dDrosophila melanogaster is a Model for Diabetes Type II …downloads.hindawi.com/journals/bmri/aip/1417528.pdf2018-03-13768 doi:10.1016/j.cnur.2017.07.002 769 6. Kahn BB, Flier JS

Review ArticleDrosophila melanogaster as a Model forDiabetes Type 2 Progression

Jeacutessica P Aacutelvarez-Rendoacuten1 Rociacuteo Salceda2 and Juan R Riesgo-Escovar 1

1 Instituto de Neurobiologıa Universidad Nacional Autonoma de Mexico Campus UNAM JuriquillaBoulevard Juriquilla No 3001 76226 Queretaro QRO Mexico2Instituto de Fisiologıa Celular Universidad Nacional Autonoma de Mexico Avenida Universidad No 3000Colonia Universidad Nacional Autonoma de Mexico Delegacion Coyoacan 04510 Ciudad de Mexico Mexico

Correspondence should be addressed to Juan R Riesgo-Escovar riesgounammx

Received 24 November 2017 Revised 3 February 2018 Accepted 13 March 2018 Published 24 April 2018

Academic Editor Daniela Grifoni

Copyright copy 2018 Jessica P Alvarez-Rendon et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Drosophila melanogaster has been used as a very versatile and potent model in the past few years for studies in metabolism andmetabolic disorders including diabetes types 1 and 2 Drosophila insulin signaling despite having seven insulin-like peptides withpartially redundant functions is very similar to the human insulin pathway and has served to study many different aspects ofdiabetes and the diabetic state Yet very few studies have addressed the chronic nature of diabetes key for understanding the full-blown disease which most studies normally explore One of the advantages of having Drosophila mutant viable combinations atdifferent levels of the insulin pathway with significantly reduced insulin pathway signaling is that the abnormal metabolic statecan be studied from the onset of the life cycle and followed throughout In this review we look at the chronic nature of impairedinsulin signaling We also compare these results to the results gleaned from vertebrate model studies

1 Introduction

Diabetes is a chronic metabolic malaise that affects and isforecast to affect many millions of people in the world [1]It is a disease caused by insulin deficiency or loss of insulinaction In addition to genetic factors certain lifestyles suchas high dietary fat content and physical inactivity are riskfactors for the development of diabetes [2] It has outpacedmany other diseases and is predicted to become one of themajor health concerns in the future [3] According to datacited by theWorld Health Organization by 2014 incidence ofdiabetes had risen to 85 [3] In Mexico for example 2017figures show that over 15 of adults are diabetic which isa very high incidence and concern [4] As of now diabetesis an incurable and incapacitating disease with a long andprotracted progression It is also a disease being diagnosedmore often in younger patients [2]

In human diabetic patients where the condition hasexisted for some time there are several comorbidities It

courses with macrovascular complications leading to heartdisease and stroke and increased cardiovascular morbidityand mortality In addition microvascular complications leadto nephropathy retinopathy and neuropathy [1] Little isknown of the onset and early progression of the diseaseexcept for familial cases which are the minority and thehigher risk of diabetes type 2 for babies where mothers hadhyperglycemia or diabetes [2 5]

Diabetes mellitus is divided into basically two types type1 and type 2 a division that reflects the cause of the metabolicdysfunction Diabetics type 1 have a reduction in insulinsecretion and as a consequence blood glucose does notattain homeostatic levels after food ingestion and digestionPhysicians normally treat them by prescribing exogenousinsulin injections on a regular basisThese diabetics representaround 10 of all diabetic patients and in most cases theircondition is due to the death of pancreatic Langerhans isletsszlig-type cells which normally secrete insulin to clear elevatedglucose levels from the bloodstream like after a meal [6]

HindawiBioMed Research InternationalVolume 2018 Article ID 1417528 16 pageshttpsdoiorg10115520181417528

2 BioMed Research International

It leads to elevated blood glucose levels as expected and togeneral body wasting

Diabetes type 2 represents the majority of cases rangingbetween 90 and 95of all diabetic patients It is characterizedby a combination of insulin resistance and insulin secretiondefects resulting in relative insulin deficiency and hyper-glycemia [6] Diabetic type 2 patients normally representpatients that have had a long progression initially sufferingfrom metabolic syndrome andor being overweight andorbeing obese for several years Environmental factors like dietand level of physical exercise also play an important role inthe inception and progression of the disease as noted above

Finally there is also a third type of diabetes gestationaldiabetes This form of diabetes occurs in pregnant womenleads to increased risk of diabetes for the offspring and maylead to diabetes type 2 in the mothers after birth [2]

There are in sum many factors causing diabetes type 2both genetic and environmental and the composite pictureis complex as it may change depending on the actualcombination present in populations and individual patients[2] While all of the factors cited above are recognizedcontributing factors it is not clear how they weigh in theinitiation and early progression of the disease Therefore itis important to elucidate the precise molecular mechanismsunderlying the development and progression of the disease

In general the diabetic state is multifactorial encom-passing several origins and progressions Studying its causeseffects and consequences is paramount in the actual diabetesldquoepidemicrdquo but it is not easy or even possible to studymany of these aspects using human patients as test subjectsScientists have developed model systems where diabetes canbe controlled to a higher extent and in which experimentalsetups with a high degree of rigor and reproducibility canbe used with genetic uniformity and highly controlledenvironments Principles uncovered in these systems canthen be applied in a more general fashion as the insulinpathway and glucose control is a common evolutionarilyconserved mechanism in the animal kingdom (Figure 1)

11 The Insulin Pathway Insulin is an anabolic hormone inglucose homeostasis in experimentally pancreatomized dogs[7] discovered by Banting and Best who won the Nobel Prizefor this discovery [8] In general in vertebrates insulin issecreted from pancreatic Langerhans islets szlig-type cells inresponse to increased glucose levels In some teleost fishinsulin is produced in Brockmannrsquos bodies [9] Secretedinsulin in the bloodstream binds to membrane receptorsespecially inmuscle cells and initiates a transduction cascadethat leads to glucose internalization and an anabolic responseIn invertebrates the insulin molecule is slightly longer hasone more disulphide bridge and is secreted from specializedneurons (insulin-producing cells or IPC) and glia in thebrain [10] Recently in a striking novel use insulin-likepeptides have been identified in the venom of certain Conusmollusks able to bind insulin receptor molecules and inducehypoglycemia in fish prey [11 12]

Insulin is a small polypeptide constituted by two chainslinked by disulphide bonds synthesized from the samegene [13] Whereas vertebrates have one insulin gene the

Drosophila genome codes for seven several insulin-like pep-tides secreted from the insulin-producing cells (IPC) of thebrain A further eightDrosophila insulin-like peptide DILP8is really a relaxin homolog binding to a different type ofreceptor and controlling corporal symmetry [14ndash17]

The Drosophila insulin-like peptides (ILPs) also havenonredundant functions [18ndash20] The ILP2 peptide has thehighest homology to the vertebrate insulin gene and issynthesized together with ILP1 ILP3 and ILP5 in the IPCsof the brain and their synthesis depends on ILP3 ILP3expression also activates the insulin pathway in the fat body[21] ILP4 ILP5 and ILP6 are expressed in the midgut ILp7is expressed in the ventral nerve chord and ILp2 is alsoexpressed in the salivary glands and imaginal discs [22]The Drosophila IPCs are the equivalent of the mammalianLangerhansrsquo islets szlig pancreatic cells [23] ILP6 is synthesizedin the fat body and can partially substitute for ILP2 andILP5 ILP2 loss-of-function mutations lead to an increase inlifespan while loss in ILP6 causes reduced growth [23 24]

An insulin monomer is around 50 amino acid residues inlength but dimers form in solution Insulin is synthesized asa single polypeptide called preproinsulin which is processedin the endoplasmic reticulum forming proinsulin whichthen undergoes maturation through the action of peptidasesreleasing a fragment called the C-peptide and the A and Bchains linked by disulfide bonds Mature insulin is exocy-tosed into the circulation by glucose stimulation and bindsto plasma membrane receptors with tyrosine kinase activity

Insulin is a potent anabolic hormone in vertebrates [25]It also exerts a variety of actions in flies including effects onglucose lipid and protein metabolism It directly promotesgrowth and proliferation in tissues rather than differentiation[26 27] In vertebrates insulin stimulates glucose uptakein skeletal muscle and fat promotes glycogen synthesis inskeletal muscle suppresses hepatic glucose production andinhibits lipolysis in adipocytes [28] Although vertebrateskeletal muscle liver and adipose tissue are considered themain target tissues of insulin action there is evidence thatinsulin has important physiological functions in other tissuessuch as the brain pancreas heart and endothelial cells[29 30] Pretty much the same is true for invertebrates inequivalent tissues where insulin action has been shown toimpinge on the physiology of many tissues including thebrain [31] In vertebrates there are insulin-growth factorbinding proteins (IGFBPs) that conform to an evolutionar-ily conserved superfamily regulating insulin-growth factorfunction in Drosophila the homolog is ecdysone-induciblegene 2 (Imp-L2) [32]

In vertebrates it is thought that insulin-like growthfactor binding proteins IGFBPs and a third protein ALS(acid-labile subunit) form ternary complexes with IGFs toregulate IGF function separating insulin functions from IGFsfunctions [33] In flies ILPs have both vertebrate insulinand IGF functions The Drosophila genome codes for aputative IGFBP-acid-labile subunit (IGFBP-ALS) homologconvoluted that has been shown to bind in vitro by ectopicexpression to ILPs and Imp-L2 forming a ternary complex[34] However mutations (even null mutations) in convolutedhave mutant phenotypes that differ from insulin pathway

BioMed Research International 3

dPI3KPI3K

dPDK1PDK1

dAktPKB

AktPKB

dTOR-C1mTOR-C1

dFOXOFOXO

d4E-BP4E-BP

dS6KS6K

dRhebRheb

dTsc1-2Tsc1-2

InRInsulinIGF

receptors

dPTENPTEN

PIP3PIP2

SlimfastCAT-1

dSREBPSREBP

Translation apparatus

PIP3

dTOR-C2mTOR-C2

Imp-L2 dASL SDRIGFBPs ASL

dMycMyc

dILPs 1ndash7Insulin

IGFs

PIP3

Amino acids

dGSK3ShaggyGSK3

IRSchico

IRS1ndash4

Figure 1The insulin signaling pathwayThe binding of insulin to its receptor initiates a phosphorylation cascade that results in the regulationof metabolism through several effectors Names for the vertebrate counterparts of the pathway appear below their Drosophila names CAT-1cationic amino acid transporter-1 Imp-L2 ecdysone-inducible gene L2 IGFBPs insulin-like growth factor binding proteins ASL acid-labile subunit SDR secreted decoy of InR dILPs 1ndash7 insulin-like ligands 1ndash7 IGFs insulin-like growth factors InR insulin receptorIRSchico insulin receptor substrate PI3K phosphatidylinositol 3-kinase (two subunits Pi3K92E is the catalytic subunit and Pi3K21B is theregulatory subunit) PIP2 phosphatidylinositol 45-bisphosphate PIP3 phosphatidylinositol 345-trisphosphate PTEN phosphatase andtensin homolog dPDK1 3-phosphoinositide dependent protein kinase-1 GSK3120573 glycogen synthase kinase 3 beta Tsc1-2 tuberous sclerosisproteins 1 and 2 Rheb Ras homolog enriched in brain TOR-C1 target of rapamycin complex 1 (the TOR-C1 complex consists primarilyof TOR regulatory associated protein of TOR (raptor) and lethal with Sec-13 protein 8 (LST8)) TOR-C2 target of rapamycin complex 2(the TOR-C2 complex consists primarily of TOR rapamycin-insensitive companion of TOR (Rictor) and stress-activated protein kinase-interacting protein 1 (Sin1)) Myc Myc protein SREBP sterol regulatory element-binding protein S6K ribosomal protein S6 kinase beta-14E-BP eukaryotic translation initiation factor 4E-binding protein 1 FoxO Forkhead box O transcription factor Dashed lines indicate anindirect interaction arrows and bar-headed lines indicate activation and inhibition respectively

mutants Convoluted mutants are larval lethal and affect tra-cheal morphogenesis and motor axon guidance In additionconvoluted has a higher homology to extracellular matrixproteins like Chaoptin than to vertebrate ALS [35 36] Takentogether all of these facts cast doubt on whether a fly ALShomolog actually exists It seems reasonable to postulate thatsince ILPs are both insulin and IGFs in flies no separation incomplexes is necessary

