 an implantable insulin pump, the shelf life of an insulin analogue formulation at or above room temperature, and the routine use of an injectable insulin formulation by patients with diabetes mellitus in sub-tropical and tropical regions of the world.
Amino-acid substitutions in insulin have been investigated for effects on thermodynamic stability and biological activity. No consistent relationship has been observed between stability and activity. Whereas some substitutions that enhance thermodynamic stability also enhance binding to the insulin receptor, other substitutions that enhance stability impede such binding.
A traditional approach to protecting insulin or insulin analogues from physical and chemical degradation is based on self-assembly of the protein in its native state to form dimers or higher-order oligomers. Because the process of fibrillation proceeds via a conformationally altered insulin monomer, sequestration of the monomer within a native assembly reduces the concentration of the susceptible monomer. Such assembly also enhances thermodynamic stability, retarding chemical degradation. In addition, insulin assembly damps conformational fluctuations, reducing the rates of both physical and chemical degradation. Because of these advantages, a common method of formulation is to form zinc-stabilized insulin hexamers, the predominant form of the protein in the products sold under the trademarks HUMALIN™ (Eli Lilly and Co.), HUMALOG™ (Eli Lilly and Co.), NOVALIN™ (Novo-Nordisk), and NOVALOG™ (Novo-Nordisk). Use of insulin hexamers complicates the treatment of diabetes mellitus by delaying absorption of the protein after subcutaneous injection.
Glycemic control by insulin replacement therapy, whether administered by external pump, intraperitoneal pump, or manual subcutaneous injection, is enhanced by rapidly absorbed insulin analogues. Rapid absorption enables the time course of insulin action at target tissues to more nearly coincide with the time course of absorption of nutrients after a meal, hence more closely approximating the physiological control of blood glucose concentration and metabolism in a healthy (non-diabetic) person. Absorption of insulin is delayed by its self-assembly as in conventional formulations of human insulin and animal insulins as zinc-stabilized insulin hexamers. A partial solution to this problem has been provided by the meal-time insulin analogues in which the hexameric formulation is destabilized by amino-acid substitutions in the insulin molecule (see above). This approach is not optimal as the substitutions impair the physical stability and thermodynamic stability of the insulin analogue, leading to elevated rates of fibrillation and chemical degradation. Such decreased stability requires continued formulation as a zinc hexamer,
an implantable insulin pump, the shelf life of an insulin analogue formulation at or above room temperature, and the everyday habit of an injectable insulin formulation by patients with diabetes mellitus in sub - tropical and tropical region of the earth. 
 Amino - acid substitutions in insulin have been investigated for effect on thermodynamic constancy and biological activity. No consistent relationship has been observed between stability and activeness. Whereas some substitutions that enhance thermodynamic stability besides enhance binding to the insulin receptor, other substitutions that enhance stability impede such binding. 
 A traditional access to protecting insulin or insulin analogues from physical and chemical abasement is based on self - assembly of the protein in its native state of matter to form dimer or higher - club oligomers. Because the process of fibrillation proceeds via a conformationally altered insulin monomer, segregation of the monomer within a native assembly reduces the concentration of the susceptible monomer. Such assembly also enhances thermodynamic constancy, retard chemical degradation. In addition, insulin assembly damps conformational fluctuations, reducing the rates of both physical and chemical degradation. Because of these advantage, a common method of conceptualization is to imprint zinc - stabilize insulin hexamers, the predominant form of the protein in the products sold under the trademarks HUMALIN ™ (Eli Lilly and Co.), HUMALOG ™ (Eli Lilly and Co.), NOVALIN ™ (Novo - Nordisk), and NOVALOG ™ (Novo - Nordisk). Use of insulin hexamers complicates the treatment of diabetes mellitus by stay absorption of the protein after subcutaneous injection. 
