Drug Industry/history</keyword><keyword>History, 19th Century</keyword><keyword>History, 20th Century</keyword><keyword>Humans</keyword><keyword>Insulin/*history/*therapeutic use</keyword><keyword>Ontario</keyword></keywords><dates><year>1993</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0149-5992 (Print) 0149-5992 (Linking)</isbn><accession-num>8299476</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8299476</url></related-urls></urls></record></Cite></EndNote>2.

Structure and Chemical Properties of Insulin:
Chemically insulin is a peptide whose amino acid sequence was identified in 1952. Insulin is composed of two peptide chains, chain A (21 amino acids) and chain B (30 amino acids) in most species. Chains A and B are linked together by two disulphide bonds, which join the N- and C-terminal helices of the chain A to the central helix of chain B. In pro-insulin, a connecting peptide called C-peptide links the N-terminus of the Chain A to the C-terminus of the Chain B ADDIN EN.CITE <EndNote><Cite><Author>Dodson</Author><Year>1998</Year><RecNum>193</RecNum><DisplayText>3</DisplayText><record><rec-number>193</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>193</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dodson, G.</author><author>Steiner, D.</author></authors></contributors><auth-address>National Institute of Medical Research, London, UK. [email protected]</auth-address><titles><title>The role of assembly in insulin&apos;s biosynthesis</title><secondary-title>Curr Opin Struct Biol</secondary-title><alt-title>Current opinion in structural biology</alt-title></titles><periodical><full-title>Curr Opin Struct Biol</full-title><abbr-1>Current opinion in structural biology</abbr-1></periodical><alt-periodical><full-title>Curr Opin Struct Biol</full-title><abbr-1>Current opinion in structural biology</abbr-1></alt-periodical><pages>189-94</pages><volume>8</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biological Transport, Active</keyword><keyword>Cytoplasmic Granules/metabolism</keyword><keyword>Golgi Apparatus/metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/*biosynthesis/*chemistry/genetics</keyword><keyword>Islets of Langerhans/metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Proinsulin/biosynthesis</keyword><keyword>Protein Conformation</keyword><keyword>Ribosomes/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0959-440X (Print) 0959-440X (Linking)</isbn><accession-num>9631292</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9631292</url></related-urls></urls></record></Cite></EndNote>3. Despite the variation in the amino acid sequence of insulin among species, certain segments of the molecule are highly conserved, such as the positions of the three disulphide bonds, both the ends of chain A and the C-terminal residues of chain B, resulting in the similar three-dimensional conformation of insulin among species. Hence, insulin from one animal is very likely to be biologically active in other species. Indeed, pig insulin has been widely used to treat human patients.

Biosynthesis:
Insulin gene is located on the short arm of chromosome 11 and is expressed in ?-cells of the islets of Langerhans of the pancreas as a single polypeptide chain, preproinsulin. In the endoplasmic reticulum lumen, the signal polypeptide chain is cleaved and subsequently folded into its characteristic three-dimensional structure of proinsulin. Secretory vesicles transfer proinsulin from the rough endoplasmic reticulum to the Golgi apparatus. In the immature storage vesicles formed from the Golgi, proinsulin is converted to insulin and C peptide. Further, the aqueous zinc and calcium-rich environment of the vesicles favours formation of zinc-containing proinsulin hexamers ADDIN EN.CITE <EndNote><Cite><Author>Dodson</Author><Year>1998</Year><RecNum>193</RecNum><DisplayText>3</DisplayText><record><rec-number>193</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>193</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dodson, G.</author><author>Steiner, D.</author></authors></contributors><auth-address>National Institute of Medical Research, London, UK. [email protected]</auth-address><titles><title>The role of assembly in insulin&apos;s biosynthesis</title><secondary-title>Curr Opin Struct Biol</secondary-title><alt-title>Current opinion in structural biology</alt-title></titles><periodical><full-title>Curr Opin Struct Biol</full-title><abbr-1>Current opinion in structural biology</abbr-1></periodical><alt-periodical><full-title>Curr Opin Struct Biol</full-title><abbr-1>Current opinion in structural biology</abbr-1></alt-periodical><pages>189-94</pages><volume>8</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Biological Transport, Active</keyword><keyword>Cytoplasmic Granules/metabolism</keyword><keyword>Golgi Apparatus/metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/*biosynthesis/*chemistry/genetics</keyword><keyword>Islets of Langerhans/metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Proinsulin/biosynthesis</keyword><keyword>Protein Conformation</keyword><keyword>Ribosomes/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0959-440X (Print) 0959-440X (Linking)</isbn><accession-num>9631292</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9631292</url></related-urls></urls></record></Cite></EndNote>3. Bound to two zinc atoms, insulin is stored in granules as a hexamer and upon exocytosis, an equimolar ratio of insulin and C-peptide are released into the peripheral circulation.

Biphasic Mode of insulin secretion:
In response to a stimulus, primarily glucose, insulin is secreted from the islet ?-cells to the portal veins in a characteristic biphasic manner; with an initial rapid phase of insulin secretion, followed by a less intense but more sustained release phase of the hormone ADDIN EN.CITE <EndNote><Cite><Author>Bratanova-Tochkova</Author><Year>2002</Year><RecNum>195</RecNum><DisplayText>4</DisplayText><record><rec-number>195</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>195</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bratanova-Tochkova, T. K.</author><author>Cheng, H.</author><author>Daniel, S.</author><author>Gunawardana, S.</author><author>Liu, Y. J.</author><author>Mulvaney-Musa, J.</author><author>Schermerhorn, T.</author><author>Straub, S. G.</author><author>Yajima, H.</author><author>Sharp, G. W.</author></authors></contributors><auth-address>Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York.</auth-address><titles><title>Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>S83-90</pages><volume>51 Suppl 1</volume><keywords><keyword>Animals</keyword><keyword>Insulin/*secretion</keyword><keyword>Islets of Langerhans/*metabolism/*secretion</keyword><keyword>Secretory Vesicles/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0012-1797 (Print) 0012-1797 (Linking)</isbn><accession-num>11815463</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11815463</url></related-urls></urls></record></Cite></EndNote>4. Increased levels of glucose induce the “first phase” of glucose-mediated insulin secretion. Glucose influx into the ?-cells enhances the ATP levels via coordinated glycolysis/TCA pathway. Elevated levels of cytoplasmic ATP/ADP ratio in ?-cell closes ATP-sensitive K+ channels (K+ATP channels) resulting in membrane depolarization and the influx of Ca2+ via L-type voltage-dependent Ca2+ channels (VDCC). Elevated cytosolic free Ca2+ concentration rapidly increases the rate of insulin exocytosis ADDIN EN.CITE <EndNote><Cite><Author>Soria</Author><Year>2004</Year><RecNum>196</RecNum><DisplayText>5</DisplayText><record><rec-number>196</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>196</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Soria, B.</author><author>Quesada, I.</author><author>Ropero, A. B.</author><author>Pertusa, J. A.</author><author>Martin, F.</author><author>Nadal, A.</author></authors></contributors><auth-address>Institute of Bioengineering, Miguel Hernandez University, Alicante, Spain. [email protected]</auth-address><titles><title>Novel players in pancreatic islet signaling: from membrane receptors to nuclear channels</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>S86-91</pages><volume>53 Suppl 1</volume><keywords><keyword>Animals</keyword><keyword>Gene Expression Regulation</keyword><keyword>Glucose/pharmacology</keyword><keyword>Humans</keyword><keyword>Ion Channels/*physiology</keyword><keyword>Islets of Langerhans/drug effects/*physiology</keyword><keyword>Models, Biological</keyword><keyword>Receptors, Cell Surface/*physiology</keyword><keyword>Receptors, Cytoplasmic and Nuclear/*physiology</keyword><keyword>Signal Transduction/*physiology</keyword></keywords><dates><year>2004</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0012-1797 (Print) 0012-1797 (Linking)</isbn><accession-num>14749271</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/14749271</url></related-urls></urls></record></Cite></EndNote>5.
However, glucose augments insulin exocytosis induced by K+ depolarization even when the K+ATP channels are fully open or closed in the presence of diazoxide or sulfonylureas, respectively; indicating the presence of both a K+ ATP channel-independent Ca2+-dependent pathway and K+ATP channel-independent Ca2+-independent pathways for insulin secretion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXRvPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 6, 7. Other mediators that potentiate insulin secretion include activation of phospholipases and protein kinase C, stimulation of adenylyl cyclase activity and activation of ? cell protein kinase A. This latter enzymatic activity may be triggered by hormones, such as GLP-1 and GIP. These hormonal inducing signalling appears to play a significant role in the second phase of glucose-mediated insulin secretion, after refilling of secretory granules translocated from reserve pools ADDIN EN.CITE <EndNote><Cite><Author>Bratanova-Tochkova</Author><Year>2002</Year><RecNum>195</RecNum><DisplayText>4</DisplayText><record><rec-number>195</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>195</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bratanova-Tochkova, T. K.</author><author>Cheng, H.</author><author>Daniel, S.</author><author>Gunawardana, S.</author><author>Liu, Y. J.</author><author>Mulvaney-Musa, J.</author><author>Schermerhorn, T.</author><author>Straub, S. G.</author><author>Yajima, H.</author><author>Sharp, G. W.</author></authors></contributors><auth-address>Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York.</auth-address><titles><title>Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>S83-90</pages><volume>51 Suppl 1</volume><keywords><keyword>Animals</keyword><keyword>Insulin/*secretion</keyword><keyword>Islets of Langerhans/*metabolism/*secretion</keyword><keyword>Secretory Vesicles/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0012-1797 (Print) 0012-1797 (Linking)</isbn><accession-num>11815463</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11815463</url></related-urls></urls></record></Cite></EndNote>4.

