Bovine Porcine

8/3/2019 Bovine Porcine

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Bovine Porcin e and Hum an Ins ulin. A pres e ntday c om parative appraisal and po licy

discuss ions .

As dau n t i n g a s t h e ov e r a l l c o s t s o f d i abe t e s c ar e t h e

day t o day c h a l l e n ge f o r i n d i v i du a l s w i t h d i abe t e s an d

po l i c y m ake r s r e l a t e s t o c h o i c e s i n d i abe t e s c ar e . W h a t

be ne fi t s do v ar i ou s c h o i c es o f i n s u l in p r ov ide an d a t w h a t

c os t . W h e t h e r t h e s e qu e s t i on s a r e a s ke d a t an i n d i v i du a l

o r n a t i on a l l e v e l , kn owi n g t h e an s we r i s f u n dam e n t a l t o

cos t e f fect iveness .

A Pan el discu ss ion in Q/ A form at s.

From th e desk of Profes s or S AM. G. P. MOSE S. B.Sc., M.D., F.R.C.P., D.Sc.,

Cha irm a n , Resea rch Society for th e Stu dy ofDiab etes in In dia Ma dra s.

THE ARK, 3 4 , CASA MAJ OR ROAD, EGMORE,CHENNAI 60 0 00 8 . INDIA. PHONE: 82 618 44 .


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Bovine Porcine and Human Insulin. A present daycomparative appraisal and policy discussions.

1 st Edition Augus t 6 th 2002

All r ights reserved. No part of this pu blication m ay be r eproduced,s tored in a retr ieval system, or tra nsm itted in any form or by means,electronics, m echan ical, photocopying, recording or otherwise without

th e permission of th e copyright owner.

Whilst t he a dvice and informa tion in th is book isbelieved to be true a nd a ccura te at t he dat e of going topress , neither the aut hor nor the publisher can acceptany legal responsibility or liability for any errors oromissions th at m ay be made.

Further information available on request from:

Prof. Sa m. G.P.Moses., B.Sc., M.D., F.R.C.P., F.A.I.I.D., D.Sc.,Chairm an , Research Society for the Stu dy of Diabetes in India Madras .

THE ARK, 3 4, CASA MAJ OR ROAD, EG MORE,CHENNAI 600 008 . INDIA. PHONE: 8261 844 .


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Bovine Porcin e and Hum an Ins ulin. A pres e nt

day c om parative appraisal and po licy

discuss ions .

An INTRODUCTION

As daunting as the over al l costs of diabetes care the day today challenge for individuals with diabetes and policy makers

relates to choices in diabetes care. What benefi ts do variouschoices of insul in provide and at what cost . Whether these

questions are asked at an individual or national level , knowingth e an swer is fu n da m ent al to cost effectiven ess .

In dia presen ts c las sic exam ple,

In 1998 ,Cost of Ins u lin therap y/ year / person $ 350

Cost of n on ins u lin therapy/ year / person $ 70

17 .5 m n diab et ics in In dia ,

Total cost of diabetes in In dia $ 2.2 Bn .Total h ealthca re bu dget for ent ire In dia $ 72 0 Mn .

Percap ita expen ditu re for al l h ealthca re $ 21- In clu din g water a n d s an ita t ion .

There is no doubt that Insul in is the mos t s tud ied Hormone inthe wor ld & no other h orm one h as been s tu died so mu ch & as

many as 45 or more animals Insul in - a lso (from Rhinocerus -

Elephant down to Rat & mouse) has been s tudied in deta i l -Many many peculiari t ies in animals & Insulin & the l ife stylecon n ect ions s tu died in an im als .

For exam ple, even Gu in ea Pig - tw o in su lin s a re foun d - na t iveinsul in plus porcine & so on - do not know the reason.


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Porcupine - quick erection of spines & more monomericIn su lin s & so on & vertebr at es & even n on vertebra tes an im al

s tudies . Thus animal Insulinology - an im al pa n creatology &animal diabetes are a l l cont inuously s tudied in comparat ive

Diabetology.

Clinical animal Insulins limited to Bovine & Porcine apart from

Human insulin. Animal Insulin Bovine & porcine used formore than 80 years s ince Bant ing & Best 1922 & no other

an im a l hormones we use in hu ma ns so mu ch e tc .

The long experience with natural insulin, bovine insulin has

been extremely satisfying both for the patients as well as theirphysicians especially after the availability of monocomponent

natural insul ins . Since 1980, synthet ic insul in manufacturedadopting recombinant DNA technology and using E.Coli or

Yeast for expression is being used with mandatory warning onhypoglycemic episodes expressed on the commercial products(BMJ 1 991 Sep 1 4; 303 (680:622-6), Lan cet 19 92; 340 (8814 ): 301-2).