Insulin or insulin-like peptides bind to the insulin recep-tor (IR) a heterotetrameric protein that consists of two extra-cellular 120572-subunits and two transmembrane 120573-subunits con-nected by disulfide bridges [37ndash40] Insulin binding oligo-merizes the receptors allowing for cross-phosphorylation of

the receptor molecules in tyrosine (tyr) residues in the IRdomain of the intracellular part of the 120573-subunit Despitesome differences vertebrate and invertebrate insulin recep-tors are equivalent [41] as chimeric fruit fly-vertebrate insulinreceptors have been shown to be activated with a similarmechanism as vertebrate insulin receptors in mammaliancells [42] In flies there is also a secreted decoy of the insulinreceptor secreted decoy of InR (Sdr) that binds some dILPsin circulation in the hemolymph necessary for the negativeregulation of Dilp action [43]

Phosphorylation in InR tyr residues in the intracellularpart of the 120573-subunit and the carboxy-terminal extensionin the fruit fly insulin receptor [44] leads to the generation


of protein binding sites This leads to the subsequent recruit-ment binding and tyr phosphorylation of members of theinsulin receptor substrate (IRS) family proteins [37] InDrosophila besides the carboxy-terminus extension of theinsulin receptor the IRS homologs chico [45] and Lnk [46] actas IRS type molecules Whereas chico is the sole IRS homologin flies [45]Lnk is the fly homolog of vertebrate SH2B adaptorproteins [47] Lnk acts as an adaptor molecule that favorsChico and InR membrane localization [46]

The phosphorylated tyrosine residues in both the acti-vated receptors and the IRS proteins create further bindingsites for other molecules like the catalytic subunit of phos-phatidylinositol 31015840 kinase (Pi3K92E) which via the regulatorysubunit Pi3K21B can now be brought in proximity to itssubstrate phosphatidylinositol (4 5) bisphosphate [48]

The phosphorylated residues of vertebrate IRS1 (or Chicoin the fruit fly) mediate an association with the SH2 domainsof the p85 regulatory subunit of phosphatidylinositol 3-kinase(Pi3K) (Pi3k21B in flies [49]) leading to activation of thep110 catalytic subunit which then catalyzes the formationof phosphatidylinositol (3 4 5) trisphosphate (PI 3 4 5-P3)from phosphatidylinositol (4 5) bisphosphate (PI 4 5-P2) inthe inner leaflet of the plasma membrane [50] This thencreates binding sites for proteins with pleckstrin homologydomains (PH) [51] like the phosphoinositide dependentkinase (PDK1) [52] and protein kinase B (PKB also knownas Akt) [53] Both proteins bind via their PH domains thephosphatidylinositol trisphosphate generated in the innermembrane leaflet of the plasma membrane via action ofPi3K92E [54 55] PDK1 a serine-threonine kinase thenphosphorylates and activates Akt [56 57]

The phosphorylating activity of Pi3K92E is counter-acted by PTEN (phosphatase and tensin homolog deletedin chromosome ten) a lipid and protein phosphatase andtumor suppressor gene in vertebrates and flies [58 59] Thelipid phosphatase activity of phosphatidylinositol (3 4 5)trisphosphate to phosphatidylinositol (4 5) bisphosphate isthought to be the main catalytic activity It is deregulatedin many tumor types in humans and in neurodegenerativediseases like Parkinsonrsquos disease [60] In Drosophila anothernegative regulator of Pi3K92E is Susi binding to the p60 reg-ulatory subunit of PI3K the 60Kd molecular weight subunit[61 62]

AktPKB is considered a critical node in insulin signalingAktPKB acts by phosphorylating many different proteins[40] In so doing AktPKB activates different outcomes (1)Glut 4-mediated glucose transport in vertebrates by activat-ing the proteinAkt substrate of 160 kDa (AS160) (2) glycogensynthesis through inhibition of glycogen synthase kinase3szlig (GSKszlig) and hence favoring glycogen synthase (GS)activity (3) protein synthesis through the mammalian targetof rapamycin (TOR) pathway (4) inhibition of the Forkheadtranscription factor FoxO a major positive catabolic regula-tor and (5) others targets such as the SIK2 (salt-induciblekinase 2) [22 63ndash66] In Drosophila Melted interacts withboth FoxO and the TOR kinase via the tuberous sclerosiscomplex 2 protein (TSC2) and acts as a bridge within theinsulin pathway regulating the activities of these two proteins[67]

Besides the direct effect on glucose metabolism GSK3120573also regulates cellularmetabolism through the inhibitory reg-ulation of transcription factors that globally control specificmetabolic programs and many of them are also regulatedby TOR complexes cell survival or proliferation (includ-ing c-Myc) the sterol regulatory element-binding proteins(SREBP1c) hypoxia-inducible factor 1-alpha (HIF1a) and thenuclear factor- (erythroid-derived 2-) like 2 (Nrf2) [68]ThusAkt signaling can stabilize these proteins by inhibitingGSK3120573and by indirectly activating TOR-C1 [27] There is evidencethat the insulin pathway control of Myc is evolutionarilyconserved in Drosophila In biochemical experiments intissue culture cells and in ectopic expression studies theDrosophila insulin pathway via inhibition of shaggy theDrosophila homolog of GSK3120573 regulated Drosophila Mycprotein stability Drosophila myc is coded by the gene diminu-tive [69 70]

Perhaps the best-documented cases of downstream com-ponents activated by AktPKB are the target of rapamycin(TOR) kinase and the FoxO transcription factor The serthrkinase TOR interacts with different proteins to form the com-plexes TOR-C1 and TOR-C2 [62 71] This kinase positivelyregulates cell growth proliferation motility and survivalTOR-C1 appears to play a role in acute feedback inhibition ofAkt negatively regulating insulin action Activation of TOR isnot direct fromAktPKB in theDrosophila ovaries AktPKBrepresses the proline-rich Akt substrate 40 kDa (PRAS40)There is also a PRAS40 homolog in vertebrates [72] In thefly ovaries PRAS40 represses TOR decoupling reproductionfrom growth in the cells of this organ [73] In other tissuesAktPKB phosphorylates and might repress TSC1 (in flies)and TSC2 which are normally thought to repress the GTP-binding protein and GTPase Rheb that activates TOR-C1 yetit is unclear whether indeed this is the case [74] TOR-C1activation leads to longer S1 phase in cells [75 76]

TOR is another central component downstream of insu-lin signaling The TOR kinase in the TOR-C1 complex phos-phorylates and regulates several proteins TOR kinase in theTOR-C1 complex phosphorylates (1) S6 kinase to promotetranslation (S6 is a component of the ribosomes) [77] (2)the translation regulatory factor 4E-BP which also promotesprotein synthesis [78] (3) the transcription factor Myc [6979 80] (4) SREBP [81] and (5) autophagy proteins (phos-phorylation of these autophagy proteins represses them)[82] TOR also regulates endocytosis to promote growth andrepress catabolism [83] Besides regulation by the insulinpathway TOR-C1 is also regulated via a nutrient sensingsignaling pathway specifically via the activity of the aminoacid transporter Slimfast [84] dS6K promotes ILP2 expres-sion in the IPCs [21] ILP secretion by IPCs is controlled bynutritional status and this nutritional status is conveyed toIPCs by fat body cells which secrete the Unpaired2 cytokinein fed conditions which regulates GABAergic neurons in thebrain releasing the GABAergic tonic inhibition they exert onthe IPCs leading to ILP secretion [85 86]

The other AktPKB well-studied target is FoxO FoxOis a transcription factor (a family in mammals) that favorscatabolism counteracts anabolism and is phosphorylated byAktPKB to repress its activity [22 87] Activation of insulin


signaling leads to acute translocation of FoxO proteins out ofthe nucleus and attenuation of their transcriptional program[88 89] In vertebrates the Forkhead box O (FoxO) familyconsists of FoxO1 FoxO3 FoxO4 and FoxO6 proteins adistinct gene encodes each oneDrosophila has only one suchgene [90 91] FoxO proteins bind to the insulin responseelement (IRE) to stimulate target gene expression on diversepathways including cell metabolism proliferation differen-tiation oxidative stress cell survival senescence autophagyand aging counteracting insulin action [92]

FoxO repression via insulin signaling activity results inan attenuation of FoxO-dependent expression of genes likethose coding for glucose 6-phosphatase or phosphoenolpyru-vate carboxykinase [93 94] Among other genes FoxO-regulated antioxidants include theMn-dependent superoxidedismutase [95] Signaling pathways that regulate stress andredox status also regulate FoxO proteins thus impinge oninsulin signaling and the diabetic state p38 AMP-activatedprotein kinase (AMPK) among othersThe NAD-dependentprotein deacetylase sirtuin-1 (Sirt1) directly modifies FoxOtranscription factors and promotes their nuclear transloca-tion and activation of target genes [96] In addition theacetylation state of histones and the FoxO coactivator PGC-1120572 (peroxisome proliferator-activated receptor 120574-coactivator-1120572) may modify the effect of a stimulus on FoxO-inducedgene transcription [97] In conclusion the FoxO genestranscription is regulated by a variety of physiological cuesand pathological stress stimuli frequently associated withincreased oxidative stress

12 Oxidative Stress and Insulin Signaling Oxidative stress isconsidered a key factor in the development and progressionof diabetes and its complications [98] In vertebrates Sestrins1ndash3 (Sesns) form a family of conserved stress-responsiveproteins [99] The Sesns regulate the insulin pathway byregulating the AMP kinase and TOR [100 101] Sesn1 wasidentified as the product of a gene (PA26) activated bythe transcription factor p53 in cells exposed to genotoxicstress Later it was isolated also as a FoxO responsive genein growth factor stimulated cells [102] Sesn 2 promotesthe degradation of Kelch-like protein 1 (Keap1) leading toupregulation of Nrf2 signaling and the induction of genesfor antioxidant enzymes The adaptor protein p62 is requiredfor the Sesn 2-dependent activation of Nrf2 [103] Sesnsblock TOR-C1 activation and thereby reduce reactive oxygenspecies accumulation [104] In Drosophila a single Sestrinhomolog has been isolated and characterized It is activatedby accumulation of reactive oxygen species and regulatesinsulin signaling Mutant flies suffer frommetabolic disarraymuscle wasting and mitochondrial dysfunction [105] TheDrosophila Sestrin acts through two GATOR protein com-plexes These GATOR complexes regulate the activity of theRagB GTPase necessary for TOR-C1 activity The DrosophilaSestrin binds to GATOR2 Bound to Sestrin GATOR2 freesGATOR1 Free GATOR1 inhibits RagB function by activatingits GTPase activity thus inhibiting TOR-C1 activation [106107] In vertebrates the GATOR complexes act in the samefashion GATOR complexes are evolutionarily conserved inmetazoans [108]