It has long been considered that there are distinct pools of insulin granules known as readily releasable pools (RRP) and reserve pools (RP). In the biphasic GSIS, initial rapid insulin exocytosis from the RRP that occurs by the K+ATP-dependent mechanism, the second phase of gradual enhancement of amplification is indicated by the K+ATP independent signal. The latter can occur with replenishment of the RRP from the RP, so the biphasic insulin release as ‘fusion and replenishment’ is proposed ADDIN EN.CITE <EndNote><Cite><Author>Bratanova-Tochkova</Author><Year>2002</Year><RecNum>195</RecNum><DisplayText>4</DisplayText><record><rec-number>195</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>195</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bratanova-Tochkova, T. K.</author><author>Cheng, H.</author><author>Daniel, S.</author><author>Gunawardana, S.</author><author>Liu, Y. J.</author><author>Mulvaney-Musa, J.</author><author>Schermerhorn, T.</author><author>Straub, S. G.</author><author>Yajima, H.</author><author>Sharp, G. W.</author></authors></contributors><auth-address>Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York.</auth-address><titles><title>Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>S83-90</pages><volume>51 Suppl 1</volume><keywords><keyword>Animals</keyword><keyword>Insulin/*secretion</keyword><keyword>Islets of Langerhans/*metabolism/*secretion</keyword><keyword>Secretory Vesicles/*metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0012-1797 (Print) 0012-1797 (Linking)</isbn><accession-num>11815463</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11815463</url></related-urls></urls></record></Cite></EndNote>4.

Factors influencing Insulin Secretion:
Secretion of insulin at physiological level is regulated by a complex interplay of numerous events as discussed below.
Incretins: Incretin hormones are released in a fed state from gut enteroendocrine cells. They potentiate nutrient-induced insulin secretion for up to 70% postprandial. These hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both known to promote proliferation/neogenesis of ?- cells and prevent their apoptosis. They regulate insulin secretion from food intake and their effects are progressively amplified with direct correlation with plasma glucose concentration. Mechanistically, incretins bind to the G protein-coupled receptors on the ?-cell membrane and increase cellular 3?,5?-cyclic adenosine monophosphate (cAMP) levels which in turn enhances GSIS through protein kinase A (PKA)-dependent and -independent mechanisms ADDIN EN.CITE <EndNote><Cite><Author>Seino</Author><Year>2005</Year><RecNum>199</RecNum><DisplayText>8</DisplayText><record><rec-number>199</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>199</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Seino, S.</author><author>Shibasaki, T.</author></authors></contributors><auth-address>Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. [email protected]</auth-address><titles><title>PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis</title><secondary-title>Physiol Rev</secondary-title><alt-title>Physiological reviews</alt-title></titles><periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></periodical><alt-periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></alt-periodical><pages>1303-42</pages><volume>85</volume><number>4</number><keywords><keyword>Action Potentials</keyword><keyword>Animals</keyword><keyword>Cyclic AMP/antagonists &amp; inhibitors/*physiology</keyword><keyword>Cyclic AMP-Dependent Protein Kinases/*physiology</keyword><keyword>Endocrine Glands/physiology</keyword><keyword>Exocrine Glands/physiology</keyword><keyword>Exocytosis/*physiology</keyword><keyword>Humans</keyword><keyword>Neurons/physiology</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0031-9333 (Print) 0031-9333 (Linking)</isbn><accession-num>16183914</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16183914</url></related-urls></urls><electronic-resource-num>10.1152/physrev.00001.2005</electronic-resource-num></record></Cite></EndNote>8.
Amino acids: Both acute and chronic phases of insulin secretion are regulated by few specific amino acids. Four amino acids namely leucine, isoleucine, alanine, and arginine play a significant role in stimulating electrical activities in ?-cell requires for insulin secretion ADDIN EN.CITE <EndNote><Cite><Author>Newsholme</Author><Year>2005</Year><RecNum>200</RecNum><DisplayText>9</DisplayText><record><rec-number>200</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>200</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Newsholme, P.</author><author>Brennan, L.</author><author>Rubi, B.</author><author>Maechler, P.</author></authors></contributors><auth-address>Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. [email protected]</auth-address><titles><title>New insights into amino acid metabolism, beta-cell function and diabetes</title><secondary-title>Clin Sci (Lond)</secondary-title><alt-title>Clinical science</alt-title></titles><periodical><full-title>Clin Sci (Lond)</full-title><abbr-1>Clinical science</abbr-1></periodical><alt-periodical><full-title>Clin Sci (Lond)</full-title><abbr-1>Clinical science</abbr-1></alt-periodical><pages>185-94</pages><volume>108</volume><number>3</number><keywords><keyword>Amino Acids/*metabolism</keyword><keyword>Calcium/metabolism</keyword><keyword>Diabetes Mellitus/*metabolism</keyword><keyword>Glucose/metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/*secretion</keyword><keyword>Islets of Langerhans/*metabolism/secretion</keyword><keyword>Mitochondria/metabolism</keyword><keyword>Signal Transduction/*physiology</keyword></keywords><dates><year>2005</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0143-5221 (Print) 0143-5221 (Linking)</isbn><accession-num>15544573</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15544573</url></related-urls></urls><electronic-resource-num>10.1042/CS20040290</electronic-resource-num></record></Cite></EndNote>9. Arginine and Alanine stimulate insulin secretion 2-10 minutes after intravenous injection by increasing the permeability of K+ ion channels leading to depolarization of membrane and opening of Ca2+ channels ADDIN EN.CITE <EndNote><Cite><Author>Wilcox</Author><Year>2005</Year><RecNum>632</RecNum><DisplayText>10</DisplayText><record><rec-number>632</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>632</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Wilcox, G.</author></authors></contributors><auth-address>Melbourne Pathology, Collingwood, VIC 3066, Australia. [email protected]</auth-address><titles><title>Insulin and insulin resistance</title><secondary-title>Clin Biochem Rev</secondary-title><alt-title>The Clinical biochemist. Reviews</alt-title></titles><periodical><full-title>Clin Biochem Rev</full-title><abbr-1>The Clinical biochemist. Reviews</abbr-1></periodical><alt-periodical><full-title>Clin Biochem Rev</full-title><abbr-1>The Clinical biochemist. Reviews</abbr-1></alt-periodical><pages>19-39</pages><volume>26</volume><number>2</number><dates><year>2005</year><pub-dates><date>May</date></pub-dates></dates><isbn>0159-8090 (Print) 0159-8090 (Linking)</isbn><accession-num>16278749</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16278749</url></related-urls></urls><custom2>1204764</custom2></record></Cite></EndNote>10. Whereas, Leucine and isoleucine enhance insulin secretion by increasing the concentration of ATP generation through Kreb Cycle ADDIN EN.CITE <EndNote><Cite><Author>Wilcox</Author><Year>2005</Year><RecNum>632</RecNum><DisplayText>10</DisplayText><record><rec-number>632</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>632</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Wilcox, G.</author></authors></contributors><auth-address>Melbourne Pathology, Collingwood, VIC 3066, Australia. [email protected]</auth-address><titles><title>Insulin and insulin resistance</title><secondary-title>Clin Biochem Rev</secondary-title><alt-title>The Clinical biochemist. Reviews</alt-title></titles><periodical><full-title>Clin Biochem Rev</full-title><abbr-1>The Clinical biochemist. Reviews</abbr-1></periodical><alt-periodical><full-title>Clin Biochem Rev</full-title><abbr-1>The Clinical biochemist. Reviews</abbr-1></alt-periodical><pages>19-39</pages><volume>26</volume><number>2</number><dates><year>2005</year><pub-dates><date>May</date></pub-dates></dates><isbn>0159-8090 (Print) 0159-8090 (Linking)</isbn><accession-num>16278749</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16278749</url></related-urls></urls><custom2>1204764</custom2></record></Cite></EndNote>10.