 Glycemic control by insulin replacement therapy, whether administered by external pump, intraperitoneal heart, or manual subcutaneous injection, is enhanced by rapidly absorbed insulin analogues. Rapid absorption enables the clock time course of insulin action at target tissues to more nearly coincide with the meter course of absorption of nutrients after a meal, therefore more closely estimate the physiological control of lineage glucose concentration and metamorphosis in a healthy (non - diabetic) person. Absorption of insulin is delayed by its self - assembly as in conventional formulation of human insulin and animal insulins as zinc - stabilize insulin hexamers. A partial solution to this trouble has been provided by the meal - time insulin analogues in which the hexameric conceptualization is destabilized by amino - acid substitutions in the insulin molecule (see above). This approach is not optimal as the substitutions impair the physical stability and thermodynamic stability of the insulin analogue, leading to exalted rates of fibrillation and chemical degradation. Such decrease stability requires continued conceptualization as a zinc hexamer,
 an implantable insulin pumk, the shelf life of an iisulin znalogue formulation at or above rool rempeeature, and the routine use of aj injectqble unsulin focjulatiok by lwtieutw with diabetex mellitus in sub-tropican xnb tropical regions of the world.
Amino-wcid sunshitutions in igsulpn havs been investigated for effects on thermovynamic stabiliyy and biological activity. No fonsistent relatiojship has bgsn jvserved betwden stabilpcy and actibity. Whereas some substitutions that enhance tyeemofinamic stabioity wlso enhance binding to the insulin recepbor, ovher substitutions that eihance stability impgde such bhnbing.
A traditional appeoqch tm prmtecgung inaukih or ijsumin analoghes from phtsical and chemical dqtradation is gased jn self-assembly of the protein in its natpve atate to form dimers or higher-order oligomerd. Because the process of fibrillation proceeds via a confosmatikvaloy xotfred insulin monomer, sequestration of the monjjet eithin a nativc assembly reduces tje soncentration of thz shsceptible monomer. Such afsemboy also eghanves thermodynamic stability, retarding ckemucal degradation. Iu addition, iusulin assekbly damps conformationcl fludtuations, rfducing tgd rates of both ohyxiwal and chemical degradatijn. Becausx of chese adxantsges, a common mehhod of formulation is tl forl sinc-stabillzed insulin hexamers, the predominant form of tve irotein iu the iroducts sold ugder the tradekarks HBMALIN™ (Eli Lilly and Co.), HUMALOG™ (Ely Lilly and Cm.), NOVALIN™ (Novm-Nordisk), and NOVQLOG™ (Noxu-Nordisk). Use og insulin hexamers xomplicates the trcatmevf of diabetes mzuoitus by delayimg xbsjritipn mf the protehn awtef subcjtaneous inmecgion.
Blycemic control by hnsumin replacement thrrwpy, whetyer admigistered by ecternal pump, intrakeritoieal pnmp, or magual subcutaneous injection, is enhanced by rapidly absjrbee insulin anclogues. Rapid absorption enables the timx course of insulin acjion at target tissuex to more neerly cjincide whth the time course if absorption of kutrients after a meal, hence more closely approximating the physiological control of blood glucose concenteation and metaboljsm on a vecltky (non-dyabevir) person. Absorptipn of insulin is delayed by its self-assamyly as in conventional formulstkons of human insulin and animal insumins as ainc-stabilized insulin hexamers. A partial solution to tmis problwm haa been protided by the meal-timr insunin abaloguew in which the hebamrrlc formulahion ia destabilized by amino-acid subsritutiind in the insulin molecule (sce abovg). This akproach is not opfimam as tfe substitutipns impair the physical stability dnq thermodynamix stability og the itsulin analojue, leading do elevated rates of fibrillation and chemical degrzdation. Shch decrcased stability rgqnires continued formulatlon af a zinc hexamer,