Reduction of energy levels in the cells causes the activa-tion of the AMP-activated protein kinase AMP kinase Thisin its turn results in TSC2 phosphorylation and subsequentTOR-C1 inhibition A hypoxic state also reduces TOR activityvia the hypoxia-inducible factor-1 (Hif-1) that affects thehypoxia-induced response genes Redd1 [109] and Scylla [110]Scylla forms a complex with charybdis negatively regulatingTOR-C1 acting downstream of AktPKB and upstream ofTSC [110]

2 Experimental Animal Models Vertebrates

Type 1 diabetes is characterized by progressive 120573-cell destruc-tion Insulin resistance in target tissues characterizes type 2diabetes The majority of obese individuals do not becomediabetic although over weight or obesity are clear risk factorsfor diabetes In the United States 875 of adults over 18years old were overweight (including obese and morbidlyobese individuals) and an estimated 122 of the populationis diabetic in 2017 [111] suggesting that 120573-pancreatic cellsfailure is required to cause hyperglycemia [112] Due to itsoverall evolutionary conservation animal models are usedto identify mechanisms principles and potential drug tar-gets besides elucidating general underpinnings of biologicalmetabolic significance Many animal models of diabetesare currently available for elucidating the pathophysiologyof diabetes and testing novel therapies for complicationsHowever since diabetes etiology is multifactorial no singleanimal model may exactly replicate the human situationSeveral of these animal models can be used to study chronicdiabetes phenotypes

In principle all of the models reviewed below couldbe used for chronic aspects of diabetes and the accrue-ment and evolution of the diabetic state In spite of thisopportunity in most cases experiments are begun when thediabetic model organisms have advanced to a frank diabeticstate (for example when the resting glucose level is above250ndash300mgdl several daysweeks after streptozotocin (STZ)injection in rats see below) It is desirable to study the initialstates starting when the STZ injection is given and studyingthe acquirement of the diabetic state as well as its ulteriorevolutionThemodels reviewed here could well serve or haveserved this purpose

21 Chemical Induction of Diabetes Alloxan and STZ treat-ments are the most used diabetes models for diabetic com-plications in vertebrates Both chemicals are toxic glucoseanalogues transported into the cells via the Glut 2 trans-porter [113] Both treatments lead to necrosis importantlyof insulin-producing cells but by different mechanismsAlloxan generates toxic free radicals leading to cell death vianecrosis STZ is cleaved generating free methylnitrosoureathat induces DNA fragmentation and necrotic cell decay[114] Although STZ may also have toxic effects on otherorgans its effectiveness and side effects depend mainly ontissue-specific Glut 2 expression animal age and nutritionalstatus [114] STZ administration to 0ndash2-day-old rats inducesan inadequate beta cell mass used as a type 2 diabetes model[115]


A variety of mammals rodents rabbits dogs pigs andnonhuman primates have been used as models of STZ-and alloxan-induced diabetes The small size of rodents andrabbits results advantageous formaintenance costs especiallyin longitudinal studies but somewhat limits sample materialavailable per animal In recent years the pig has gainedimportance because of its size and close similarity to humanphysiology Minipigs have clear advantages over domesticpigs and genetic modifications leading to diabetic pheno-types have been developed [116]

22 Genetic Vertebrate Models of Diabetes Yet to daterodents represent the predominant vertebrate species usedin biomedical research because of traditional use and accu-mulated knowledge known animal husbandry evolutionar-ily conserved metabolic pathways the capacity to conductexperiments in organs and study physiology and morerecently genetic manipulation possibilities Among themseveral genetic mutant strains are extensively used depend-ing on the diabetic aspect under study

The Akita mice have an Ins2+C96Y mutation a singlenucleotide substitution in the insulin 2 gene (Ins2) Thismutation causes reduced insulin secretion resulting in thedevelopment of type 1 diabetes [117] The dbdb mouse isthe most popular model of type 2 diabetes They have adeletion mutation in the leptin receptor resulting in defectivereceptor function for the adipocyte-derived hormone leptinThis mutation leads to the developing of obesity insulinresistance and diabetes [118] Other mutants with alteredmetabolism such as the agouti (Ay)mouse a polygenicmodelof obesity-induced diabetes and theApoEminusminus (apoliporoteinE deficient) mouse an atherosclerosis model are available[119ndash122]

The Zucker fatty (ZF) rat ports a homozygous missensemutation (fatty fa) in the leptin receptor gene and developsobesity without diabetes although rats develop progressiveinsulin resistance and glucose intolerance [123] The Wistarfatty (WF) rat is a congenic strain of the Wistar Kyotorat that also has a fafa homozygous missense mutation inthe leptin receptor gene This strain develops obesity [124125] The Otsuka Long-Evans Tokushima Fatty (OLETF)rat is a recognized model of type 2 diabetes Rats showimpaired glucose tolerance observed from 8 weeks of agehyperglycemia and peripheral insulin resistance [126 127]The Goto-Kakizaki (GK) rat is a model of nonobese type 2diabetes This is a Wistar substrain that develops mild hyper-glycemia insulin resistance and hiperinsulinemia [128ndash131]The ZDF-Lepr119891119886Crl rat was originated in a colony of Zuckerrats expressing type 2 diabetes among other models [132ndash134]

In addition there are also a variety of different poly-genic models of obesity that include the KK-AY mice [135]New Zealand obese (NZO) mice [136] the TALLYHOJngmice [137] and the OLETF rats [127] besides diet-inducedmodels of obesity [30] These models also lead to diabeticstates

3 Invertebrate Insulin Signaling

Besides vertebrate diabetes models two main invertebratemodels have been used in experiments These two inverte-brate models are the nematode Caenorhabditis elegans andthe fruit fly Drosophila melanogaster

31 Caenorhabditis elegans In the nematode Caenorhabditiselegans some of the insulin pathway main components werefirst characterized like the nematode homolog age-1 InC elegans faulty insulin signaling leads to life extensionmetabolism changes disrupted growth and stress resiliencereminiscent of some diabetic phenotypes [138 139]

In this nematode the insulin pathway genes were dis-covered by virtue of their control of dauer larva for-mation and longevity evidencing a relationship betweenagingnutritionlifespan [140] Dauer larvae are formedbetween larval stages two and three and represent an alterna-tive third larval stage that can survive harsh environmentalconditions for up to four months The pivotal genes in theC elegans insulin pathway are evolutionarily conserved Theinsulin receptor homolog is daf-2 (from abnormal dauerformation) the IRS homolog is ist-1 [141] the PI3K catalyticsubunit is age-1 (from aging alteration) and the regulatorysubunit is aap-1 [141] PTEN is daf-18 Akt is Akt-1 and Akt-2and FoxO is daf-16 [142] Similar to the case inDrosophila theinsulin pathway is unique and required for many functionsincluding nutritional assessment and metabolism growthlifecycle longevity and behavior The study of dauer larvaeformation in C elegans has already yielded insights intometabolicnutritional control and longevity with relevanceto humans [143] There have also been studies regardingbehavior modifications degenerative diseases and the rolesplayed by FoxO transcription factors in the worm andhumans [144] Learningmemory and organismal growth arealso other chronic conditions where research in C elegansinsulin pathway has pinpointed general functions [142]

32 Drosophila andDiabetes Dmelanogaster insulin signal-ing has been evolutionarily conserved and both types 1 and2 diabetes can be modeled Reducing or nearly abrogatingexpression of the insulin-like peptides (ILP) in the fly canachieve type 1 diabetes [23] On the other hand severalmanipulations can lead to diabetes type 2 mutations inthe insulin pathway components downstream from the ILPs[27 45] dietary manipulations leading to obesity metabolicimbalance and hyperglycemia [145ndash148] or studies in otherDrosophila species with different lifestylesdiets [149 150]As these different experimental protocols applied in genet-ically homogeneous fly populations converge essentially ina reproducibly diabetic state and faulty insulin signalingthey can all be used for longitudinal studies characterizingthe accruement and evolution of compromised diabeticsignaling diabetic phenotypes and their consequences

Drosophila is uniquely poised to study the insulin path-way and diabetes chronic aspects it has a very well-developedgenetic toolkit simply not available or not as easily amenableand with higher genetic background homogeneity and rigoras other models a very highly polished sequenced genome


a ldquosimplifiedrdquo insulin pathway with components exhibitingfar less redundancy than for example vertebratemodels andthe availability of different species with similar sequencedgenomes that represent ldquonaturalrdquo experiments with differentlifestyles and diets among other advantages It is particularlyof note the capacity to generate different types of geneticmosaics in the whole organism allowing study and analysisof the cell tissue and organismal consequences and cellindependence ofmutations and the localization of functionalldquofocirdquo Another related advantage is the possibility of generat-ing space and time limited geneticmosaics that can be used todistinguish between developmental defects versus metabolicdefects for example

321 Different Drosophila Species Lead to Different LifestylesMost of the well-known Drosophila species are saprophytic[151] Inside this big genus (over 2000 species describedso far) there are both generalist and specialist ones withomnivorous or restricted dietsThe environmental conditionsthat each population faces together with the availabilityof nutrients altitude latitude temperature and so on canimpinge on differences and adaptations that have effectswhether direct or indirect on insulin signaling It canaffect the levels of activity and in general the lifestyle ofpopulationsThere are studies examining the effect of varyingdiets in different Drosophila species whether or not theysupport life of the organisms in a long-term basis [149 150152] Some of these changes may or may not have to dowith adaptations involving the insulin pathway [153 154]In any case the fact that the genomes plus many otherecological and genomic variables are already known [155ndash157]implies a great advantage for insulin pathway studies of theseecologically diverse species [158] This avenue of researchrepresents a window of opportunity as there are more andmore Drosophila species characterized that can be cultivatedin the laboratory with their genomes sequenced available forstudy [159]

Other examples of studies with different Drosophilaspecies include D simulans where metabolic rate longevityand resistance to stress have been studied [160 161]D sechel-lia found only in the Seychelles archipelago and requiringthe fruitMorinda citrifolia as specialized and niche nutritiontoxic for other species has been thoroughly researched [162163] A recent adaptation of a population of D yakuba tothe same nutritional resource as D sechellia in an islandpopulation (as opposed to conspecific populations in thecontinent) namely Morinda fruit is strikingThis representsa particularly interesting case of a recent adaptation to amajor diet shift [164] D mojavensis requires cacti as afeeding resource and has even specialized to different hostcacti in different populations [165] Together they may allowdissection of the mechanisms behind the differences andpreferences for specific nutrients oviposition sites and theirtolerance and metabolism For exampleD mojavensis showsa better resistance to the presence of alcohol a product of thefermentation of cacti [166] It will be interesting to study inthese examples the changes if any in the insulin pathway dueto their specialized and restricted nutritional resources andhow might a diabetic state alter their metabolism

322 Drosophila melanogaster and Insulin Signaling In Dmelanogaster the growth of the organism is regulated byinsulin signaling and the interaction of this signal with thelevels of juvenile hormone and ecdysone Additionally thereis the role played by the kinase TOR of the insulin pathwaywhich as stated above couples growth with the amount ofavailable nutrients [167] at least in part via the amino acidtransporter Slimfast [84] Since the fruit fly is a poikilother-mic organism it is affected by ambient temperature in a directway presenting a larger size at lower temperatures and anincrease in size with latitude and altitude [168] The numberof ovarioles in females is also susceptible to these factorsbeing lower in tropical populations and it has been shownthat insulin signaling activity underlies these differences [169170]