Free fatty acid (FFA): FFAs are important for normal functioning of pancreatic ?-cells however, a chronic excess of FFAs particularly saturated FFAs cause lipotoxicity which is associated with induction of insulin resistance ADDIN EN.CITE <EndNote><Cite><Author>Boden</Author><Year>2005</Year><RecNum>201</RecNum><DisplayText>11</DisplayText><record><rec-number>201</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>201</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Boden, G.</author></authors></contributors><auth-address>Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140, USA. [email protected]</auth-address><titles><title>Free fatty acids and insulin secretion in humans</title><secondary-title>Curr Diab Rep</secondary-title><alt-title>Current diabetes reports</alt-title></titles><periodical><full-title>Curr Diab Rep</full-title><abbr-1>Current diabetes reports</abbr-1></periodical><alt-periodical><full-title>Curr Diab Rep</full-title><abbr-1>Current diabetes reports</abbr-1></alt-periodical><pages>167-70</pages><volume>5</volume><number>3</number><keywords><keyword>Diabetes Mellitus, Type 2/epidemiology/prevention &amp; control</keyword><keyword>Fatty Acids, Nonesterified/*blood/*pharmacology</keyword><keyword>Humans</keyword><keyword>Insulin/blood/*secretion</keyword><keyword>Prediabetic State/blood</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1534-4827 (Print) 1534-4827 (Linking)</isbn><accession-num>15929861</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15929861</url></related-urls></urls></record></Cite></EndNote>11. Yet, short-term (hours) exposure at the physiological concentration of FFA augments GSIS independent of K+ATP channel PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb21hdHN1PC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48
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ADDIN EN.CITE.DATA 12, 13. An agonist of GPR40, the membrane receptor for FFA, elevates intracellular Ca2+ levels through activation of phospholipase C and protein kinase D1 and thus resulting in exocytosis on insulin granules ADDIN EN.CITE <EndNote><Cite><Author>Kaku</Author><Year>2013</Year><RecNum>204</RecNum><DisplayText>14</DisplayText><record><rec-number>204</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>204</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Kaku, K.</author><author>Araki, T.</author><author>Yoshinaka, R.</author></authors></contributors><auth-address>Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Okayama, Japan. [email protected]</auth-address><titles><title>Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes</title><secondary-title>Diabetes Care</secondary-title><alt-title>Diabetes care</alt-title></titles><periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></periodical><alt-periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></alt-periodical><pages>245-50</pages><volume>36</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Asian Continental Ancestry Group</keyword><keyword>Benzofurans/adverse effects/*therapeutic use</keyword><keyword>Diabetes Mellitus, Type 2/*drug therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Receptors, G-Protein-Coupled/*antagonists &amp; inhibitors</keyword><keyword>Sulfones/adverse effects/*therapeutic use</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1935-5548 (Electronic) 0149-5992 (Linking)</isbn><accession-num>23086138</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23086138</url></related-urls></urls><custom2>3554318</custom2><electronic-resource-num>10.2337/dc12-0872</electronic-resource-num></record></Cite></EndNote>14.
Parasympathetic Nerves and Neuropeptides: Neuroendocrine regulation of insulin secretion has been proposed, however, the molecular insights are still emerging. Preliminary activation of the parasympathetic nervous system in response to food enhances cephalic phase of insulin secretion. Here, acetylcholine binds to the cholinergic muscarinic receptors on islet cells leading to hydrolysis of phospholipids, accumulation of cellular inositol 1, 4, 5-triphosphate thereby activating PKC, resulting in enhanced GSIS ADDIN EN.CITE <EndNote><Cite><Author>Gilon</Author><Year>2001</Year><RecNum>206</RecNum><DisplayText>15</DisplayText><record><rec-number>206</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>206</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Gilon, P.</author><author>Henquin, J. C.</author></authors></contributors><auth-address>Unite d&apos;Endocrinologie et Metabolisme, University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium. [email protected]</auth-address><titles><title>Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function</title><secondary-title>Endocr Rev</secondary-title><alt-title>Endocrine reviews</alt-title></titles><periodical><full-title>Endocr Rev</full-title><abbr-1>Endocrine reviews</abbr-1></periodical><alt-periodical><full-title>Endocr Rev</full-title><abbr-1>Endocrine reviews</abbr-1></alt-periodical><pages>565-604</pages><volume>22</volume><number>5</number><keywords><keyword>Acetylcholine/pharmacology</keyword><keyword>Animals</keyword><keyword>Cholinergic Fibers/*physiology</keyword><keyword>Humans</keyword><keyword>Insulin/secretion</keyword><keyword>Islets of Langerhans/drug effects/innervation/*physiology</keyword><keyword>Parasympathetic Nervous System/physiology</keyword><keyword>Sympathetic Nervous System/physiology</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0163-769X (Print) 0163-769X (Linking)</isbn><accession-num>11588141</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11588141</url></related-urls></urls><electronic-resource-num>10.1210/edrv.22.5.0440</electronic-resource-num></record></Cite></EndNote>15. Similarly, pituitary adenylate cyclase-activating polypeptide (PACAP) and ?-adrenoceptors, also enhances insulin secretion at the picomolar range by increasing cellular cAMP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYWRhPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 16. Interestingly, the mechanism is shunted during fasting or under low plasma glucose state. Conversely, during stress, sympathetic nervous system suppresses insulin secretion by increasing noradrenaline. Noradrenaline binds to the ?2-adrenergic receptor and activates the heterotrimeric G protein which activates the K+ ATP channels resulting in inhibition of Ca2+ channel and insulin secretion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFvPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 17. Also, Somatostatin, secreted from pancreatic ?-cells, suppresses insulin secretion by binding to the specific heterotrimeric G protein-coupled receptor.
Thus, insulin secretion is a complex multifactorial event that is finely tuned by a variety of stimulatory and inhibitory signals produced in response to nutrients, hormones and neural inputs (Figure 1.1).
Insulin signalling:
Insulin signalling triggers the uptake of glucose, fatty acids, and amino acids into the liver, adipose and skeletal muscle promoting storage of these nutrients. Insulin signalling is triggered by binding of insulin to the extracellular domains on insulin receptor (Figure 1.2). The insulin receptor is composed of two extracellular domains: two alpha subunits (?-subunits) and two Beta transmembrane subunits (?-subunits). Binding of insulin to the ?-subunits of insulin receptor induces a conformational change which leads to activation of the kinase activity in the ?-subunits resulting in trans-phosphorylation between ?-subunits that allows the recruitment and activation of insulin receptor substrate (IRS) proteins, subsequently. Activated receptor phosphorylates IRS at multiple tyrosine residues that form binding sites for intracellular molecules that contain Src-homology2 (SH2) domains such as PI3-kinase (PI3K). PI3K, by two SH2 domains in its regulatory subunits, binds to the phospho-tyrosine sites on IRS leading to the activation of its catalytic subunit, which then rapidly phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to the lipid second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3) at the plasma membrane.

Membrane-bound activated PIP3 recruits and activates PDK-1 (3-phosphoinositide-dependent protein kinase 1) that acts as the major upstream kinase responsible for the phosphorylation and activation of the downstream AGC kinases. PDK1 phosphorylates and activates the crucial insulin responsive AGC protein kinase Akt, at Thr308 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGVzc2k8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 19, 20.

Insulin signalling through Akt:
Based on numerous clinical and biochemical studies, it is clear that Akt signalling plays a central role in insulin-stimulated glucose uptake in both skeletal muscle and adipose while inhibiting hepatic glucose output from the liver. Insulin activated Akt phosphorylates a number of downstream substrates at Ser/Thr residues which carry out a wide variety of functions such as glucose absorption and its utilization, as well as the synthesis of glycogen, protein, and lipid in response to insulin. Apart from Akt, the role of atypical PKCs and SH2 domain proteins such as Grb2 and Shc in mediating the action of insulin are also well reported and are discussed in brief later.

Role of Akt in transcription & Lipid biosynthesis: The Forkhead box O (Foxo) family are transcription factors that control the expression of lipogenic and gluconeogenic genes. Akt blocks the transcriptional activity of FoxO protein by phosphorylating it at several sites which provides docking sites for the binding 14-3-3 family of proteins, thereby excluding FoxO from the nucleus ADDIN EN.CITE <EndNote><Cite><Author>Tzivion</Author><Year>2011</Year><RecNum>216</RecNum><DisplayText>21</DisplayText><record><rec-number>216</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>216</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Tzivion, G.</author><author>Dobson, M.</author><author>Ramakrishnan, G.</author></authors></contributors><auth-address>Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS 39216, USA. [email protected]</auth-address><titles><title>FoxO transcription factors; Regulation by AKT and 14-3-3 proteins</title><secondary-title>Biochim Biophys Acta</secondary-title><alt-title>Biochimica et biophysica acta</alt-title></titles><periodical><full-title>Biochim Biophys Acta</full-title><abbr-1>Biochimica et biophysica acta</abbr-1></periodical><alt-periodical><full-title>Biochim Biophys Acta</full-title><abbr-1>Biochimica et biophysica acta</abbr-1></alt-periodical><pages>1938-45</pages><volume>1813</volume><number>11</number><keywords><keyword>14-3-3 Proteins/*metabolism</keyword><keyword>Animals</keyword><keyword>Forkhead Box Protein O1</keyword><keyword>Forkhead Box Protein O3</keyword><keyword>Forkhead Transcription Factors/*metabolism</keyword><keyword>Humans</keyword><keyword>Protein Binding</keyword><keyword>Proto-Oncogene Proteins c-akt/*metabolism</keyword><keyword>Proto-Oncogene Proteins c-mdm2/metabolism</keyword><keyword>Transcription Factors/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0006-3002 (Print) 0006-3002 (Linking)</isbn><accession-num>21708191</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21708191</url></related-urls></urls><electronic-resource-num>10.1016/j.bbamcr.2011.06.002</electronic-resource-num></record></Cite></EndNote>21. Further, Akt-dependent phosphorylation of PGC-1? impairs its ability to promote gluconeogenesis and fatty acid oxidation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 24 .
Role of Akt in glucose uptake: The impact of Akt in augmenting glucose uptake from peripheral circulation has been studied in all insulin-sensitive organs: Liver, Muscle, and Adipose. It is well established that glucose absorption from circulation is mediated by GLUT4 (Glucose Transporter 4). Among the three Akt isoforms, Akt2 is primarily involved in insulin-stimulated GLUT4 translocation. Preliminary studies suggest that the GTPase-activating protein Akt substrate of 160 kDa (AS160), also called TBC1D4 (TBC1 Domain Family Member 4), and its homolog TBC1D1, which are substrates of Akt are directly involved in regulating GLUT4 translocation in insulin and contraction-mediated glucose uptake PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW5vPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 25-28. Upon insulin stimulus, Akt phosphorylates and deactivates AS160 resulting in translocation of GLUT4 to the periphery by reducing the “tethering” of the vesicle, by proteins called TUG and also by increasing the activity of Rab proteins which stimulates the translocation of these vesicles containing GLUT4 to the periphery ADDIN EN.CITE <EndNote><Cite><Author>Leney</Author><Year>2009</Year><RecNum>208</RecNum><DisplayText>29</DisplayText><record><rec-number>208</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>208</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Leney, S. E.</author><author>Tavare, J. M.</author></authors></contributors><auth-address>Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.</auth-address><titles><title>The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets</title><secondary-title>J Endocrinol</secondary-title><alt-title>The Journal of endocrinology</alt-title></titles><periodical><full-title>J Endocrinol</full-title><abbr-1>The Journal of endocrinology</abbr-1></periodical><alt-periodical><full-title>J Endocrinol</full-title><abbr-1>The Journal of endocrinology</abbr-1></alt-periodical><pages>1-18</pages><volume>203</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Cell Membrane/metabolism</keyword><keyword>Diabetes Mellitus/drug therapy/metabolism</keyword><keyword>Glucose/*metabolism</keyword><keyword>Glucose Transporter Type 4/*metabolism</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/*metabolism</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1479-6805 (Electronic) 0022-0795 (Linking)</isbn><accession-num>19389739</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19389739</url></related-urls></urls><electronic-resource-num>10.1677/JOE-09-0037</electronic-resource-num></record></Cite></EndNote>29.
Role of Akt in protein synthesis: Apart from regulating metabolism, insulin also plays a dominant role in promoting cellular proliferation. Hence it was speculated that Akt can regulate the protein translational machinery activity, most energy consuming biosynthetic machinery of the cell. One of the key regulators of transcriptional, translational, and post-translational mechanisms activated downstream of PI3K is the protein kinase complex, the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 consists of the core subunits mTOR, a regulatory-associated protein of mTOR (Raptor), and mammalian lethal with SEC13 protein 8 (mLST8), plus two endogenous inhibitors of the complex, 40kDa Proline-rich Akt substrate (PRAS40) and DEP domain-containing mTOR-interacting protein (DEPTOR) ADDIN EN.CITE <EndNote><Cite><Author>Laplante</Author><Year>2012</Year><RecNum>210</RecNum><DisplayText>30</DisplayText><record><rec-number>210</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>210</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Laplante, M.</author><author>Sabatini, D. M.</author></authors></contributors><auth-address>Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.</auth-address><titles><title>mTOR signaling in growth control and disease</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>274-93</pages><volume>149</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Metabolic Diseases/metabolism</keyword><keyword>Neoplasms/metabolism</keyword><keyword>Neurodegenerative Diseases/metabolism</keyword><keyword>*Signal Transduction</keyword><keyword>Stem Cells/metabolism</keyword><keyword>TOR Serine-Threonine Kinases/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr 13</date></pub-dates></dates><isbn>1097-4172 (Electronic) 0092-8674 (Linking)</isbn><accession-num>22500797</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22500797</url></related-urls></urls><custom2>3331679</custom2><electronic-resource-num>10.1016/j.cell.2012.03.017</electronic-resource-num></record></Cite></EndNote>30. It is proposed that Akt inhibits the TSC (Tuberous sclerosis proteins) complex, the specific GAP for the small GTPase Rheb, through multi-site phosphorylation of the TSC2 subunit which relieves inhibition of Rheb, allowing it to become activate and stimulate mTORC1 kinase activity. Once mTORC1 is activated by RHEB, the simultaneous phosphorylation of its inhibitory subunit PRAS40 by Akt and mTORC1 itself causes PRAS40 to dissociate from mTORC1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWJibGU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 31. Mechanistically, mTORC1 complex upon activation phosphorylates 4E-binding protein 1 (4E-BP1) which hampers its interaction with eIF4E (Eukaryotic translation initiation factor 4E) resulting in enhanced eIF4E driven cap-dependent translation. In addition, the mTORC1 complex also activates ribosomal protein S6 kinases S6K1 and S6K2 that phosphorylates ribosomal S6 protein and eIF4B to regulate cap-independent protein biosynthesis.