Early study showed no difference with regard to three-dimensional s t ructure of the bovine, porcine and synthet icinsulin (J Pharm Sci 1998; 87:170-6).

The binding affinity of insulin to insulin receptors at the threemajor si te of insulin action namely muscle, adipocyte and

hepatocyte , as wel l as the post receptor events in terms of autophosphorylat ion of insul in receptor substra te have been

found to be s imilar with bovine, porcine a n d recombinantlyprod uced s y nthetic ins ulins (Diabetic Med 1 997 ; 14: 104 4 50).

Onset of act ion synthet ic insul in has been found to be faster

by about 15 minutes due to i t s rapid absorpt ion. This effecthowever has been found to have nonbearing on the overall

glycemic control achieved, though offlate there have been


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several reports of hypoglycemia unawareness following the useof synthetic insulin. Even in pregnancy no difference have

been observed in terms of neonatal macrosomia and ponderalindex between users of bovine and synthetically produced

insulin. A careful review of literature showed no relationshipbetween insul in ant ibodies produced and long-term

complications of diabetes l ike ret inopathy, neuropathy andnephropa thy (Diabetes Care 1989;12:641-648).

Synthet ic insul in was int roduced primari ly wi th the promise

t ha t cost of insulin therapy would come down remarkably andinsulin antibody formation may not occur with its use. In reality

however after two decades of i ts use i t has been observed thatsynthetic insulin also cause formation of antibodies in

su bs tan t ia l nu m ber of u sers (55% ).

The major projected benefi t of GE insulin viz-substantialreduct ion in cost has never been realised. We do not know

why? Paradoxically despite 20 years of technology use ofproduction the cost of synthetically produced insulin

con t in u es to m oun t th reaten in g to price out of exis ten ce thosewho depend on i t for t reatment . Unl ike in the west t reatment

cost of most Indian pat ients is not met by insurance and

patients have to fund for th em selves. Th ere is also th e pr oblemof in ad equa te ma n power for pa t ient edu cat ion.

Porcine & Human Insul in are in one boat (S GPM) - since onlyone amino acid sequence less. The small difference between

human and porcine preparat ion seems to be of no c l inicalimportance. (Diabete s ; Vol 34 : Su pple 2 , 1985 )

After 1975 Insul in is the f is t hormone manufactured by

Genetic Engineering.

So naturally since al l the insulins are in use in diabetic

patients a periodic comparative appraisal is done by clinicalscientists & some policies made in different countries

including INDIA.


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How did th is su bjec t of "Relook in to anim al insulins " -

come up in present era. We are now in post - post newer

ins ulin ERA? Why do we h ave th is de bate? (A Prelude )

We are now in the post - post newer Insulin Era & Insulinan a logu es e ra .

The subjects of "Relook into animal Insulins" - have come

up because of the following reasons - some l ike the subjectsom e do not like th e su bject - ph ar m a & m edical person n el.

Th is s u bject h as been s cien tifically com e up - Not Becau sePharma companies have re int roduced animal insul ins - N0

Not ATALL.

Th e relat ive scient ific app ra isa l of Hu m an In su lin & an im alInsulin - well studied & still being studied.

At th e mom en t th e cost Ben efit & Socioecon om ic & In su lin

Bu rden in In dia deserves s pecial discu ss ion.

All this does not mean to stop the scientific progress of

Human Insul ins & other hormonal products . This progresswill goon & on .

Th u s In su lin ology a s a s pecial dr u g sp ecia lity (on pa r withAsp rinology - on p a r with st a tinology ha s a ll com e to sta y).

An im al com pa ra tive pa n creatology, com pa ra tiveInsulinology & animal Insulin has al l come to stay (apart

from com m ercial an im al In su lin s)

It m ay be part icu lar ly good th at a few ph ar m a com pa n ieshave boldly re int roduced animal Insul ins , ensuring highest

pu rity. In th e bar gain, Purity of Ins ulin h as become s up remo.

More s tudies & more progress in animal insul ins versusHu m an In su lin is wish ed all su ccess


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Th u s th e deb at es in th is ar ea of in su lin ology are

u n avoidab le and m ay open u p ext ra th ou ghts .

QUESTION 1:

Bovine - Porcine & Hu ma n ins u lin s are all mu tual - natural

analogues well accepted to human patients (actually the subject

of insulin analogues was born out of this idea) and insulin

receptor systems and well worked out for years - what are all

the commen ts ?

Bovin e / Porcin e & Hum an in su lin s a pa rt from th e In su linusage for over 80 years has now been well declared as

"Mu tu al" / "Nat u ra l" an a logu es , th ou gh it was kn ownearlier.