Besides growth hormones diet and temperature gutmicrobiota can modulate insulin pathway activity Betweenpopulations and lines there are differences in the micro-biome and this influences insulin signaling [171 172] Strainsinfected with theWolbachia endosymbiont exhibit increasedinsulin signaling whereas lack ofWolbachia worsens insulinmutants phenotypes particularly the decline in fecundityand adult weight [173] Loss of ILPs in the brain on theother hand extends lifespan if Wolbachia is present [24]Lactobacillus partially rescues growth in poorly fed larvae andAcetobacter pomorum also modulates insulin signaling [174175] All of these factors have to be taken into considerationideally when longitudinal studies are performed since manyof these factors may vary with age independent of the statusof the fly

Longevity has also been tied at times with insulin sig-naling [176ndash178] Experimental model organism lines thatwere selected because of their increased lifespan oftenpresent changes in the insulin pathway Hoffman et al [179]performedWGS and GWAS studies on long-livedDrosophilastrains and found that the metabolites that decline withage are associated with glycolysis and the metabolism ofglycophospholipids Changes were observed associated withage and sex in biogenic amines and carnitines required forthe transfer of fatty acids in the mitochondria where theypass through beta-oxidation generating acetyl-coA requiredfor the Krebs cycle

323 Inducing the Diabetic State through Diet ProvidingDrosophila diets with increased or decreased nutrients pro-vokes the deregulation of its metabolism and of insulinsignaling High-sugar as well as high-protein diets increaseinsulin-like peptide expression (ILPs) [148 180] this initialincrease in ILP expression is consistent with what is observedin vertebrates in the accruement of insulin resistance wherethe organism initially tries to increase its insulin produc-tion to compensate for excess nutrient input However invertebrates the eventual deterioration of beta cells leads toultimate failure of this initial compensation [181] Similarlyin overfed flies the fat body secondarily reduces its insulinresponse to increased circulating ILPs and this diminutiondecreases significantly as flies age rendering flies completelyresistant at advanced ages [147] These results support theobservation that a diet rich in fat initially increases levels of


different ILPs rescuing at a first stage the overfed phenotypeby means of hyperinsulinemia This increase in insulinsignaling plus hyperglycemia though leads to an increase infree fatty acids by inappropriate lipolysis and the generationof insulin resistance particularly in the fat bodyHigh fat dietsalso contribute to heart dysfunction [145 182]

Sugar lipid and protein variation in diets have led toeffects in fertility longevity sugar and fat accumulationweight changes induction of insulin resistance and aging[147 183] In general the results are consistent with proteinand carbohydrate balance determining lifespan In somecases diets high in carbohydrates and low in proteins allowgreater longevity often accompanied by lower fecundity Inother studies extra protein intake results in lean and longerlived flies while carbohydrate intake leads to obese fliesfinally balanced intermediate carbohydrateprotein ratiosdiets have also been found to lead to longer-lived flies [183ndash187]

Dietary restriction has been variously applied to fliesoften leading to longer life-spans and insulin signalinginvolvement [188ndash190] Dietary restriction effects are alsoseen in immunity via insulin signaling regulation [191]The insulin signaling is clearly part of the equation in allthese studies although it may not be the sole determinant[192 193] One such type of dietary restriction is caloricrestriction Caloric restriction is defined as a reduction incaloric intake without malnutrition and has shown in severalmodels a positive effect on calorie consumption includingyeast and C elegans besides D melanogaster [194ndash196]Another variation of diet manipulation with nutritional andlifespan consequences is methionine availability in the diet[197] Also parental obesity leads to transgenerational effects[198]

Clearly diet manipulation can be used to generate andevolve diabetic states akin to diabetes type 2 in flies and byits very nature it is easily amenable for longitudinal studiesYet an important problem besieging all these studies andone that may explain conflicting results is that all these dietregimes are semidefined chemically at best so that studiesthat modify diets are very difficult to compareThey typicallydefine ldquoproteinrdquo as amount of yeast in the medium orldquocarbohydraterdquo as unrefined sugar or molasses for examplewhich are clearly broad generalizations as yeast cells havecarbohydrates lipids and other nutrients besides proteinsand unrefined sugar or molasses are not only composedof carbohydrates In the future diets should strive to bedefined chemically so that they can be comparable and usedreproducibly by different laboratories In addition total con-sumption should bemeasured since unconstrained flies havefree access to their food source and are able to regulate theircaloric intake at least in the case of D melanogaster [183]Also these studies are subject to environmental variationsthe use of different sexes different genetic backgroundsdifferent strains different age of flies and so on all of whichaffect the outcome of the studies And while these studiesshow that changes in diet have clear effects on the bodyand insulin signaling lack of definition constitutes a limitingfactor in these experimental approaches

324 Diabetes in Flies by Virtue of Mutations in the InsulinPathway Flies homozygous mutant for genes in the insulinpathway are born diabetic There are advantages to thisapproach the nature of the defect is known and the geneticbackground and environmental conditions can be controlledin a rigorous manner The different stages of the lifecyclecan also be exploited with stages where feeding occurs(larvae adults) and stages without food input (pupae) Faultyinsulin signaling by virtue of mutations can both be used tomodel diabetes type 1 (ILPs loss-of-function mutations [23]and even explore genes regulating insulin secretion [199])and also diabetes type 2 with loss-of-function mutations inthe rest of the pathway as the net effect would be insulinresistance [27 31 71] Furthermore both whole organismscan be mutant (in hypomorphic conditions as null allelesare mostly lethal) or only in selected tissues and organs([18 45 48 77 91 200 201] among other references citedthroughout this review)

Drosophila has seven insulin-like peptides (ILPs) Theyare partially redundant so knock-outs for a particular ILPusually havemoderate effects and it is necessary to havemorethan one ILP gene loss-of-function mutation to generatelethality [23 24] In contrast mutations in InR Dp110 andother components of the pathway are homozygous lethal soheterozygous (as there are somedominant effects [45 202]) orheteroallelic flies are often usedThe latter have the benefit ofallocating more robustly the defects observed to the studiedmutation (for example see [31]) chico (the insulin receptorsubstrate fly homolog) is a particular case The homozygousmutant chico1 allelewas originally described as viable helpingestablish the typical mutant phenotypes of partial loss-of-function of insulin pathway mutants [45] Later it was foundout that when devoid of the endosymbiontWolbachia chicoloss-of-function conditions are homozygous lethal under-scoring the close association between gut microbiota andinsulin signaling [173]

The most common phenotypes caused by mutants in theinsulin pathway are a decrease in fertility decreased size oforganisms changes in longevity (decrease in normal con-ditions often an increase in longevity when there is caloricrestriction) defects in fat body morphology in heart retinaand brain physiology increased levels of triacylglyceridesand higher amounts of circulating sugars in the hemolymph[31 45 71 145 147 203ndash205]

InsulinTOR pathway function is critical in the regula-tion of growth autophagy cell and organism survival andanabolism (regulating lipid and carbohydrate homeostasis)[22] Lack of nutrients or ATP impedes its function andoverfeeding can lead to loss of balance insulin participatesin the accumulation of lipids and carbohydrates so that anexcessive intake of nutrients can lead to hyperactivation of thepathway and lipid and glycogen accumulation TOR kinaseis regulated by insulin signaling and by amino acids actingas a central point in metabolism regulation It has also beenimplicated in aging [206ndash208]

Besides nutritional input there are other conditions thatregulate insulin signaling as an example one such state is thesystemic response to stress (which of course is activated by


lack of nutrition among other stimuli) One such stress trig-ger is infection and innate immunity activation Activationof Toll in the fat body leads to the induction of immunityredistribution of resources and activation of JNK andNFK-120573by inflammation Here attenuation of insulin signaling leadsto FoxO activity which regulates genes participating in stressresponse andmetabolic control blockade of gluconeogenesisglycogenolysis and the use of storage lipids for catabolism[209] It may also increase longevity if FoxO is upregulatedin adipose or intestinal tissue [210] In addition chronicintestinal activation of FoxOmay lead to deregulation of lipidhomeostasis [211]

325 Towards the Characterization of Chronic Diabetes inFlies What can be studied in these fly diabetes models in alongitudinal study Nearly every aspect of diabetes mellitusmentioned so far from initial phenotypes to its evolutionand consequences at old age up to death We have discussedabove metabolic imbalances and longevity as two of the moststudied effects [212 213] Other mutant phenotypes includedecreased fertility and altered physiology of various organsand systems (nervous system heart fat tissue musclesetc) for example showing involvement of nervous systemfunction electrical activity or octopamine neurotransmission[214 215] or heart dysfunction [216]

Perturbations like chronic stress can be addressed andthe effects of external factors on the diabetic state such asnutritional variation light regime and temperature can alsobe addressed for example the effect of artificial sweetenersupon insulin pathway signaling [217] or the effect of xeno-biotics on the insulin pathway [218] Fundamentally thoughthe inception and ldquonormalrdquo progression of the mutant condi-tion or the diseased state can be closely followed for examplethe relationship between sleep and metabolism alterationsvia insulin signaling [219ndash221] Unfortunately to this day fewstudies have consciously addressed these chronic aspects ofdiabetes although some do compare flies at different stageslike during oogenesis [222] or pupariation [223] or neuriteremodeling [224] or adult stages [225]

Most of the studies to date that touch on longitudinalaspects address longevity fertility [226] and its phenocriticalperiod [23 202 227 228] like the earlier appearance of loco-motor defects [229] size and growth phenotypes [45 200201 230] and metabolism [71] In summary the Drosophilamodel represents a window of opportunity not only to studyfundamental aspects of diabetes and the diabetic state butalso its complications and the effect of various externalstimuli and factors in the accruement and development of thedisease Future studies will undoubtedly target and addressthese issues to a much greater extent

4 Conclusions

Notwithstanding the ubiquity and utility of vertebratemodelsof diabetes (especially rodent models) and when comparedwith other experimental models of diabetes Drosophila hasclear advantages Despite sometimes ill-defined parametersin diet regimes and environment the model strengthsnamely a robust extensive and highly developed genetic

system with a plethora of isolated and characterized insulinpathway and general metabolism genes ease of manipulationand use low cost high fertility and numbers short genera-tion time high evolutionary conservation and homogeneousgenetic backgrounds among other positive characteristicsmake the fly a premier system for insulin pathway andmetabolic studies

Although many aspects of diabetes mellitus have beenstudied in the different fly models specially there is stilla dearth of longitudinal studies In such studies ideallyexception should be taken of the differences that occur inmetabolism and lifestyle normally as flies age that is to saythese studies should always par appropriate control flies withexperimental ones throughout the life cycle with the samegenetic background to effectively tease away differences dueto the occurrence and evolution of the diabetic state fromnormal aging This is especially true of a disease that touchesmany different aspects of the organismsrsquo wellbeing and onethat by its very nature is very pleiotropic and polygenic

Notwithstanding this the fruit fly represents one of themore promising rigorous and thoroughly researchedmodelsof diabetes in which we carry out such research Due togreat evolutionary conservation it allows for particularlydetailed and controlled studies covering nearly all aspects ofthis chronic and fatal disease Compared to other availablemodels that is vertebrate studies be it organismal or evencell tissue culture ones the fly favorably compares allowingfor more holistic and encompassing approaches

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

References

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[2] L Chen D J Magliano and P Z Zimmet ldquoThe worldwideepidemiology of type 2 diabetes mellitusmdashpresent and futureperspectivesrdquo Nature Reviews Endocrinology vol 8 no 4 pp228ndash236 2012

[3] C D Mathers and D Loncar ldquoProjections of global mortalityand burden of disease from 2002 to 2030rdquo PLoS Medicine vol3 no 11 article e442 2006

[4] OECD ldquoDiabetes prevalencerdquo inHealth at aGlance 2017 OECDIndicators OECD Publishing Paris France 2017