Negative regulators of insulin signalling:
Intensity and duration of the signal play an important role in determining the specificity of the response. Uncontrolled signalling of insulin lead to severe perturbations in metabolism and often associated with tumorigenesis, hence, the ability to turn off the insulin signal in a rapid manner at different levels is critical. On the other hand, some of these inhibitory mechanisms can be altered in pathophysiological conditions to ameliorate insulin resistance.

Phosphoprotein Phosphatases:
Protein tyrosine phosphatases:
Protein tyrosine phosphatases like protein-tyrosine phosphatase 1B (PTP1B) and leukocyte common antigen-related protein tyrosine phosphatase (LAR) have known to dephosphorylate the tyrosine residues on activated insulin receptor and IGF-1 receptor, as well as IRS proteins, thereby reducing their activity ADDIN EN.CITE <EndNote><Cite><Author>Goldstein</Author><Year>1998</Year><RecNum>250</RecNum><DisplayText>32</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>250</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Goldstein, B. J.</author><author>Ahmad, F.</author><author>Ding, W.</author><author>Li, P. M.</author><author>Zhang, W. R.</author></authors></contributors><auth-address>Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA.</auth-address><titles><title>Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases</title><secondary-title>Mol Cell Biochem</secondary-title><alt-title>Molecular and cellular biochemistry</alt-title></titles><periodical><full-title>Mol Cell Biochem</full-title><abbr-1>Molecular and cellular biochemistry</abbr-1></periodical><alt-periodical><full-title>Mol Cell Biochem</full-title><abbr-1>Molecular and cellular biochemistry</abbr-1></alt-periodical><pages>91-9</pages><volume>182</volume><number>1-2</number><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Insulin/*physiology</keyword><keyword>Protein Tyrosine Phosphatases/*physiology</keyword><keyword>Signal Transduction/drug effects/*physiology</keyword><keyword>Subcellular Fractions/enzymology/physiology</keyword></keywords><dates><year>1998</year><pub-dates><date>May</date></pub-dates></dates><isbn>0300-8177 (Print) 0300-8177 (Linking)</isbn><accession-num>9609118</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9609118</url></related-urls></urls></record></Cite></EndNote>32. LAR belongs to a subfamily of receptor PTPs. Till date the role of LAR in regulating insulin signalling under normal conditions in vivo is still unclear, however selective overexpression of LAR in the muscle of transgenic mice, to levels comparable to those reported in insulin-resistant human, resulted in whole-body insulin resistance with decreased IRS?2 phosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWJvbG90bnk8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFy
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ADDIN EN.CITE.DATA 41, 42. The overexpression of PTP1B in muscle impaired insulin sensitivity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWJvbG90bnk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWJvbG90bnk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy
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ADDIN EN.CITE.DATA 43, consistently, mice lacking the PTP1B gene showed enhanced insulin sensitivity, increased insulin receptor phosphorylation in muscle and liver, and were resistant to high fat-diet-induced obesity and insulin resistance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGNoZWJseTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA 45-47.

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ADDIN EN.CITE.DATA 48, 49. Hence, to determine that the enhanced insulin sensitivity in PTP1B–/– mice are due to the direct effect on insulin receptor signalling not because of indirect effects resulting from leanness, homozygous PTP1B–/– mice were crossed with mice with a double heterozygous deficiency of insulin receptor and IRS-1 alleles (DHet). PTP1B deficiency reduces the severe hyperinsulinemia, insulin resistance, hyperglycemia, and ?-cell hypertrophy in DHet mice without affecting their body weight.

TCPTP (T-cell protein tyrosine phosphatase) is another ubiquitously expressed tyrosine-specific phosphatase with two splice variants TC48, having a catalytic domain similar to PTP1B and TC45 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxpYzwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 36. Despite the high degree of sequence identity in the catalytic domain, PTP1B and TCPTP are non-redundant in nature and act in a temporally distinct manner to cooperatively regulate insulin receptor phosphorylation and signalling in the same cell. The insulin receptor is reported as a cellular substrate of TCPTP and activation and signalling through insulin receptor is enhanced in TCPTP ablated cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxpYzwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 50. TCPTP?/? immortalized mouse embryo fibroblasts (MEFs) showed an elevated or prolonged insulin receptor phosphorylation and PI3K/Akt signalling compared to TCPTP+/+ or TCPTP (TC45 or TC48) reconstituted MEFs. Insulin receptor ?-subunit phosphorylation at Y1162/Y1163 and Y972 both are elevated in PTP1B?/? MEFs, whereas Y972 phosphorylation was elevated and Y1162/Y1163 phosphorylation was sustained in TCPTP?/? MEFs, indicating that PTP1B and TCPTP differentially contribute to the regulation of insulin receptor phosphorylation and signalling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxpYzwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 36. Further, elevated Akt signalling was reported in human hepatoma HepG2 cells upon suppression of TCPTP protein levels and inactivation of reactive oxygen species produced in response to insulin has been shown by TC45, similar to PTP1B ADDIN EN.CITE <EndNote><Cite><Author>Meng</Author><Year>2004</Year><RecNum>272</RecNum><DisplayText>51</DisplayText><record><rec-number>272</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>272</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meng, T. C.</author><author>Buckley, D. A.</author><author>Galic, S.</author><author>Tiganis, T.</author><author>Tonks, N. K.</author></authors></contributors><auth-address>Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.</auth-address><titles><title>Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>37716-25</pages><volume>279</volume><number>36</number><keywords><keyword>Animals</keyword><keyword>Base Sequence</keyword><keyword>DNA Primers</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/pharmacology</keyword><keyword>Insulin/*metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Phosphorylation</keyword><keyword>Protein Tyrosine Phosphatase, Non-Receptor Type 1</keyword><keyword>Protein Tyrosine Phosphatase, Non-Receptor Type 2</keyword><keyword>Protein Tyrosine Phosphatases/*metabolism</keyword><keyword>Rats</keyword><keyword>*Signal Transduction/drug effects</keyword></keywords><dates><year>2004</year><pub-dates><date>Sep 3</date></pub-dates></dates><isbn>0021-9258 (Print) 0021-9258 (Linking)</isbn><accession-num>15192089</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15192089</url></related-urls></urls><electronic-resource-num>10.1074/jbc.M404606200</electronic-resource-num></record></Cite></EndNote>51.