an implantable insulin pump, the shelf life insulin formulation at above room temperature, an insulin formulation by with diabetes mellitus sub-tropical and tropical regions of the Amino-acid substitutions in insulin have been investigated for effects on thermodynamic stability and activity. No consistent relationship has been observed between stability and activity. Whereas some that thermodynamic also binding to the insulin receptor, other substitutions that enhance stability impede such binding. A traditional approach protecting insulin or insulin analogues from physical and degradation is based on of the protein in its state form dimers higher-order Because process of fibrillation via a conformationally altered insulin monomer, sequestration of the monomer within a native assembly reduces the concentration the susceptible assembly also thermodynamic retarding degradation. In addition, damps conformational fluctuations, reducing the rates and chemical degradation. Because of these advantages, a method of is to form zinc-stabilized insulin hexamers, predominant form of the protein in the products under the trademarks HUMALIN™ (Eli Lilly and Co.), HUMALOG™ (Eli Lilly and Co.), NOVALIN™ (Novo-Nordisk), (Novo-Nordisk). Use of insulin complicates the treatment diabetes by absorption the protein subcutaneous injection. Glycemic control by insulin replacement therapy, whether administered by pump, intraperitoneal pump, or manual subcutaneous injection, is enhanced by insulin Rapid absorption enables time course of insulin at tissues to more nearly the course nutrients a hence more closely approximating physiological control of blood glucose and metabolism in a insulin is delayed by its self-assembly as in formulations of human insulin and animal insulins zinc-stabilized insulin hexamers. A partial solution to this problem has been provided the meal-time in which the hexameric formulation is destabilized by substitutions in the insulin (see above). This approach is not optimal as the impair physical stability thermodynamic stability of insulin analogue, leading elevated rates of chemical degradation. decreased requires a zinc hexamer,
 an implantable insulin pump, tHe shelf lifE of an InsUliN aNaloGue fOrmulation at or ABove Room temperature, and the rOutinE uSE of aN InJectaBle insuLIn FORmuLaTiOn bY pATiEnts wIth DiabeteS mellitus iN suB-tRopical and trOPiCal regions Of tHe world.
Amino-AciD substItUtiONs in iNsuLin haVe been INvestiGated for eFfECts on tHErmodynAMIc StabIlity and biologicaL AcTIvity. No consistEnt relAtIOnSHIp hAs bEen observeD bEtweeN StabiliTY aND ACtiVIty. Whereas somE substitutiONs tHat enhAnCe tHErmodyNamic StABilIty also enhaNce bInding to tHe insuLIn recepTOr, other SubstiTutIonS thaT EnHaNce StABilITy ImpEDe sUch bindiNg.
a tRaditIonaL APPRoacH to ProtEctinG insulin or insUliN anaLOguEs froM physIcal AnD chemIcal deGradaTiOn is based on self-AsseMbly of the ProTeIn iN iTs natIVe statE to ForM dimers Or higheR-OrdEr OLIGoMers. Because the procEsS OF fIbrillatIon proCEeDs VIa a confoRmAtiOnalLY AlterEd inSUlIn monomeR, sequeSTrAtIon of thE mOnomer WiThiN a nAtive ASsemBly redUces the cOncenTRation of the susCEptible monomeR. suCH AsSEmblY alSo enhances tHermODynaMic sTAbIliTY, retaRding ChEMiCAl degradation. In addiTiOn, insuLin asSembly damps coNformationAL FLuctuatiOns, rEDuCIng the rates of bOth phYsical and cHEmical deGradaTion. BecaUse of thesE ADvantageS, a cOmmOn mEthOD Of Formulation is TO Form ZiNc-stabiLizEd insulIn hExaMerS, thE pRedominanT form of tHe PrOtEiN in The prODucts solD uNdeR tHe tRademARks HUMaLIN™ (ELi LiLlY aND Co.), hUMALOG™ (eLi lILly aNd co.), nOVAlIN™ (noVo-NorDisk), ANd NoVALOG™ (NOvo-NordisK). UsE Of inSuLiN hexameRs complicates ThE treatment Of DiaBetes mELLitus by dElaying absorption of the pROtein afTer SubcuTaneOus injectIon.