[5] S Dodds ldquoThe How-To for Type 2 An Overview of Diagnosisand Management of Type 2 Diabetes Mellitusrdquo Nursing Clinicsof North America vol 52 no 4 pp 513ndash522 2017

[6] B B Kahn and J S Flier ldquoObesity and insulin resistancerdquo TheJournal of Clinical Investigation vol 106 no 4 pp 473ndash4812000

[7] F G Banting C H Best J B Collip W R Campbell and AA Fletcher ldquoPancreatic Extracts in the Treatment of DiabetesMellitusrdquo Canadian Medical Association Journal vol 12 no 3pp 141ndash146 1922


[8] AB NM AB NM Frederick G Banting-Facts 2014[9] J S Fortin A Santamaria-Bouvier S Lair A D Dallaire and

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[10] T IkeyaM Galic P Belawat K Nairz and E Hafen ldquoNutrient-dependent expression of insulin-like peptides from neuroen-docrine cells in the CNS contributes to growth regulation inDrosophilardquoCurrent Biology vol 12 no 15 pp 1293ndash1300 2002

[11] J G Menting J Gajewiak C A MacRaild et al ldquoA minimizedhuman insulin-receptor-binding motif revealed in a Conusgeographus venom insulinrdquo Nature Structural amp MolecularBiology vol 23 no 10 pp 916ndash920 2016

[12] H Safavi-Hemami J Gajewiak S Karanth et al ldquoSpecializedinsulin is used for chemical warfare by fish-hunting cone snailsrdquoProceedings of the National Acadamy of Sciences of the UnitedStates of America vol 112 no 6 pp 1743ndash1748 2015

[13] G I Bell R L Pictet W J Rutter B Cordell E Tischer and HM Goodman ldquoSequence of the human insulin generdquo Naturevol 284 no 5751 pp 26ndash32 1980

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[15] J Colombani D S Andersen L Boulan et al ldquoDrosophilaLgr3 Couples Organ Growth with Maturation and EnsuresDevelopmental Stabilityrdquo Current Biology vol 25 no 20 pp2723ndash2729 2015

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[46] I Almudi I Poernbacher E Hafen and H Stocker ldquoTheLnkSH2B adaptor provides a fail-safe mechanism to establishthe Insulin receptor-Chico interactionrdquo Cell Communicationand Signaling vol 11 no 1 article no 26 2013

[47] C Werz K Kohler E Hafen and H Stocker ldquoThe DrosophilaSH2B family adaptor Lnk acts in parallel to chico in the insulinsignaling pathwayrdquo PLoS Genetics vol 5 no 8 Article IDe1000596 2009

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[49] D Weinkove S J Leevers L K MacDougall and M D Water-field ldquop60 is an adaptor for the Drosophila phosphoinositide3-kinase Dp110rdquo The Journal of Biological Chemistry vol 272no 23 pp 14606ndash14610 1997

[50] B Vanhaesebroeck S J Leevers G Panayotou and M DWaterfield ldquoPhosphoinositide 3-kinases a conserved family ofsignal transducersrdquo Trends in Biochemical Sciences vol 22 no7 pp 267ndash272 1997

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[53] T F Franke K D Tartof and P N Tsichlis ldquoThe SH2-likeAkt homology (AH) domain of c-akt is present in multiplecopies in the genome of vertebrate and invertebrate eucaryotesCloning and characterization of the Drosophila melanogasterc-akt homolog Dakt1rdquo Oncogene vol 9 no 1 pp 141ndash148 1994

[54] D J Powell E Hajduch G Kular and H S Hundal ldquoCeramidedisables 3-phosphoinositide binding to the pleckstrin homol-ogy domain of protein kinase B (PKB)Akt by a PKC120577-dependent mechanismrdquoMolecular and Cellular Biology vol 23no 21 pp 7794ndash7808 2003

[55] J R Bayascas ldquoDissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathwaysrdquo CellCycle vol 7 no 19 pp 2978ndash2982 2008

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[59] H Huang C J Potter W Tao et al ldquoPTEN affects cellsize cell proliferation and apoptosis during Drosophila eyedevelopmentrdquo Development vol 126 no 23 pp 5365ndash53721999

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[78] A A Teleman Y-W Chen and S M Cohen ldquo4E-BP functionsas ametabolic brake used under stress conditions but not duringnormal growthrdquoGenes amp Development vol 19 no 16 pp 1844ndash1848 2005

[79] A A Teleman V Hietakangas A C Sayadian and S MCohen ldquoNutritional Control of Protein Biosynthetic Capacityby Insulin via Myc in Drosophilardquo Cell Metabolism vol 7 no 1pp 21ndash32 2008

[80] Y Kuo H Huang T Cai and T Wang ldquoTarget of rapamycincomplex 2 regulates cell growth viaMyc in drosophilardquo ScientificReports vol 5 Article ID 10339 2015

[81] T Porstmann C R Santos B Griffiths et al ldquoSREBP activityis regulated by mTORC1 and contributes to Akt-dependent cellgrowthrdquo Cell Metabolism vol 8 no 3 pp 224ndash236 2008

[82] M L Toth T Sigmond E Borsos et al ldquoLongevity path-ways converge on autophagy genes to regulate life span inCaenorhabditis elegansrdquo Autophagy vol 4 no 3 pp 330ndash3382008

[83] K M Hennig J Colombani and T P Neufeld ldquoTORcoordinates bulk and targeted endocytosis in the Drosophilamelanogaster fat body to regulate cell growthrdquo The Journal ofCell Biology vol 173 no 6 pp 963ndash974 2006

[84] J Colombani S Raisin S Pantalacci T Radimerski J Mon-tagne and P Leopold ldquoA nutrient sensor mechanism controlsDrosophila growthrdquo Cell vol 114 no 6 pp 739ndash749 2003

[85] C Geminard E J Rulifson and P Leopold ldquoRemote Control ofInsulin Secretion by Fat Cells in Drosophilardquo Cell Metabolismvol 10 no 3 pp 199ndash207 2009

[86] A Rajan and N Perrimon ldquoDrosophila cytokine unpaired2 regulates physiological homeostasis by remotely controllinginsulin secretionrdquo Cell vol 151 no 1 pp 123ndash137 2012

[87] S Lee and H H Dong ldquoFoxO integration of insulin signalingwith glucose and lipid metabolismrdquo Journal of Endocrinologyvol 233 no 2 pp R67ndashR79 2017

[88] A Brunet A Bonni M J Zigmond et al ldquoAkt promotescell survival by phosphorylating and inhibiting a forkheadtranscription factorrdquo Cell vol 96 no 6 pp 857ndash868 1999

[89] G J P L Kops N D de Ruiter A M M De Vries-Smits D RPowell J L Bos and B M T Burgering ldquoDirect control of theForkhead transcription factor AFX by protein kinase BrdquoNaturevol 398 no 6728 pp 630ndash634 1999

[90] J M Kramer J T Davidge J M Lockyer and B E StaveleyldquoExpression of Drosophila FOXO regulates growth and canphenocopy starvationrdquo BMC Developmental Biology vol 3article 5 2003

[91] M A Junger F Rintelen H Stocker et al ldquoThe Drosophilaforkhead transcription factor FOXO mediates the reduction incell number associated with reduced insulin signalingrdquo Journalof Biological Chemistry vol 2 no 3 article 20 2003

[92] D Accili and K C Arden ldquoFoxOs at the crossroads of cellularmetabolism differentiation and transformationrdquo Cell vol 117no 4 pp 421ndash426 2004

[93] D Schmoll K S Walker D R Alessi et al ldquoRegulationof glucose-6-phosphatase gene expression by protein kinaseB120572 and the Forkhead transcription factor FKHR Evidencefor insulin response unit-dependent and -independent effectsof insulin on promoter activityrdquo The Journal of BiologicalChemistry vol 275 no 46 pp 36324ndash36333 2000

[94] A Barthel D Schmoll and T G Unterman ldquoFoxO proteinsin insulin action and metabolismrdquo Trends in Endocrinology ampMetabolism vol 16 no 4 pp 183ndash189 2005

[95] G J P L Kops T B Dansen P E Polderman et al ldquoForkheadtranscription factor FOXO3a protects quiescent cells fromoxidative stressrdquo Nature vol 419 no 6904 pp 316ndash321 2002

[96] A E Webb and A Brunet ldquoFOXO transcription factors Keyregulators of cellular quality controlrdquo Trends in BiochemicalSciences vol 39 no 4 pp 159ndash169 2014

[97] J T Rodgers C Lerin W Haas S P Gygi B M Spiegelmanand P Puigserver ldquoNutrient control of glucose homeostasisthrough a complex of PGC-1120572 and SIRT1rdquo Nature vol 434 no7029 pp 113ndash118 2005

[98] A Erol ldquoInsulin resistance is an evolutionarily conservedphysiological mechanism at the cellular level for protectionagainst increased oxidative stressrdquo BioEssays vol 29 no 8 pp811ndash818 2007

[99] A V Budanov J H Lee and M Karin ldquoStressinrsquo Sestrins takean aging fightrdquo EMBO Molecular Medicine vol 2 no 10 pp388ndash400 2010

[100] J H Lee A V Budanov and M Karin ldquoSestrins orchestratecellularmetabolism to attenuate agingrdquoCellMetabolism vol 18no 6 pp 792ndash801 2013

[101] A Parmigiani A Nourbakhsh B Ding et al ldquoSestrins InhibitmTORC1 Kinase Activation through the GATOR ComplexrdquoCell Reports vol 9 no 4 pp 1281ndash1291 2014

[102] V Nogueira Y Park C-C Chen et al ldquoAkt determinesreplicative senescence and oxidative or oncogenic prematuresenescence and sensitizes cells to oxidative apoptosisrdquo CancerCell vol 14 no 6 pp 458ndash470 2008

[103] S H Bae S H Sung S Y Oh et al ldquoSestrins activate Nrf2 bypromoting p62-dependent autophagic degradation of keap1 andprevent oxidative liver damagerdquo Cell Metabolism vol 17 no 1pp 73ndash84 2013

[104] A V Budanov and M Karin ldquop53 target genes sestrin1 andsestrin2 connect genotoxic stress and mTOR signalingrdquo Cellvol 134 no 3 pp 451ndash460 2008

[105] J H Lee A V Budanov E J Park et al ldquoSestrin as a feedbackinhibitor of TOR that prevents age-related pathologiesrdquo Sciencevol 327 no 5970 pp 1223ndash1228 2010

[106] J S Kim S H Ro M Kim et al ldquoCorrigendum Sestrin2inhibits mTORC1 through modulation of GATOR complexesrdquoScientific Reports vol 5 article 14029 2015

[107] J S Kim S H Ro M Kim et al ldquoSestrin2 inhibits mTORC1through modulation of GATOR complexesrdquo Scientific Reportsvol 5 article 9502 2015

[108] M Peng N Yin and M O Li ldquoSZT2 dictates GATOR controlof mTORC1 signallingrdquo Nature vol 543 no 7645 pp 433ndash4372017

[109] J Brugarolas K Lei R L Hurley et al ldquoRegulation of mTORfunction in response to hypoxia by REDD1 and the TSC1TSC2tumor suppressor complexrdquo Genes amp Development vol 18 no23 pp 2893ndash2904 2004


[110] J H Reiling and E Hafen ldquoThe hypoxia-induced paralogsScylla and Charybdis inhibit growth by down-regulating S6Kactivity upstream of TSC in DrosophilardquoGenes ampDevelopmentvol 18 no 23 pp 2879ndash2892 2004

[111] Prevention CfDCa ldquoNational Diabetes Statistics ReportNational Institute of Diabetes and Digestive and KidneyDiseasesrdquo 2017 httpswwwcdcgovdiabetespdfsdatastatis-ticsnational-diabetes-statistics-reportpdf