Serine/threonine phosphatases:
Phosphorylations at the Serine/threonine residues play an important in the metabolic actions of insulin. Serine/threonine phosphorylation of either the insulin receptor or IRS proteins acts to limit the insulin signalling while, it maintains the downstream proteins like serine/threonine kinases Akt and protein kinase C ? (PKC ?) in an active state PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3BwczwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 52. However, the phosphatases that catalyse corresponding dephosphorylation events have not been well identified. The role of serine-threonine phosphatases, such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), has not been fully elucidated. PP1-? is recently reported to dephosphorylate Akt substrate of 160 kDa (AS160) at Ser588 and Thr642 two key sites that control insulin-stimulated glucose transport in skeletal muscle PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFybWE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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However, the most studied serine/threonine phosphatase controlling the action of insulin is Protein phosphatase 2A (PP2A). Accounting for about 80% of serine/threonine phosphatase activity in cells, it regulates the activity of some of the key mediators of insulin action such as Akt, PKC, S6K, ERK, and IKK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsd2FyZDwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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AG==
ADDIN EN.CITE.DATA 54. Inhibition of PP2A by okadaic acid activates glucose transport and GLUT4 translocation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWc8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWc8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 55. Indeed, PP2A is reported to directly dephosphorylate and inactivate both Akt and PKC ?, leading to the attenuation of glucose transport in 3T3-L1 adipocytes. Forced expression of small t-antigen that inhibits the association of PP2A with its substrate, in 3T3-L1 adipocytes enhanced the activity of Akt and protein kinase C ? (PKC ?) independent of wortmannin and upregulated basal as well as insulin-stimulated glucose uptake, which was inhibited upon expression of dominant negative Akt (DN-Akt) but not DN-PKC ? expression.
Other serine/threonine phosphatases were also implicated in interfering with insulin action. Protein phosphatases 2B (PP2B), also known as calcineurin, has been shown to dephosphorylate Akt. Overexpression of constitutively active calcineurin triggered a significant decreased Akt phosphorylation, while overexpression of MCIP1.4, an endogenous inhibitor of calcineurin, had the opposite effect PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 58, 59. (Detailed description of the inhibitory role of PHLPP in insulin action is described in the section 1.7.4).

Lipid Phosphatases:
Lipid phosphatases like PTEN and SHIP regulate insulin signalling by modulating PIP3 levels. PTEN (phosphatase and tensin homolog deleted on chromosome 10) was identified in a search for tumour suppressors on chromosome 10q23, a hot spot for loss of heterozygosity in many advanced-stage human tumours. It possesses both protein and lipid phosphatase activity. The lipid phosphatase activity attributes to its tumour suppressor role, while the protein phosphatase activity is intra-molecular and regulatory in nature ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2012</Year><RecNum>276</RecNum><DisplayText>60</DisplayText><record><rec-number>276</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>276</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Zhang, X. C.</author><author>Piccini, A.</author><author>Myers, M. P.</author><author>Van Aelst, L.</author><author>Tonks, N. K.</author></authors></contributors><auth-address>Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.</auth-address><titles><title>Functional analysis of the protein phosphatase activity of PTEN</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>457-64</pages><volume>444</volume><number>3</number><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Animals, Newborn</keyword><keyword>Dendritic Spines/*enzymology/ultrastructure</keyword><keyword>Enzyme Activation/physiology</keyword><keyword>Hippocampus/*enzymology/ultrastructure</keyword><keyword>Molecular Sequence Data</keyword><keyword>Organ Culture Techniques</keyword><keyword>PTEN Phosphohydrolase/biosynthesis/genetics/*physiology</keyword><keyword>Phosphoprotein Phosphatases/biosynthesis/genetics/physiology</keyword><keyword>Rats</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>1470-8728 (Electronic) 0264-6021 (Linking)</isbn><accession-num>22413754</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22413754</url></related-urls></urls><custom2>3365644</custom2><electronic-resource-num>10.1042/BJ20120098</electronic-resource-num></record></Cite></EndNote>60. PTEN functions in the cell as a phosphatidylinositol 3-phosphatase that dephosphorylates D3 phosphate of the inositol ring of PI(3,4,5)P3 (PIP3) to produce phosphatidylinositol 4,5-bisphosphate PI(4,5)P2 (PIP2) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NeWVyczwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 61. The link between the PI3K pathway and PTEN was paved by the finding that deletion of Pten in mouse embryonic fibroblasts (MEFs) activated AKT and elevated intracellular PIP3 levels PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFtYm9saWM8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFy
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ADDIN EN.CITE.DATA 62. In addition, the reintroduction of PTEN in mutant PTEN tumour cell lines lowered Akt phosphorylation and cell death that could be rescued by myristoylated Akt, and inactivation of Pten in mice led to tumours with increased AKT phosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdXp1a2k8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 65-67 and mice with whole-body PTEN haploinsufficiency, (as Pten deletion in mice is embryonic lethal), show improved glucose tolerance and increased insulin sensitivity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 69, as the expression of SHIP1 is limited to hematopoietic and lymphoid cells. Involvement of SHIP2 in impeding insulin action was anticipated as mutations in the SHIP2 gene, INPPL1, show genetic susceptibility of rats and human to type 2 diabetes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJpb248L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 70. Depletion of SHIP2 using antisense oligonucleotides improved the muscle insulin sensitivity in a diet-induced metabolic syndrome rat model PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdWV0dG5lcjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+
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ADDIN EN.CITE.DATA 72. Conversely, SHIP2-overexpressing mice show reduced insulin-induced Akt activation in the liver, fat, and skeletal muscle PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWdhd2E8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 73 (Kagawa et al. 2008) and impaired neuroprotective effects of insulin in the brain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2VkYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 74.

Adaptor Proteins:
The cytoplasmic adaptor proteins like Grb10 and Grb14 bind to the insulin receptor and to a lesser extent IGF-1receptor to prevent access of substrates to the activated receptors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2x0PC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 78. Similar to GRB10, Grb14 knockout mice display increased glucose tolerance and insulin sensitivity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29uZXk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29uZXk8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 79 and enhanced expression of Grb14 was noted in adipose tissue of insulin resistant animal models and type 2 diabetic (T2D) patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJpb3U8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 80. The suppressor of cytokine signalling (SOCS) adaptor proteins, SOCS1 and SOCS3, also negatively regulate insulin signalling by either inhibiting the kinase activity of the insulin receptor or competing with the IRS proteins to bind to the receptor or by degrading the IRS proteins PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbWFudWVsbGk8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFy
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ADDIN EN.CITE.DATA 81-83. Elevated expression of both SOCS1 and SOCS3 are also noted in obese subjects.

Tribbles homolog 3 (Trb3), a mammalian homolog of Drosophila tribbles, is a member of the family of pseudo-kinases that act as adaptor proteins and disrupts insulin signalling by binding directly to Akt and blocking activation of the kinase. Trb3 is an ER stress-inducible gene which is expressed in multiple tissues with strikingly different metabolic functions. In liver, elevated expression of Trb3 is detected upon fasting and in diabetic conditions. Ectopic expression of Trb3 in liver results in hyperglycemia, decreased glycogen content and impaired glucose tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 84, while knockdown of Trb3 in mouse liver by RNAi improves glucose tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb288L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 85. In Type 2 diabetic mice and humans the expression of Trb3 in pancreatic ?-cells is elevated which correlates with the inhibition of glucose-stimulated insulin secretion and impaired glucose homeostasis displayed by the pancreas specific Trb3 overexpressing mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaWV3PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 87. However, in adipose tissue Trb3 functions independent of Akt and promotes lipolysis by triggering the ubiquitination and degradation of acetyl-CoA carboxylase. Transgenic mice expressing Trb3 in adipose tissue are protected from diet-induced obesity because of enhanced fatty acid oxidation and exhibited increased insulin sensitivity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5RaTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 88.

Another novel negative regulator of Akt activity is inositol pyrophosphate IP7, (diphosphoinositol pentakisphosphate 5-PP-1(1,2,3,4,6)IP5). Insulin and IGF-1 induce the expression of IP7 which inhibits Akt T308 phosphorylation and membrane translocation and subsequent activation of insulin signalling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFrcmFib3J0eTwvQXV0aG9yPjxZZWFyPjIwMTA8L1ll
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ADDIN EN.CITE.DATA 89. Loss of the enzyme IP6K1 involved in IP7 formation improved insulin responsiveness in mice.