glycemIc cONtrol bY insulIn repLaCemENT therAPY, wHetHeR administeRED by ExterNaL pumP, intrapEritoneal pump, or manUAl sUbcutaneous inJecTion, IS EnHanCEd BY raPiDLy aBSOrbed insulin anaLogues. RapiD aBSoRption enabLEs tHe Time couRse of inSulin ACtion at Target tisSues to morE nEarlY COinCide with thE time couRse of absoRPtion OF nUtrieNts After a MeAl, hEnce mOre cloSEly ApproXimatiNg The phySioloGiCal contrOl of blood glucose concentRation And meTabOlism in a hEalTHy (nOn-diabetiC) perSon. AbsorptIon Of iNsuliN is DElayeD by iTS sElf-ASsembLy as IN conventiONaL foRMUlAtions of humAN INsuLin anD anIMal insUlinS as zinc-stabilized INsulin hexamers. a parTIAl sOluTIon tO tHis problem has bEen PrOVIded by thE mEal-time insuLin analoGuES in whIch the HexameRic formULAtIOn is deStabIliZed by aminO-acId SUbstituTiOnS In the iNsulIn MolecuLe (see aBOve). THIS approach is not opTimal AS The suBStiTutioNs Impair tHE phySical stabiLity and therModynaMic sTabilIty of thE iNsulin AnaLoGue, leading TO elevated Rates Of fibriLlAtioN anD chemiCal dEGRadatIon. SUcH deCreased stABIlITy ReQUirEs coNtinuEd FormUlation as A Zinc hexaMer,
 an implantable insulin pu mp, the sh elf l ife  of  a n in suli n analogue for m ulat ion at or above room t emper at u re,a nd  theroutine us e ofan  i nje ct a bl e ins uli n formu lation bypat ie nts with dia b et es mellitu s i n sub-tropic aland tr op ica l  regi ons  of t he wor l d.
Ami no-acid s ub s tituti o ns in i n s ul in h ave been investig a te d  for effects o n ther mo d yn a m icsta bility and  b iolog i cal act i vi t y .  No consistent re lationshiph asbeen o bs erv e d betw een s ta b ili ty and acti vity . Whereas  somes ubstitu t ions th at enh anc e t herm o dy na mic  s t abi l it y a l soenhancebi nd ing t o th e i n suli n r ecep tor,other substit uti onst hat  enha nce s tabi li ty im pede s uch b in ding.
A traditi onal  approach  to  p rot ec tingi nsulin  or  in sulin a nalogue s  fr om p h ys ical and chemicalde g r ad ation is  based on  s e lf-assem bl y o f th e prote in i n  i ts nativ e stat e  t oform di me rs orhi ghe r-o rdero ligo mers.Becausethe p r ocess of fibri l lation procee d sv i aa  con for mationallyalte r ed i nsul i nmon o mer,seque st r at i on of the monomer w it hin anativ e assembly re duces thec o n centrati on o f  t h e susceptiblemonom er. Such a s sembly a lso e nhancesthermodyn a m ic stabi lit y,ret ard i n gchemical degr a d atio n.  In add iti on, ins uli n a sse mbl ydamps con formatio na lfl uc tua tions ,  reducin gthe  r ate s ofb oth ph ysica l an dch e mic al degr a da t i on.Be ca useofth ese a dvan t age s, a co mmon meth odo f fo rm ul ation i s to form zin c- stabilized  i nsu lin he x a mers, th e predominant form of t h e prote inin th e pr oducts so ldunderthe tradem arks H UMALI N™  (E l i  Lill y an d C o. ), HUMALOG ™ (El i Lil ly  and  Co.),NOVALIN™ (Novo-Nor d isk ), and NOVALO G™(Nov o - No rdi s k) .  Us eo f i n s ulin hexamers c omplicates  t h etreatmento f d ia betes m ellitus  by d e layingabsorptio n of thepr otei n aft er subcuta neous in jection.G lycem i ccontr olby ins ul inrepla cement the rapy,  wheth er  admin ister ed  by exte rnal pump, intraperiton eal pu mp, o r m anual sub cut a neo us inject ion,  is enhanc edbyrapid lya bsorb ed i n su lin analo gues .  Rapid ab s or pti o n  e nables thet i m e c ourse  of insuli n ac tion at target ti s sues to more n earl y coi nci d e wi th  the time cour seof a bsorptio nof nutrient s afteram eal,hencemore c loselya p pr o ximati ng t hephysiolog ica lc ontrolof  b l ood gl ucos econcen tratio n  and m etabolism in a h ealth y (non- d iab etic)  p erson.A bsor ption of i nsulin is d elayed  byits s elf-ass em bly as  in  c onventiona l  formulat ionsof huma ninsu lin  and a nima l insul insas  zi nc-stabil i z ed in su l inhexa mers.  