[112] S E Kahn ldquoThe relative contributions of insulin resistance andbeta-cell dysfunction to the pathophysiology of type 2 diabetesrdquoDiabetologia vol 46 no 1 pp 3ndash19 2003

[113] S Bonner-Weir ldquoRegulation of pancreatic beta-cell mass invivordquo Recent Progress in Hormone Research vol 49 pp 91ndash1041994

[114] M O Larsen M Wilken C F Gotfredsen R D CarrO Svendsen and B Rolin ldquoMild streptozotocin diabetes inthe Gottingen minipig A novel model of moderate insulindeficiency and diabetesrdquo American Journal of Physiology-Endocrinology andMetabolism vol 282 no 6 pp E1342ndashE13512002

[115] A P Rolo and C M Palmeira ldquoDiabetes and mitochondrialfunction role of hyperglycemia and oxidative stressrdquoToxicologyand Applied Pharmacology vol 212 no 2 pp 167ndash178 2006

[116] N G Hattangady and M S Rajadhyaksha ldquoA brief review ofin vitro models of diabetic neuropathyrdquo International Journalof Diabetes in Developing Countries vol 29 no 4 pp 143ndash1492009

[117] J Wang T Takeuchi S Tanaka et al ldquoA mutation in theinsulin 2 gene induces diabetes with severe pancreatic 120573-cell dysfunction in the Mody mouserdquo The Journal of ClinicalInvestigation vol 103 no 1 pp 27ndash37 1999

[118] K P Hummel M M Dickie and D L Coleman ldquoDiabetes anewmutation in themouserdquo Science vol 153 no 3740 pp 1127-1128 1966

[119] H G Martinez M P Quinones F Jimenez et al ldquoCriticalrole of chemokine (CndashC motif) receptor 2 (CCR2) in theKKAy+Apoendashndash mouse model of the metabolic syndromerdquoDiabetologia vol 54 no 10 pp 2660ndash2668 2011

[120] J A Piedrahita S H Zhang J R Hagaman PM Oliver andNMaeda ldquoGeneration of mice carrying a mutant apolipoproteinE gene inactivated by gene targeting in embryonic stem cellsrdquoProceedings of the National Acadamy of Sciences of the UnitedStates of America vol 89 no 10 pp 4471ndash4475 1992

[121] K SMeir andE Leitersdorf ldquoAtherosclerosis in the apolipopro-tein E-deficient mouse a decade of progressrdquo ArteriosclerosisThrombosis and Vascular Biology vol 24 no 6 pp 1006ndash10142004

[122] T Matsuo and A Shino ldquoInduction of diabetic alterationsby goldthioglucose-obesity in KK ICR and C57BL micerdquoDiabetologia vol 8 no 6 pp 391ndash397 1972

[123] ldquoRegulation of food intake in fatty and lean growing Zuckerratsrdquo Nutrition Reviews vol 35 no 7 pp 181ndash183 1977

[124] H Ikeda A Shino T Matsuo H Iwatsuka and Z SuzuokildquoA new genetically obese-hyperglycemic rat (Wistar fatty)rdquoDiabetes vol 30 no 12 pp 1045ndash1050 1981

[125] MKitada A Takeda TNagai H Ito K Kanasaki andDKoyaldquoDietary restriction ameliorates diabetic nephropathy throughanti-inflammatory effects and regulation of the autophagy viarestoration of sirt1 in diabetic wistar fatty (fafa) rats a modelof type 2 diabetesrdquo Journal of Diabetes Research vol 2011 ArticleID 908185 11 pages 2011

[126] Y Katsuda T Sasase H Tadaki et al ldquoContribution of hyper-glycemia on diabetic complications in obese type 2 diabeticSDT fatty rats Effects of SGLT inhibitor phlorizinrdquo Journal ofExperimental Animal Science vol 64 no 2 pp 161ndash169 2014

[127] Y Katsuda T Ohta K Miyajima et al ldquoDiabetic complicationsin obese type 2 diabetic rat modelsrdquo Journal of ExperimentalAnimal Science vol 63 no 2 pp 121ndash132 2014

[128] M S H Akash K Rehman and S Chen ldquoGoto-kakizaki ratsIts suitability as non-obese diabetic animal model for sponta-neous type 2 diabetes mellitusrdquo Current Diabetes Reviews vol9 no 5 pp 387ndash396 2013

[129] C-G Ostenson and S Efendic ldquoIslet gene expression andfunction in type 2 diabetes studies in theGoto-Kakizaki rat andhumansrdquo Diabetes Obesity and Metabolism vol 9 supplement2 pp 180ndash186 2007

[130] E Broslashndum H Nilsson and C Aalkjaeligr ldquoFunctionalAbnormalities in Isolated Arteries from Goto-Kakizakiand Streptozotocin-treated Diabetic Rat Modelsrdquo Hormoneand Metabolic Research vol 37 pp 56ndash60 2005

[131] U Janssen A Vassiliadou S G Riley A O Phillips andJ Floege ldquoThe quest for a model of type II diabetes withnephropathyTheGotoKakizaki ratrdquo Journal of Nephrology vol17 no 6 pp 769ndash773 2004

[132] T Arndt D Wedekind A Jorns et al ldquoA novel Dock8gene mutation confers diabetogenic susceptibility in theLEW1AR1Ztm-iddm rat an animal model of human type 1diabetesrdquo Diabetologia vol 58 no 12 pp 2800ndash2809 2015

[133] A Jorns A Gunther H-J Hedrich D Wedekind M Tiedgeand S Lenzen ldquoImmune cell infiltration cytokine expressionand 120573-cell apoptosis during the development of type 1 diabetesin the spontaneously diabetic LEW1AR1Ztm-iddm ratrdquo Dia-betes vol 54 no 7 pp 2041ndash2052 2005

[134] S Lenzen M Tiedge M Elsner et al ldquoThe LEW1AR1Ztm-iddm rat a new model of spontaneous insulin-dependentdiabetes mellitusrdquo Diabetologia vol 44 no 9 pp 1189ndash11962001

[135] G Chakraborty S Thumpayil D-E Lafontant W Woubnehand J H Toney ldquoAge dependence of glucose tolerance inadult KK-A y mice a model of non-insulin dependent diabetesmellitusrdquo Lab Animal vol 38 no 11 pp 364ndash368 2009

[136] MCVeroni J Proietto andRG Larkins ldquoEvolution of insulinresistance in New Zealand obese micerdquo Diabetes vol 40 no 11pp 1480ndash1487 1991

[137] J Denvir G Boskovic J Fan D A Primerano J K Parkmanand J H Kim ldquoWhole genome sequence analysis of theTALLYHOJng mouserdquo BMC Genomics vol 17 no 1 article no907 2016

[138] P Bharill S Ayyadevara R Alla and R J Shmookler ReisldquoExtreme depletion of PIP3 accompanies the increased life spanand stress tolerance of PI3K-null C elegans mutantsrdquo Frontiersin Genetics vol 4 Article 34 2013

[139] M S Gami and C A Wolkow ldquoStudies of Caenorhabditiselegans DAF-2insulin signaling reveal targets for pharmaco-logical manipulation of lifespanrdquo Aging Cell vol 5 no 1 pp31ndash37 2006

[140] D L RiddleMM Swanson and P S Albert ldquoInteracting genesin nematode dauer larva formationrdquo Nature vol 290 no 5808pp 668ndash671 1981

[141] C A Wolkow M J Munoz D L Riddle and G RuvkunldquoInsulin receptor substrate and p55 orthologous adaptor pro-teins function in the Caenorhabditis elegans daf-2insulin-like


signaling pathwayrdquoThe Journal of Biological Chemistry vol 277no 51 pp 49591ndash49597 2002

[142] C T Murphy and P J Hu ldquoInsulininsulin-like growth factorsignaling in C elegansrdquoWormBook pp 1ndash43 2013

[143] Y Suh G Atzmon M-O Cho et al ldquoFunctionally significantinsulin-like growth factor I receptormutations in centenariansrdquoProceedings of the National Acadamy of Sciences of the UnitedStates of America vol 105 no 9 pp 3438ndash3442 2008

[144] K Hesp G Smant and J E Kammenga ldquoCaenorhabditiselegans DAF-16FOXO transcription factor and its mammalianhomologs associate with age-related diseaserdquo ExperimentalGerontology vol 72 pp 1ndash7 2015

[145] R T Birse J Choi K Reardon et al ldquoHigh-fat-diet-inducedobesity and heart dysfunction are regulated by the TOR path-way in Drosophilardquo Cell Metabolism vol 12 no 5 pp 533ndash5442010

[146] J Kim andT P Neufeld ldquoDietary sugar promotes systemic TORactivation in Drosophila through AKH-dependent selectivesecretion of Dilp3rdquo Nature Communications vol 6 article no7846 2015

[147] S N S Morris C Coogan K Chamseddin et al ldquoDevelop-ment of diet-induced insulin resistance in adult Drosophilamelanogasterrdquo Biochimica et Biophysica Acta vol 1822 no 8pp 1230ndash1237 2012

[148] L P Musselman J L Fink K Narzinski et al ldquoA high-sugar diet produces obesity and insulin resistance in wild-typeDrosophilardquo Disease Models amp Mechanisms vol 4 no 6 pp842ndash849 2011

[149] L M Matzkin S Johnson C Paight G Bozinovic and TA Markow ldquoDietary protein and sugar differentially affectdevelopment and metabolic pools in ecologically diverseDrosophilardquo Journal of Nutrition vol 141 no 6 pp 1127ndash11332011

[150] L M Matzkin S Johnson C Paight and T A MarkowldquoPreadult Parental Diet Affects Offspring Development andMetabolism in Drosophila melanogasterrdquo PLoS ONE vol 8 no3 Article ID e59530 2013

[151] T A Markow P M OrsquoGrady and ebrary Inc ldquoDrosophila aguide to species identification and userdquo 2006

[152] L M Matzkin T D Watts B G Bitler C A Machado andT A Markow ldquoFunctional genomics of cactus host shifts inDrosophila mojavensisrdquo Molecular Ecology vol 15 no 14 pp4635ndash4643 2006

[153] L M Matzkin K Mutsaka S Johnson and T A MarkowldquoMetabolic pools differ among ecologically diverse Drosophilaspeciesrdquo Journal of Insect Physiology vol 55 no 12 pp 1145ndash1150 2009

[154] T A Markow L M Matzkin and T D Watts ldquoDesiccationresistance in four Drosophila species Sex and populationeffectsrdquo Flight Journal vol 1 no 5 pp 268ndash273 2007

[155] A Sanchez-Flores F Penaloza J Carpinteyro-Ponce et alldquoGenome evolution in three species of cactophilic drosophilardquoG3 Genes Genomes Genetics vol 6 no 10 pp 3097ndash3105 2016

[156] S W Schaeffer A Bhutkar B F McAllister et al ldquoPolytenechromosomal maps of 11 drosophila species The order ofgenomic scaffolds inferred from genetic and physical mapsrdquoGenetics vol 179 no 3 pp 1601ndash1655 2008

[157] X Song J L Goicoechea J S S Ammiraju et al ldquoThe 19genomes of Drosophila A BAC library resource for genus-wide and genome-scale comparative evolutionary researchrdquoGenetics vol 187 no 4 pp 1023ndash1030 2011

[158] D Alvarez-Ponce M Aguade and J Rozas ldquoNetwork-levelmolecular evolutionary analysis of the insulinTOR signaltransduction pathway across 12 Drosophila genomesrdquo GenomeResearch vol 19 no 2 pp 234ndash242 2009

[159] Cornell-University Drosophila Stock Center 2017 httpblogscornelledudrosophila