Inhibitory Ser/Thr phosphorylation:
To propagate signalling, insulin requires tyrosine phosphorylation of insulin receptor/IGF-1receptor and IRS proteins, while serine and threonine phosphorylation turns the signalling off. The suppressed tyrosine kinase activity of insulin receptor is linked to its enhance Ser phosphorylation in insulin-resistant rodents and human PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJhc2lrPC9BdXRob3I+PFllYXI+MTk5MDwvWWVhcj48
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ADDIN EN.CITE.DATA 90-92. However, Ser/Thr phosphorylation of IRS proteins has a dual function. Although multiple inhibitory Ser phosphorylation sites have been detected on IRS1 protein ADDIN EN.CITE <EndNote><Cite><Author>Boura-Halfon</Author><Year>2009</Year><RecNum>310</RecNum><DisplayText>93</DisplayText><record><rec-number>310</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>310</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Boura-Halfon, S.</author><author>Zick, Y.</author></authors></contributors><auth-address>Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100 Israel.</auth-address><titles><title>Phosphorylation of IRS proteins, insulin action, and insulin resistance</title><secondary-title>Am J Physiol Endocrinol Metab</secondary-title><alt-title>American journal of physiology. Endocrinology and metabolism</alt-title></titles><periodical><full-title>Am J Physiol Endocrinol Metab</full-title><abbr-1>American journal of physiology. Endocrinology and metabolism</abbr-1></periodical><alt-periodical><full-title>Am J Physiol Endocrinol Metab</full-title><abbr-1>American journal of physiology. Endocrinology and metabolism</abbr-1></alt-periodical><pages>E581-91</pages><volume>296</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Insulin/metabolism/*physiology</keyword><keyword>Insulin Receptor Substrate Proteins/*metabolism/physiology</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Models, Biological</keyword><keyword>Phosphorylation/physiology</keyword><keyword>Protein-Serine-Threonine Kinases/metabolism/physiology</keyword><keyword>Receptor, Insulin/metabolism</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0193-1849 (Print) 0193-1849 (Linking)</isbn><accession-num>18728222</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18728222</url></related-urls></urls><electronic-resource-num>10.1152/ajpendo.90437.2008</electronic-resource-num></record></Cite></EndNote>93, modifications at Ser-307 is widely studied PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ3VpcnJlPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA 94. Phosphorylation at Ser-307 residues within the P-Tyr-binding (PTB) domain of IRS-1 by insulin-stimulated Akt protects IRS proteins from the rapid dephosphorylation and maintains IRS in Tyr phosphorylated active conformation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXo8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 95, 101. The potential candidate for the negative feedback loop in insulin signalling is the mTORC1-S6K pathway which enhances phosphorylation of Ser residues at the C-terminus of IRS-1 leading to inhibition of insulin-stimulated Tyr phosphorylation of IRS-1 and its ability to bind to PI3K PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 105, while constitutive activation of S6K in TSC-2 knockout fibroblasts resulted in hyper phosphorylation and degradation of IRS-1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJyaW5ndG9uPC9BdXRob3I+PFllYXI+MjAwNDwvWWVh
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ADDIN EN.CITE.DATA 106. In addition, mTORC1 also phosphorylates and stabilizes Grb10, leading to feedback inhibition of insulin signalling PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ic3U8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 111-113. Atypical PKC-? also inhibits insulin signalling by inducing serine phosphorylation of IRS-1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXZpY2hhbmRyYW48L0F1dGhvcj48WWVhcj4yMDAxPC9Z
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ADDIN EN.CITE.DATA 115.
In brief, insulin signalling controls glucose and lipid metabolism, predominantly via action on insulin-sensitive tissues like liver, skeletal muscle, and adipose tissue. Precise regulation of this signalling cascade is important for apt adaption of energy homeostasis. Insulin signalling contains several critical nodes, controlled both positively and negatively, to ascertain appropriate signal duration as well as intensity (Figure 1.3). Several nodes in the insulin signalling cascade are negatively controlled by the action of phosphatases and/or inhibitory proteins. Perturbations in these signalling pathways can lead to insulin resistance. Based on numerous studies, supported by cell-based, animal models as well as clinical observations, the causes of insulin resistance are numerous and the mechanisms are multifactorial. Below, we discuss different drivers which lead to deregulation of gene and inhibitory protein modifications resulting in impaired insulin action.

Insulin resistance and its drivers:
Insulin resistance (IR) is the hallmark feature of most patients with Type 2 diabetes mellitus (T2D) and is attributed to the sub-optimal response of the body to insulin. Clinically, the term “insulin resistance” implies to elevated levels of insulin (hyperinsulinemia) which is required to maintain normoglycemia. At the molecular level of the cell, IR is defined as the inadequate transmission of insulin signalling from the insulin receptor to the downstream substrates involved in several metabolic and mitogenic cellular functions ADDIN EN.CITE <EndNote><Cite><Author>Ginsberg</Author><Year>2000</Year><RecNum>211</RecNum><DisplayText>116</DisplayText><record><rec-number>211</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>211</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ginsberg, H. N.</author></authors></contributors><auth-address>Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA. [email protected]</auth-address><titles><title>Insulin resistance and cardiovascular disease</title><secondary-title>J Clin Invest</secondary-title><alt-title>The Journal of clinical investigation</alt-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><alt-periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></alt-periodical><pages>453-8</pages><volume>106</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Arteriosclerosis/etiology/physiopathology</keyword><keyword>Blood Coagulation/physiology</keyword><keyword>Cardiovascular Diseases/*etiology/physiopathology</keyword><keyword>Fatty Acids/metabolism</keyword><keyword>Humans</keyword><keyword>Hyperlipidemias/etiology/physiopathology</keyword><keyword>Hypertension/etiology/physiopathology</keyword><keyword>Insulin/blood</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Lipoproteins, VLDL/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Triglycerides/metabolism</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-9738 (Print) 0021-9738 (Linking)</isbn><accession-num>10953019</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/10953019</url></related-urls></urls><custom2>380256</custom2><electronic-resource-num>10.1172/JCI10762</electronic-resource-num></record></Cite></EndNote>116. In fact, the pathogenesis of type 2 diabetes involves abnormalities in both insulin action as well as secretion ADDIN EN.CITE <EndNote><Cite><Author>Saltiel</Author><Year>2001</Year><RecNum>212</RecNum><DisplayText>117</DisplayText><record><rec-number>212</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>212</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Saltiel, A. R.</author></authors></contributors><auth-address>Department of Medicine, Life Sciences Institute, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.</auth-address><titles><title>New perspectives into the molecular pathogenesis and treatment of type 2 diabetes</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>517-29</pages><volume>104</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Diabetes Mellitus, Type 2/*etiology/genetics/*metabolism/physiopathology/*therapy</keyword><keyword>Glycogen/biosynthesis</keyword><keyword>Humans</keyword><keyword>Insulin/metabolism</keyword><keyword>Insulin Resistance</keyword><keyword>Islets of Langerhans/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Obesity</keyword><keyword>Protein-Tyrosine Kinases/metabolism</keyword><keyword>Receptor, Insulin/metabolism</keyword><keyword>Receptors, Cytoplasmic and Nuclear/metabolism</keyword><keyword>Signal Transduction</keyword><keyword>Transcription Factors/metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Feb 23</date></pub-dates></dates><isbn>0092-8674 (Print) 0092-8674 (Linking)</isbn><accession-num>11239409</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11239409</url></related-urls></urls></record></Cite></EndNote>117. Based on numerous clinical, pre-clinical and cellular studies, several genetic and environmental factors are directly linked to the pathogenesis of IR (Figure 1.4). Some of these factors are discussed in brief below.
1.4.1.Genetic causes of insulin resistance:
A genetic point of view of IR is thought of due to the inheritance of a number of mutations in a variety of genes. Three complementary approaches have been applied in the search for mutations: mutational analysis of candidate genes; linkage analysis of candidate genes or chromosomal regions for IR in familial T2D; and random genome mapping with quantitative trait loci (QTL) analysis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaWxsaW9qYTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 119, 120. Few of the mutations /genetic alterations which are studied in detail are listed here.

Nonsense or missense mutations in the extracellular ligand-binding domain or intracellular tyrosine kinase domain of the insulin receptor that leads to severely reduced insulin binding, altered kinetics of insulin binding, or reduced tyrosine kinase activity, or promoter defects leading to reduced receptor mRNA expression are detected in leprechaunism, Rabson-Mendenhall syndrome, or the type-A syndrome of IR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWhuPC9BdXRob3I+PFllYXI+MTk3NjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 121, 122 . On the other hand polymorphism of IRS-1 like G972R PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbG1pbmQ8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 126. On the contrary, polymorphisms in the PTEN gene, leading to enhanced activity of the enzyme, resulted in reduced insulin-induced Akt activation in three Japanese type-2 diabetic subjects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc2hpaGFyYTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jc2hpaGFyYTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA 127. Interestingly, individuals with PTEN haploinsufficiency are obese as well as insulin sensitive, with a decreased risk of T2D but increased risk of cancer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWw8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 128. A gain-of-function mutation (Q84R) in Trb3, a pseudo-kinase which hampers Akt activity, decreases insulin-stimulated Akt phosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcnVkZW50ZTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA 131.
Considerable recent progress has been made in the identification of the loci associated with inheritance of IR. However, further work is required to decipher the functional relationship between these genetic variants and insulin action. Identification and validation of these loci will aid to translate this knowledge into clinical practice and help in the management of pathology related to IR.
1.4.2.Environmental causes of insulin resistance:
Identification of genetic markers has generated several hypotheses regarding genetics and insulin action but is unable to explain the significant portion of complications associated with T2D. Numerous environmental factors like unhealthy food, barriers to physical activity, stress and social isolation are some of the factors that act as unexplained drivers in the development of T2D/IR. In fact, Atul Butte and his colleagues designed a pilot study to assess the impact of the environmental factors on IR and noted that there are 266 different factors which can affect the insulin signalling ADDIN EN.CITE <EndNote><Cite><Author>Patel</Author><Year>2010</Year><RecNum>636</RecNum><DisplayText>132</DisplayText><record><rec-number>636</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>636</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Patel, C. J.</author><author>Bhattacharya, J.</author><author>Butte, A. J.</author></authors></contributors><auth-address>Department of Pediatrics and Medicine, Stanford University School of Medicine, Stanford, California, USA.</auth-address><titles><title>An Environment-Wide Association Study (EWAS) on type 2 diabetes mellitus</title><secondary-title>PLoS One</secondary-title><alt-title>PloS one</alt-title></titles><periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></periodical><alt-periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></alt-periodical><pages>e10746</pages><volume>5</volume><number>5</number><keywords><keyword>Carotenoids/blood</keyword><keyword>Cohort Studies</keyword><keyword>Diabetes Mellitus, Type 2/*blood</keyword><keyword>*Environment</keyword><keyword>Genetics, Population</keyword><keyword>Health Surveys</keyword><keyword>Humans</keyword><keyword>Pesticides/blood</keyword><keyword>Polychlorinated Biphenyls/blood</keyword><keyword>Reproducibility of Results</keyword><keyword>gamma-Tocopherol/blood</keyword></keywords><dates><year>2010</year><pub-dates><date>May 20</date></pub-dates></dates><isbn>1932-6203 (Electronic) 1932-6203 (Linking)</isbn><accession-num>20505766</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20505766</url></related-urls></urls><custom2>2873978</custom2><electronic-resource-num>10.1371/journal.pone.0010746</electronic-resource-num></record></Cite></EndNote>132. Some of these physiological parameters that play a central role in developing IR are noted in brief below.