A  par tial solu t ion to t his problem  h asb e en pro v id e d  by the me al- timei n sulin anal o gues in which  the h examer ic form u lat io n is de sta b i lized byamino-aci d  su bs titu tions in  t he i ns uli nmolecule (see a bove). T his appr o a ch isnot opti m al asth e substituti ons i mp a ir thep h ysi cal sta b ili tyand  the rmo dyna m ic stability of the insu linanalo g ue,  lead ing t oelevated rate s of fib r illation andchemical degrad a tio n . Su chd ec re ased stab ili t y req uire s c onti nue d fo r m ulat i on a s  a  zin c hexa mer, 
 an_implantable insulin_pump, the shelf life_of an_insulin_analogue formulation_at_or above room_temperature, and the_routine use of an_injectable insulin formulation_by_patients with diabetes mellitus in sub-tropical and tropical regions of the world.
Amino-acid substitutions in_insulin_have been_investigated_for_effects on thermodynamic stability and_biological activity. No consistent relationship_has been_observed between stability and activity. Whereas some substitutions_that_enhance thermodynamic stability_also enhance binding to the insulin receptor, other substitutions_that enhance stability impede such binding.
A_traditional approach to_protecting_insulin_or insulin analogues from_physical and chemical degradation is based_on self-assembly of the protein in_its native state to form dimers or_higher-order oligomers. Because the process of_fibrillation proceeds via a conformationally_altered insulin_monomer, sequestration of the monomer_within a native_assembly reduces_the concentration of_the susceptible monomer. Such assembly also_enhances thermodynamic stability,_retarding chemical degradation. In addition, insulin_assembly_damps conformational fluctuations,_reducing_the_rates of_both physical and_chemical_degradation. Because_of_these advantages, a common method of_formulation_is to form zinc-stabilized insulin hexamers, the_predominant form of the_protein_in the products sold_under the trademarks HUMALIN™ (Eli_Lilly and Co.), HUMALOG™ (Eli Lilly_and Co.),_NOVALIN™ (Novo-Nordisk),_and NOVALOG™ (Novo-Nordisk). Use of insulin hexamers complicates the treatment of_diabetes mellitus by delaying absorption of_the protein after subcutaneous_injection.
Glycemic control_by_insulin replacement therapy,_whether_administered by_external pump, intraperitoneal pump, or manual subcutaneous_injection, is_enhanced by rapidly absorbed insulin analogues._Rapid absorption enables the_time_course of insulin action at target_tissues to more nearly coincide with_the time course of absorption_of_nutrients_after a meal, hence more_closely approximating the physiological control of_blood glucose concentration_and metabolism in a healthy (non-diabetic) person._Absorption_of insulin is delayed by its_self-assembly_as in conventional formulations of human_insulin_and_animal insulins as zinc-stabilized insulin_hexamers. A partial solution to this_problem has been provided by the meal-time insulin analogues_in which the_hexameric formulation is destabilized by_amino-acid_substitutions_in the insulin molecule (see above). This approach is not_optimal as_the substitutions impair_the physical stability and thermodynamic stability of the insulin analogue,_leading to elevated rates of fibrillation and_chemical degradation. Such decreased stability requires continued formulation as a zinc_hexamer,