[160] JW O Ballard R GMelvin J T Miller and S D Katewa ldquoSexdifferences in survival and mitochondrial bioenergetics duringaging in DrosophilardquoAging Cell vol 6 no 5 pp 699ndash708 2007

[161] R G Melvin W A Van Voorhies and J W O BallardldquoWorking harder to stay alive metabolic rate increases with agein Drosophila simulans but does not correlate with life spanrdquoJournal of Insect Physiology vol 53 no 12 pp 1300ndash1306 2007

[162] CD Jones ldquoThe genetics of adaptation inDrosophila sechelliardquoGenetica vol 123 no 1-2 pp 137ndash145 2005

[163] M Amlou B Moreteau and J R David ldquoGenetic analysisof Drosophila sechellia specialization Oviposition behaviortoward the major aliphatic acids of its host plantrdquo BehaviorGenetics vol 28 no 6 pp 455ndash464 1998

[164] A Yassin V Debat H Bastide N Gidaszewski J R David andJ E Pool ldquoRecurrent specialization on a toxic fruit in an islandDrosophila populationrdquo Proceedings of the National Acadamy ofSciences of the United States of America vol 113 no 17 pp 4771ndash4776 2016

[165] L M Matzkin ldquoEcological genomics of host shifts inDrosophila mojavensisrdquo Advances in Experimental Medicineand Biology vol 781 pp 233ndash247 2014

[166] W T Starmer W B Heed and E S Rockwood Sluss ldquoExten-sion of longevity in Drosophila mojavensis by environmen-tal ethanol differences between subracesrdquo Proceedings of theNational Acadamy of Sciences of the United States of Americavol 74 no 1 pp 387ndash391 1977

[167] C K Mirth and A W Shingleton ldquoIntegrating body and organsize inDrosophila Recent advances and outstanding problemsrdquoFrontiers in Endocrinology vol 3 Article ID Article 49 2012

[168] M Jalal T Andersen and D O Hessen ldquoTemperature anddevelopmental responses of body and cell size in Drosophilaeffects of polyploidy and genome configurationrdquo Journal ofThermal Biology vol 51 pp 1ndash14 2015

[169] A B Paaby and P S Schmidt ldquoDissecting the genetics oflongevity in drosophila melanogasterrdquo Flight Journal vol 3 no1 pp 29ndash38 2009

[170] D A Green II and C G Extavour ldquoInsulin signalling under-lies both plasticity and divergence of a reproductive traitin Drosophilardquo Proceedings of the Royal Society B BiologicalScience vol 281 no 1779 Article ID 20132673 2014

[171] A C-N Wong A J Dobson and A E Douglas ldquoGutmicrobiota dictates the metabolic response of Drosophila todietrdquo Journal of Experimental Biology vol 217 no 11 pp 1894ndash1901 2014

[172] J M Chaston A J Dobson P D Newell and A E Dou-glas ldquoHost genetic control of the microbiota mediates theDrosophila nutritional phenotyperdquo Applied and EnvironmentalMicrobiology vol 82 no 2 pp 671ndash679 2016

[173] T Ikeya S Broughton N Alic R Grandison and L Par-tridge ldquoThe endosymbiont Wolbachia increases insulinIGF-like signalling in Drosophilardquo Proceedings of the Royal SocietyB Biological Science vol 276 no 1674 pp 3799ndash3807 2009

[174] S C Shin S-H Kim H You et al ldquoDrosophila microbiomemodulates host developmental and metabolic homeostasis viainsulin signalingrdquo Science vol 334 no 6056 pp 670ndash674 2011


[175] P D Newell and A E Douglas ldquoInterspecies InteractionsDetermine the Impact of the Gut Microbiota on Nutrient Allo-cation in Drosophila melanogasterrdquoApplied and EnvironmentalMicrobiology vol 80 no 2 pp 788ndash796 2014

[176] J M Toivonen and L Partridge ldquoEndocrine regulation ofaging and reproduction in DrosophilardquoMolecular and CellularEndocrinology vol 299 no 1 pp 39ndash50 2009

[177] C S Erdogan B W Hansen and O Vang ldquoAre invertebratesrelevant models in ageing research Focus on the effects ofrapamycin on TORrdquo Mechanisms of Ageing and Developmentvol 153 pp 22ndash29 2016

[178] K-J Min R Yamamoto S Buch M Pankratz and M TatarldquoDrosophila lifespan control by dietary restriction independentof insulin-like signalingrdquo Aging Cell vol 7 no 2 pp 199ndash2062008

[179] J M Hoffman Q A Soltow S Li A Sidik D P Jones andD E L Promislow ldquoEffects of age sex and genotype on high-sensitivity metabolomic profiles in the fruit fly Drosophilamelanogasterrdquo Aging Cell vol 13 no 4 pp 596ndash604 2014

[180] S Buch C Melcher M Bauer J Katzenberger and M JPankratz ldquoOpposing Effects of Dietary Protein and SugarRegulate a Transcriptional Target of Drosophila Insulin-likePeptide Signalingrdquo Cell Metabolism vol 7 no 4 pp 321ndash3322008

[181] V T Samuel and G I Shulman ldquoThe pathogenesis of insulinresistance integrating signaling pathways and substrate fluxrdquoThe Journal of Clinical Investigation vol 126 no 1 pp 12ndash222016

[182] E T Heinrichsen H Zhang J E Robinson et al ldquoMetabolicand transcriptional response to a high-fat diet in Drosophilamelanogasterrdquo Molecular Metabolism vol 3 no 1 pp 42ndash542014

[183] K D Bruce S Hoxha G B Carvalho et al ldquoHigh carbohy-drate-low protein consumption maximizes Drosophila lifes-panrdquo Experimental Gerontology vol 48 no 10 pp 1129ndash11352013

[184] K P Lee ldquoDietary protein Carbohydrate balance is a crit-ical modulator of lifespan and reproduction in Drosophilamelanogaster A test using a chemically defined dietrdquo Journalof Insect Physiology vol 75 pp 12ndash19 2015

[185] D A Skorupa A Dervisefendic J Zwiener and S D PletcherldquoDietary composition specifies consumption obesity and lifes-pan in Drosophila melanogasterrdquo Aging Cell vol 7 no 4 pp478ndash490 2008

[186] S D Pletcher S Libert andD Skorupa ldquoFlies and their GoldenApplesThe effect of dietary restriction onDrosophila aging andage-dependent gene expressionrdquo Ageing Research Reviews vol4 no 4 pp 451ndash480 2005

[187] M Tatar S Post and K Yu ldquoNutrient control of Drosophilalongevityrdquo Trends in Endocrinology amp Metabolism vol 25 no10 pp 509ndash517 2014

[188] M DW Piper D Skorupa and L Partridge ldquoDiet metabolismand lifespan in Drosophilardquo Experimental Gerontology vol 40no 11 pp 857ndash862 2005

[189] L Partridge M D Piper and W Mair ldquoDietary restriction inDrosophilardquo Mechanisms of Ageing and Development vol 126no 9 pp 938ndash950 2005

[190] W Mair M D W Piper and L Partridge ldquoCalories donot explain extension of life span by dietary restriction inDrosophilardquo PLoS Biology vol 3 no 7 article e223 2005

[191] J-E Lee M Rayyan A Liao I Edery and S D Pletcher ldquoAcuteDietary Restriction Acts via TOR PP2A and Myc Signaling toBoost Innate Immunity in DrosophilardquoCell Reports vol 20 no2 pp 479ndash490 2017

[192] T Lian U Gaur D Yang D Li Y Li and M Yang ldquoEpi-genetic mechanisms of dietary restriction induced aging inDrosophilardquo Experimental Gerontology vol 72 pp 38ndash44 2015

[193] S Post and M Tatar ldquoNutritional geometric profiles ofinsulinIGF expression in Drosophila melanogasterrdquo PLoSONE vol 11 no 5 Article ID e0155628 2016

[194] B Lakowski and S Hekimi ldquoThe genetics of caloric restrictioninCaenorhabditis elegansrdquo Proceedings of the National Acadamyof Sciences of the United States of America vol 95 no 22 pp13091ndash13096 1998

[195] S-J Lin M Kaeberlein A A Andalis et al ldquoCalorie restrictionextends Saccharomyces cerevisiae lifespan by increasing respira-tionrdquo Nature vol 418 no 6895 pp 344ndash348 2002

[196] WMair P Goymer S D Pletcher and L Partridge ldquoDemogra-phy of dietary restriction and death in Drosophilardquo Science vol301 no 5640 pp 1731ndash1733 2003

[197] B C Lee A Kaya S Ma et al ldquoMethionine restriction extendslifespan of Drosophila melanogaster under conditions of lowamino-acid statusrdquoNature Communications vol 5 article 35922014

[198] R A S Palu S A Praggastis and C S Thummel ldquoParentalobesity leads to metabolic changes in the F2 generation inDrosophilardquo Molecular Metabolism vol 6 no 7 pp 631ndash6392017

[199] S Park R W Alfa S M Topper G E S Kim L Kockeland S K Kim ldquoA Genetic Strategy to Measure CirculatingDrosophila Insulin Reveals Genes Regulating Insulin Produc-tion and Secretionrdquo PLoS Genetics vol 10 no 8 Article IDe1004555 2014

[200] S Oldham R Bohni H Stocker W Brogiolo and E HafenldquoGenetic control of size in Drosophilardquo Philosophical Transac-tions of the Royal Society B Biological Sciences vol 355 no 1399pp 945ndash952 2000

[201] S Oldham and E Hafen ldquoInsulinIGF and target of rapamycinsignaling a TOR de force in growth controlrdquo Trends in CellBiology vol 13 no 2 pp 79ndash85 2003

[202] D J Clancy D Gems L G Harshman et al ldquoExtension of life-span by loss of CHICO a Drosophila insulin receptor substrateproteinrdquo Science vol 292 no 5514 pp 104ndash106 2001

[203] R W Alfa and S K Kim ldquoUsing Drosophila to discovermechanisms underlying type 2 diabetesrdquo Disease Models ampMechanisms vol 9 no 4 pp 365ndash376 2016

[204] R S Garofalo ldquoGenetic analysis of insulin signaling inDrosophilardquo Trends in Endocrinology ampMetabolism vol 13 no4 pp 156ndash162 2002

[205] M Lehmann ldquoEndocrine and physiological regulation ofneutral fat storage in Drosophilardquo Molecular and CellularEndocrinology vol 461 pp 165ndash177 2018

[206] L Partridge ldquoSome highlights of research on aging withinvertebrates 2010rdquo Aging Cell vol 10 no 1 pp 5ndash9 2011

[207] L Partridge N Alic I Bjedov and M D W Piper ldquoAgeingin Drosophila the role of the insulinIgf and TOR signallingnetworkrdquo Experimental Gerontology vol 46 no 5 pp 376ndash3812011

[208] D S Hwangbo B Gersham M Tu M Palmer and M TatarldquoDrosophila dFOXO controls lifespan and regulates insulinsignalling in brain and fat bodyrdquo Nature vol 429 no 6991 pp562ndash566 2004


[209] J R DiAngelo M L Bland S Bambina S Cherry and MJ Birnbaum ldquoThe immune response attenuates growth andnutrient storage in Drosophila by reducing insulin signalingrdquoProceedings of the National Acadamy of Sciences of the UnitedStates of America vol 106 no 49 pp 20853ndash20858 2009

[210] B Biteau J Karpac S Supoyo M Degennaro R Lehmannand H Jasper ldquoLifespan extension by preserving proliferativehomeostasis in Drosophilardquo PLoS Genetics vol 6 no 10 pe1001159 2010