Circadian Rhythm: Almost all physiological responses are synchronised by the day-night rhythm. Circadian asynchrony in humans due to factors such as work in shifts, jet lag, and/or sleep disruption, can have profound effects on both normal body weights as well as on glucose/lipid homeostasis. The influence of the circadian clock on insulin secretion and glucose homeostasis is demonstrated by the periodic regulation of the associated hormones like leptin, glucagon, cortisol, growth hormone, catecholamines, PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXNzPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 133, 134. Another linkage between the physiological clock and IR is revealed by the increased risk of obesity and diabetes due to short sleep duration (due to e.g., insomnia and/or circadian disruption) ADDIN EN.CITE <EndNote><Cite><Author>Knutson</Author><Year>2008</Year><RecNum>641</RecNum><DisplayText>135</DisplayText><record><rec-number>641</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>641</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Knutson, K. L.</author><author>Van Cauter, E.</author></authors></contributors><auth-address>Department of Health Studies, University of Chicago, Chicago, IL 60637, USA.</auth-address><titles><title>Associations between sleep loss and increased risk of obesity and diabetes</title><secondary-title>Ann N Y Acad Sci</secondary-title><alt-title>Annals of the New York Academy of Sciences</alt-title></titles><periodical><full-title>Ann N Y Acad Sci</full-title><abbr-1>Annals of the New York Academy of Sciences</abbr-1></periodical><alt-periodical><full-title>Ann N Y Acad Sci</full-title><abbr-1>Annals of the New York Academy of Sciences</abbr-1></alt-periodical><pages>287-304</pages><volume>1129</volume><keywords><keyword>Appetite/physiology</keyword><keyword>Diabetes Mellitus/*etiology/*physiopathology</keyword><keyword>Glucose/metabolism</keyword><keyword>Humans</keyword><keyword>Obesity/*complications/*physiopathology</keyword><keyword>Risk Factors</keyword><keyword>Sleep Deprivation/*complications/epidemiology/*physiopathology</keyword></keywords><dates><year>2008</year></dates><isbn>0077-8923 (Print) 0077-8923 (Linking)</isbn><accession-num>18591489</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18591489</url></related-urls></urls><custom2>4394987</custom2><electronic-resource-num>10.1196/annals.1417.033</electronic-resource-num></record></Cite></EndNote>135.
Food intake and physical activity: The epidemic of obesity is an unintended biological consequence arising resulting from the imbalance between energy consumed and energy burnt ADDIN EN.CITE <EndNote><Cite><Author>Hill</Author><Year>2006</Year><RecNum>644</RecNum><DisplayText>136</DisplayText><record><rec-number>644</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>644</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Hill, J. O.</author></authors></contributors><auth-address>Center for Human Nutrition, University of Colorado School of Medicine, Denver, Colorado 80262, USA. [email protected]</auth-address><titles><title>Understanding and addressing the epidemic of obesity: an energy balance perspective</title><secondary-title>Endocr Rev</secondary-title><alt-title>Endocrine reviews</alt-title></titles><periodical><full-title>Endocr Rev</full-title><abbr-1>Endocrine reviews</abbr-1></periodical><alt-periodical><full-title>Endocr Rev</full-title><abbr-1>Endocrine reviews</abbr-1></alt-periodical><pages>750-61</pages><volume>27</volume><number>7</number><keywords><keyword>Disease Outbreaks/*prevention &amp; control</keyword><keyword>Energy Metabolism/genetics/*physiology</keyword><keyword>Global Health</keyword><keyword>Humans</keyword><keyword>Motor Activity/physiology</keyword><keyword>Obesity/*epidemiology/genetics/*physiopathology/therapy</keyword><keyword>Social Environment</keyword><keyword>Weight Gain/genetics/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0163-769X (Print) 0163-769X (Linking)</isbn><accession-num>17122359</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17122359</url></related-urls></urls><electronic-resource-num>10.1210/er.2006-0032</electronic-resource-num></record></Cite></EndNote>136. Overeating not only includes the presentation of a large quantity of food but also easy access to food, social acceptance and minimal information about the energy content of the food. Contrary to food availability, physical activity has declined steadily in the last 50 years due to enhanced sedentary activities, thus resulting in burning fewer calories. Thus the imbalance generated due to improper energy burning leads to an alteration in the endocrine systems regulating the energy homeostasis, resulting in IR ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2010</Year><RecNum>645</RecNum><DisplayText>137</DisplayText><record><rec-number>645</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>645</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Kim, S. H.</author><author>Reaven, G.</author></authors></contributors><auth-address>Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [email protected]</auth-address><titles><title>Obesity and insulin resistance: an ongoing saga</title><secondary-title>Diabetes</secondary-title><alt-title>Diabetes</alt-title></titles><periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></periodical><alt-periodical><full-title>Diabetes</full-title><abbr-1>Diabetes</abbr-1></alt-periodical><pages>2105-6</pages><volume>59</volume><number>9</number><keywords><keyword>Adipose Tissue/anatomy &amp; histology</keyword><keyword>Humans</keyword><keyword>Hypertrophy/epidemiology</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Obesity/complications/*epidemiology</keyword><keyword>Obesity, Abdominal/epidemiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1939-327X (Electronic) 0012-1797 (Linking)</isbn><accession-num>20805385</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20805385</url></related-urls></urls><custom2>2927930</custom2><electronic-resource-num>10.2337/db10-0766</electronic-resource-num></record></Cite></EndNote>137.
Endocrine disruptors: Environmental chemicals are known to impair the functioning of the endocrine system associated with human fertility and reproductive toxicity ADDIN EN.CITE <EndNote><Cite><Author>Olea</Author><Year>2007</Year><RecNum>646</RecNum><DisplayText>138</DisplayText><record><rec-number>646</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>646</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Olea, N.</author><author>Fernandez, M. F.</author></authors></contributors><auth-address>Lab Medical Investigations, Hospital S Cecilio-University of Granada, Granada, Spain. [email protected]</auth-address><titles><title>Chemicals in the environment and human male fertility</title><secondary-title>Occup Environ Med</secondary-title><alt-title>Occupational and environmental medicine</alt-title></titles><periodical><full-title>Occup Environ Med</full-title><abbr-1>Occupational and environmental medicine</abbr-1></periodical><alt-periodical><full-title>Occup Environ Med</full-title><abbr-1>Occupational and environmental medicine</abbr-1></alt-periodical><pages>430-1</pages><volume>64</volume><number>7</number><keywords><keyword>Air Pollutants, Occupational/toxicity</keyword><keyword>Endocrine Disruptors/toxicity</keyword><keyword>Environmental Pollution/*adverse effects</keyword><keyword>Humans</keyword><keyword>Infertility, Male/*chemically induced</keyword><keyword>Male</keyword><keyword>Occupational Exposure</keyword><keyword>Sperm Count</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1470-7926 (Electronic) 1351-0711 (Linking)</isbn><accession-num>17582086</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17582086</url></related-urls></urls><custom2>2078473</custom2><electronic-resource-num>10.1136/oem.2007.033621</electronic-resource-num></record></Cite></EndNote>138. Endocrine disruptors are chemically active ingredients includes estrogen receptor agonist biphenol A (BPA (commonly used in plastic water bottles and microwave resistant plastic wear) and androgen receptor agonist phthalates (generally used in PVC water pipes). As a consequence of the alteration in steroid receptor activities, a deregulation in adipocytes differentiation is noted which may alter the insulin sensitivity leading to its resistance ADDIN EN.CITE <EndNote><Cite><Author>Kelishadi</Author><Year>2013</Year><RecNum>672</RecNum><DisplayText>139</DisplayText><record><rec-number>672</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>672</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Kelishadi, R.</author><author>Poursafa, P.</author><author>Jamshidi, F.</author></authors></contributors><auth-address>Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan 81676-36954, Iran.</auth-address><titles><title>Role of environmental chemicals in obesity: a systematic review on the current evidence</title><secondary-title>J Environ Public Health</secondary-title><alt-title>Journal of environmental and public health</alt-title></titles><periodical><full-title>J Environ Public Health</full-title><abbr-1>Journal of environmental and public health</abbr-1></periodical><alt-periodical><full-title>J Environ Public Health</full-title><abbr-1>Journal of environmental and public health</abbr-1></alt-periodical><pages>896789</pages><volume>2013</volume><keywords><keyword>Animals</keyword><keyword>Environmental Pollutants/*toxicity</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Mice</keyword><keyword>Obesity/*chemically induced/epidemiology</keyword><keyword>Prevalence</keyword></keywords><dates><year>2013</year></dates><isbn>1687-9813 (Electronic) 1687-9805 (Linking)</isbn><accession-num>23840234</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23840234</url></related-urls></urls><custom2>3687513</custom2><electronic-resource-num>10.1155/2013/896789</electronic-resource-num></record></Cite></EndNote>139 .
Stress: Stress is the body’s response to a threat, often called the “fight-or-flight” response. In recent years, the roles of chronic stress and/or depression as an independent risk factor for decreased insulin sensitivity and development of diabetes is gaining recognition ADDIN EN.CITE ;EndNote;;Cite;;Author;Kelly;/Author;;Year;2015;/Year;;RecNum;647;/RecNum;;DisplayText;140;/DisplayText;;record;;rec-number;647;/rec-number;;foreign-keys;;key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”;647;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Kelly, S. J.;/author;;author;Ismail, M.;/author;;/authors;;/contributors;;auth-address;Center for Health and Social Care Research, Sheffield Hallam University, Sheffield S10 2BP, United Kingdom; email: [email protected];/auth-address;;titles;;title;Stress and type 2 diabetes: a review of how stress contributes to the development of type 2 diabetes;/title;;secondary-title;Annu Rev Public Health;/secondary-title;;alt-title;Annual review of public health;/alt-title;;/titles;;periodical;;full-title;Annu Rev Public Health;/full-title;;abbr-1;Annual review of public health;/abbr-1;;/periodical;;alt-periodical;;full-title;Annu Rev Public Health;/full-title;;abbr-1;Annual review of public health;/abbr-1;;/alt-periodical;;pages;441-62;/pages;;volume;36;/volume;;keywords;;keyword;Aggression/psychology;/keyword;;keyword;Conflict (Psychology);/keyword;;keyword;Diabetes Mellitus, Type 2/*etiology/psychology</keyword><keyword>Humans</keyword><keyword>Mental Disorders/complications</keyword><keyword>Psychology</keyword><keyword>Risk Factors</keyword><keyword>Socioeconomic Factors</keyword><keyword>Stress, Psychological/*complications</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar 18</date></pub-dates></dates><isbn>1545-2093 (Electronic) 0163-7525 (Linking)</isbn><accession-num>25581145</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/25581145</url></related-urls></urls><electronic-resource-num>10.1146/annurev-publhealth-031914-122921</electronic-resource-num></record></Cite></EndNote>140. However, the underlying mechanisms linking IR and acute psychological stress are very limited. Stress hormones, particularly cortisol, raise blood glucose levels and blood pressure to provide muscle with sufficient energy required for flight or fight response ADDIN EN.CITE <EndNote><Cite><Author>Ayada</Author><Year>2015</Year><RecNum>669</RecNum><DisplayText>141</DisplayText><record><rec-number>669</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>669</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ayada, C.</author><author>Toru, U.</author><author>Korkut, Y.</author></authors></contributors><auth-address>Department of Physiology, Medical Faculty, Dumlupinar University, Kutahya, Turkey. Department of Chest Diseases, Medical Faculty, Dumlupinar University, Kutahya, Turkey. Department of Family Medicine, Medical Faculty, Dumlupinar University, Kutahya, Turkey.</auth-address><titles><title>The relationship of stress and blood pressure effectors</title><secondary-title>Hippokratia</secondary-title><alt-title>Hippokratia</alt-title></titles><periodical><full-title>Hippokratia</full-title><abbr-1>Hippokratia</abbr-1></periodical><alt-periodical><full-title>Hippokratia</full-title><abbr-1>Hippokratia</abbr-1></alt-periodical><pages>99-108</pages><volume>19</volume><number>2</number><dates><year>2015</year><pub-dates><date>Apr-Jun</date></pub-dates></dates><isbn>1108-4189 (Print) 1108-4189 (Linking)</isbn><accession-num>27418756</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/27418756</url></related-urls></urls><custom2>4938117</custom2></record></Cite></EndNote>141. Cortisol also acts on the liver to enhance hepatic glucose output for sustained muscular activity. Interestingly, stress is a life-saving response, but with modern times, chronic stress has emerged as a prime driver for the development of IR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PemNhbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 142.

1.4.3. Molecular causes of insulin resistance:
1.4.3.a. Lipotoxicity/ dyslipidemia:
Lipotoxicity is a pathological condition of ectopic accumulation of lipids, especially fatty acids in non-adipose tissues that causes functional impairments in several metabolic pathways and thus plays a central role in the development of IR as well as pancreatic beta cell dysfunction ADDIN EN.CITE <EndNote><Cite><Author>Biden</Author><Year>2014</Year><RecNum>648</RecNum><DisplayText>143</DisplayText><record><rec-number>648</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>648</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Biden, T. J.</author><author>Boslem, E.</author><author>Chu, K. Y.</author><author>Sue, N.</author></authors></contributors><auth-address>Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. Electronic address: [email protected] Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.</auth-address><titles><title>Lipotoxic endoplasmic reticulum stress, beta cell failure, and type 2 diabetes mellitus</title><secondary-title>Trends Endocrinol Metab</secondary-title><alt-title>Trends in endocrinology and metabolism: TEM</alt-title></titles><periodical><full-title>Trends Endocrinol Metab</full-title><abbr-1>Trends in endocrinology and metabolism: TEM</abbr-1></periodical><alt-periodical><full-title>Trends Endocrinol Metab</full-title><abbr-1>Trends in endocrinology and metabolism: TEM</abbr-1></alt-periodical><pages>389-98</pages><volume>25</volume><number>8</number><keywords><keyword>Animals</keyword><keyword>Apoptosis/physiology</keyword><keyword>Diabetes Mellitus, Type 2/*metabolism</keyword><keyword>Endoplasmic Reticulum/metabolism</keyword><keyword>Endoplasmic Reticulum Stress/*physiology</keyword><keyword>Insulin-Secreting Cells/*metabolism</keyword><keyword>Unfolded Protein Response/physiology</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1879-3061 (Electronic) 1043-2760 (Linking)</isbn><accession-num>24656915</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/24656915</url></related-urls></urls><electronic-resource-num>10.1016/j.tem.2014.02.003</electronic-resource-num></record></Cite></EndNote>143. IR and T2D patients are associated with abnormal lipid metabolism with elevated levels of circulatory concentration of free fatty acid (FFA) and excess lipid deposition in the skeletal muscle PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KdW5nPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 144. Increase in plasma FFA reduces insulin-stimulated glucose uptake and inhibits insulin-mediated PI3-kinase activity in skeletal muscle ADDIN EN.CITE <EndNote><Cite><Author>DeFronzo</Author><Year>2009</Year><RecNum>360</RecNum><DisplayText>145</DisplayText><record><rec-number>360</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>360</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>DeFronzo, R. A.</author><author>Tripathy, D.</author></authors></contributors><auth-address>University of Texas Health Science Center, San Antonio, Texas, USA. [email protected]</auth-address><titles><title>Skeletal muscle insulin resistance is the primary defect in type 2 diabetes</title><secondary-title>Diabetes Care</secondary-title><alt-title>Diabetes care</alt-title></titles><periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></periodical><alt-periodical><full-title>Diabetes Care</full-title><abbr-1>Diabetes care</abbr-1></alt-periodical><pages>S157-63</pages><volume>32 Suppl 2</volume><keywords><keyword>Blood Glucose/metabolism</keyword><keyword>Diabetes Mellitus, Type 2/*physiopathology</keyword><keyword>Fatty Acids, Nonesterified/metabolism</keyword><keyword>Glucose Clamp Technique</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/physiology/secretion</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Muscle, Skeletal/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1935-5548 (Electronic) 0149-5992 (Linking)</isbn><accession-num>19875544</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19875544</url></related-urls></urls><custom2>2811436</custom2><electronic-resource-num>10.2337/dc09-S302</electronic-resource-num></record></Cite></EndNote>145, whereas reduction of plasma lipid content improves insulin action in the insulin-sensitive organs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmVnb3I8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 146.

In addition to the above, multiple lipid intermediates were reported to promote IR. Elevated circulating FFA observed in obesity causes IR through activation of negative regulators of insulin signalling like JNK, IKK, and PKC that induces IRS-1 phosphorylation at Ser307 ADDIN EN.CITE <EndNote><Cite><Author>Schenk</Author><Year>2008</Year><RecNum>412</RecNum><DisplayText>147</DisplayText><record><rec-number>412</rec-number><foreign-keys><key app=”EN” db-id=”pdtsaved7ppwr0e0s2qvz2zf0wxrx2xd0aav”>412</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Schenk, S.</author><author>Saberi, M.</author><author>Olefsky, J. M.</author></authors></contributors><auth-address>Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California 92093, USA.</auth-address><titles><title>Insulin sensitivity: modulation by nutrients and inflammation</title><secondary-title>J Clin Invest</secondary-title><alt-title>The Journal of clinical investigation</alt-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><alt-periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></alt-periodical><pages>2992-3002</pages><volume>118</volume><number>9</number><keywords><keyword>Adipose Tissue/metabolism</keyword><keyword>Animals</keyword><keyword>Body Weight</keyword><keyword>Diabetes Mellitus, Type 2/metabolism</keyword><keyword>Endoplasmic Reticulum/metabolism</keyword><keyword>Humans</keyword><keyword>Inflammation/*complications</keyword><keyword>Insulin/*metabolism/secretion</keyword><keyword>Insulin Resistance</keyword><keyword>Liver/metabolism</keyword><keyword>Macrophages/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Muscle, Skeletal/metabolism</keyword><keyword>Obesity/complications</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0021-9738 (Print) 0021-9738 (Linking)</isbn><accession-num>18769626</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18769626</url></related-urls></urls><custom2>2522344</custom2><electronic-resource-num>10.1172/JCI34260</electronic-resource-num></record></Cite></EndNote>147. FFA like palmitate promotes IR via induction of ER stress, production of cytokine, and activation of JNK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PemNhbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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