[211] J Karpac B Biteau and H Jasper ldquoMisregulation of anAdaptive Metabolic Response Contributes to the Age-RelatedDisruption of Lipid Homeostasis in Drosophilardquo Cell Reportsvol 4 no 6 pp 1250ndash1261 2013

[212] W Song D Cheng S Hong et al ldquoMidgut-Derived ActivinRegulates Glucagon-like Action in the Fat Body and GlycemicControlrdquo Cell Metabolism vol 25 no 2 pp 386ndash399 2017

[213] L P Musselman J L Fink and T J Baranski ldquoCoA pro-tects against the deleterious effects of caloric overload inDrosophila1rdquo Journal of Lipid Research vol 57 no 3 pp 380ndash387 2016

[214] H Augustin K McGourty M J Allen et al ldquoReduced insulinsignaling maintains electrical transmission in a neural circuitin aging fliesrdquo PLoS Biology vol 15 no 9 Article ID e20016552017

[215] Y Li J Hoffmann Y Li et al ldquoOctopamine controls starvationresistance life span and metabolic traits in Drosophilardquo Scien-tific Reports vol 6 Article ID 35359 2016

[216] J Na L P Musselman J Pendse et al ldquoA Drosophila Model ofHigh Sugar Diet-Induced Cardiomyopathyrdquo PLoS Genetics vol9 no 1 Article ID e1003175 2013

[217] Q-PWang Y Q Lin L Zhang et al ldquoSucralose Promotes FoodIntake through NPY and a Neuronal Fasting Responserdquo CellMetabolism vol 24 no 1 pp 75ndash90 2016

[218] M J Williams L Wiemerslage P Gohel S Kheder L VKothegala and H B Schioth ldquoDibutyl phthalate exposuredisrupts evolutionarily conserved insulin and glucagon-likesignaling in drosophilamalesrdquo Endocrinology vol 157 no 6 pp2309ndash2321 2016

[219] M E Yurgel P Masek J DiAngelo and A C Keene ldquoGeneticdissection of sleepndashmetabolism interactions in the fruit flyrdquoJournal of Comparative Physiology A Neuroethology SensoryNeural and Behavioral Physiology vol 201 no 9 pp 869ndash8772015

[220] M Robertson and A C Keene ldquoMolecular mechanisms of age-related sleep loss in the fruit fly-amini-reviewrdquoGerontology vol59 no 4 pp 334ndash339 2013

[221] X Cong H Wang Z Liu C He C An and Z Zhao ldquoReg-ulation of sleep by insulin-like peptide system in drosophilamelanogasterrdquo SLEEP vol 38 no 7 pp 1075ndash1083 2015

[222] L B Mensah D C I Goberdhan and C Wilson ldquoMTORC1signalling mediates PI3K-dependent large lipid droplet accu-mulation in Drosophila ovarian nurse cellsrdquo Biology Open vol6 no 5 pp 563ndash570 2017

[223] Y Liu S Liao J A Veenstra and D R Nassel ldquoDrosophilainsulin-like peptide 1 (DILP1) is transiently expressed dur-ing non-feeding stages and reproductive dormancyrdquo ScientificReports vol 6 Article ID 26620 2016

[224] T Gu T Zhao and R S Hewes ldquoInsulin signaling regulatesneurite growth during metamorphic neuronal remodelingrdquoBiology Open vol 3 no 1 pp 81ndash93 2014

[225] A T Haselton and Y-W C Fridell ldquoAdult Drosophilamelanogaster as a model for the study of glucose homeostasisrdquoAGING vol 2 no 8 pp 523ndash526 2010

[226] H-J Hsu and D Drummond-Barbosa ldquoInsulin levels con-trol female germline stem cell maintenance via the niche inDrosophilardquo Proceedings of the National Acadamy of Sciences ofthe United States of America vol 106 no 4 pp 1117ndash1121 2009

[227] D J Clancy D Gems E Hafen S J Leevers and L PartridgeldquoDietary restriction in long-lived dwarf fliesrdquo Science vol 296no 5566 p 319 2002

[228] M E Giannakou M Goss M A Junger E Hafen S J Leeversand L Partridge ldquoLong-lived Drosophila with over-expresseddFOXO in adult fat bodyrdquo Science vol 305 no 5682 p 3612004

[229] M A Jones J W Gargano D Rhodenizer I Martin PBhandari and M Grotewiel ldquoA forward genetic screen inDrosophila implicates insulin signaling in age-related locomo-tor impairmentrdquo Experimental Gerontology vol 44 no 8 pp532ndash540 2009

[230] T Glatter R B Schittenhelm O Rinner et al ldquoModularityand hormone sensitivity of theDrosophilamelanogaster insulinreceptortarget of rapamycin interaction proteomerdquo MolecularSystems Biology vol 7 article no 547 2011

Hindawiwwwhindawicom

International Journal of

Volume 2018

Zoology

Hindawiwwwhindawicom Volume 2018

Anatomy Research International

PeptidesInternational Journal of



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It leads to elevated blood glucose levels as expected and togeneral body wasting

Diabetes type 2 represents the majority of cases rangingbetween 90 and 95of all diabetic patients It is characterizedby a combination of insulin resistance and insulin secretiondefects resulting in relative insulin deficiency and hyper-glycemia [6] Diabetic type 2 patients normally representpatients that have had a long progression initially sufferingfrom metabolic syndrome andor being overweight andorbeing obese for several years Environmental factors like dietand level of physical exercise also play an important role inthe inception and progression of the disease as noted above

Finally there is also a third type of diabetes gestationaldiabetes This form of diabetes occurs in pregnant womenleads to increased risk of diabetes for the offspring and maylead to diabetes type 2 in the mothers after birth [2]

There are in sum many factors causing diabetes type 2both genetic and environmental and the composite pictureis complex as it may change depending on the actualcombination present in populations and individual patients[2] While all of the factors cited above are recognizedcontributing factors it is not clear how they weigh in theinitiation and early progression of the disease Therefore itis important to elucidate the precise molecular mechanismsunderlying the development and progression of the disease

In general the diabetic state is multifactorial encom-passing several origins and progressions Studying its causeseffects and consequences is paramount in the actual diabetesldquoepidemicrdquo but it is not easy or even possible to studymany of these aspects using human patients as test subjectsScientists have developed model systems where diabetes canbe controlled to a higher extent and in which experimentalsetups with a high degree of rigor and reproducibility canbe used with genetic uniformity and highly controlledenvironments Principles uncovered in these systems canthen be applied in a more general fashion as the insulinpathway and glucose control is a common evolutionarilyconserved mechanism in the animal kingdom (Figure 1)

11 The Insulin Pathway Insulin is an anabolic hormone inglucose homeostasis in experimentally pancreatomized dogs[7] discovered by Banting and Best who won the Nobel Prizefor this discovery [8] In general in vertebrates insulin issecreted from pancreatic Langerhans islets szlig-type cells inresponse to increased glucose levels In some teleost fishinsulin is produced in Brockmannrsquos bodies [9] Secretedinsulin in the bloodstream binds to membrane receptorsespecially inmuscle cells and initiates a transduction cascadethat leads to glucose internalization and an anabolic responseIn invertebrates the insulin molecule is slightly longer hasone more disulphide bridge and is secreted from specializedneurons (insulin-producing cells or IPC) and glia in thebrain [10] Recently in a striking novel use insulin-likepeptides have been identified in the venom of certain Conusmollusks able to bind insulin receptor molecules and inducehypoglycemia in fish prey [11 12]

Insulin is a small polypeptide constituted by two chainslinked by disulphide bonds synthesized from the samegene [13] Whereas vertebrates have one insulin gene the

Drosophila genome codes for seven several insulin-like pep-tides secreted from the insulin-producing cells (IPC) of thebrain A further eightDrosophila insulin-like peptide DILP8is really a relaxin homolog binding to a different type ofreceptor and controlling corporal symmetry [14ndash17]

The Drosophila insulin-like peptides (ILPs) also havenonredundant functions [18ndash20] The ILP2 peptide has thehighest homology to the vertebrate insulin gene and issynthesized together with ILP1 ILP3 and ILP5 in the IPCsof the brain and their synthesis depends on ILP3 ILP3expression also activates the insulin pathway in the fat body[21] ILP4 ILP5 and ILP6 are expressed in the midgut ILp7is expressed in the ventral nerve chord and ILp2 is alsoexpressed in the salivary glands and imaginal discs [22]The Drosophila IPCs are the equivalent of the mammalianLangerhansrsquo islets szlig pancreatic cells [23] ILP6 is synthesizedin the fat body and can partially substitute for ILP2 andILP5 ILP2 loss-of-function mutations lead to an increase inlifespan while loss in ILP6 causes reduced growth [23 24]

An insulin monomer is around 50 amino acid residues inlength but dimers form in solution Insulin is synthesized asa single polypeptide called preproinsulin which is processedin the endoplasmic reticulum forming proinsulin whichthen undergoes maturation through the action of peptidasesreleasing a fragment called the C-peptide and the A and Bchains linked by disulfide bonds Mature insulin is exocy-tosed into the circulation by glucose stimulation and bindsto plasma membrane receptors with tyrosine kinase activity

Insulin is a potent anabolic hormone in vertebrates [25]It also exerts a variety of actions in flies including effects onglucose lipid and protein metabolism It directly promotesgrowth and proliferation in tissues rather than differentiation[26 27] In vertebrates insulin stimulates glucose uptakein skeletal muscle and fat promotes glycogen synthesis inskeletal muscle suppresses hepatic glucose production andinhibits lipolysis in adipocytes [28] Although vertebrateskeletal muscle liver and adipose tissue are considered themain target tissues of insulin action there is evidence thatinsulin has important physiological functions in other tissuessuch as the brain pancreas heart and endothelial cells[29 30] Pretty much the same is true for invertebrates inequivalent tissues where insulin action has been shown toimpinge on the physiology of many tissues including thebrain [31] In vertebrates there are insulin-growth factorbinding proteins (IGFBPs) that conform to an evolutionar-ily conserved superfamily regulating insulin-growth factorfunction in Drosophila the homolog is ecdysone-induciblegene 2 (Imp-L2) [32]

In vertebrates it is thought that insulin-like growthfactor binding proteins IGFBPs and a third protein ALS(acid-labile subunit) form ternary complexes with IGFs toregulate IGF function separating insulin functions from IGFsfunctions [33] In flies ILPs have both vertebrate insulinand IGF functions The Drosophila genome codes for aputative IGFBP-acid-labile subunit (IGFBP-ALS) homologconvoluted that has been shown to bind in vitro by ectopicexpression to ILPs and Imp-L2 forming a ternary complex[34] However mutations (even null mutations) in convolutedhave mutant phenotypes that differ from insulin pathway


dPI3KPI3K

dPDK1PDK1

dAktPKB

AktPKB

dTOR-C1mTOR-C1

dFOXOFOXO

d4E-BP4E-BP

dS6KS6K

dRhebRheb

dTsc1-2Tsc1-2

InRInsulinIGF

receptors

dPTENPTEN

PIP3PIP2

SlimfastCAT-1

dSREBPSREBP


PIP3

dTOR-C2mTOR-C2


dMycMyc


IGFs

PIP3

Amino acids

dGSK3ShaggyGSK3

IRSchico

IRS1ndash4




























































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dPDK1PDK1

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dTOR-C1mTOR-C1

dFOXOFOXO

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dS6KS6K

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Volume 2018







































































































































































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Volume 2018


Documents

dDrosophila melanogaster is a Model for Diabetes Type II …downloads.hindawi.com/journals/bmri/aip/1417528.pdf2018-03-13768 doi:10.1016/j.cnur.2017.07.002 769 6. Kahn BB, Flier JS