Now officially declared as Mutual Natural analogues afterthe advent of synthetic Genetic Engineering analogues since

1997 / 1998 onw a r ds .

The whole subject of analogues was born out of the idea of

Bovin e / Porcin e & Hu m an In su lin - a ll th e thr ee ar e able tosi t on ins u lin receptors & give th e perform a n ce.

Incidental ly the mutual natural analogues were very safe:(no mitogenicity) (no cardiogenesis) no other side effect

unlike the present day analogues l ike "Glargine" , Longa ctin g an alogues & even pro in su lin an alogu es etc with

var ious con tra dictory h ar m fu l reports h ere and th ere .

Incidentally the Genetic Engineering Insulin companies arealso rest less. Surprisingly rest less in going onmanufacturing analogues . so the quest ion is often ra ised &

discussed in panel discussions "Do we need s o many ins ulinanalogues" - "Do we rea lly need th em in In su lin pr a ctice?


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Replace Human Insul in wi th Human Insul in in one s loganall though (at the same t ime now trying to combine

a n a logu es + Hu m a n In su lin (eg. Lisp ro + NPH) on ly topromote sales a t increased cost . what is the ra t ionale?? ;

th a t pu zzles m an y senior d iab etologists l ike m e an d oth ers.

Bren t Hoad leys In su lin Pa ten t Resea rch a n d Fin dings:Feb 2 8, 20 01 Hoadleygold, inc, Bren t h oadley PhD.

In his book 1984, George Orwell wrote about newspeak.

This is now the language used by the pharmaceut icals tocreate billions of dollars in profit from genetically

engineering insulin-like molecules.

Pharmaceuticals will tell you the foreign protein insulinsource is the pancreas of a pig or cow. When given names

such as humalog, l antus or novorapid by giantcorp ora tion s, a foreign p rotein b ecomes a won der a n a log of

human insul in . The t ru th i s a l l three of these subs tancesare foreign proteins in some cases not even an insulinmolecule. All could be considered new growth hormones

with very little being known about long term effects.

Dia betics n eed to app ly for long-term guinea pig sta tu s.

Thus Insulin Restlessness in Pharma minds etc. Probably can not be

helped.


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QUESTION 2:

Porcine & Human insulin go together in the present day in one

boat for various reas ons . Hum an is ed Porcine (S emi s y nthetic)

is als o us ed as hum an ins ulin .w hat are the ideas ?

Human insul ins have many theore t ica l advantages , but in

reali ty i ts status can be best expressed by the following l inefrom Han d Ch rist ia n An ders ons Fa irytale.

THE EMPERORS NEW CLOTHES :

HE HAS NOTHING ON

The small difference between purified human and porcineprepa ration s eem s to be of n o clinical imp ortance.

Diab etes Vol 34

Su ppl., 2 19 85.

If it is s o let u s look in to th e fa cts .

The a m ino a c id s equ ence in Hum an / Porc ine / Bovine &

con n ects ch ains - br iefed as

Bovin e Porcin e Hu m an

A8 Ala TR TR

A10 Va l Iso Iso

A30 Ala Ala TR


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58 amino acids are ident ical . None of the changes are at sites

crucial to the binding or action of insulins . Hence no significant

difference between species of insulin in receptor binding and

action of insulin . Theoretically changes in amino acid could

affect the solubility and diffusion properties of insulin molecules (Clin ics in En docr inology an d Met ab olism vol II, No 2. P.D. Hom e, K.G. M. M. Albert i)

Human Zinc Insul in c rys ta l s a t t rac t more water than beef and pork. But s tudies of absorpt ion, act ion of Insul in havenot revoked any clear cut differences between porcine &

Hum an Insu lins .

Porcine insulin is capable of many modifications.purification, Highly purified and mon ocompon en t ins ulin

and enzyme modification of aminoacid to make semisynthe t ic hu m an ins u lin is all pos s ible w ith porcine ins ulin.

- Porcin e In su lin goes in sa m e boat as Hu m an In su lin &

even in an im als with two in su lin s (Gu in ea p ig - n at ivein su lin + porcin e in su lin ar e th e dou ble gen e effects) - to be

n oted Proba bly porcine ins ulin goes along w ith an y an ima land als o for Humans .

All types of Diabetes react in same way with porcine &Human Insul ins . Thus there are no major c l inical

differences.

Suppression of C peptide was equal. Similar effects ofin su lin on C pept ide an d b lood glu cose a n d p yru vate .

Insul in has wide spread metabol ic effects on carbohydrate ,

protein and l ipid metabol ism. By measuring intermediarym etab olites Bioequ ivalence of th e in su lin s in term s ofres pon se of blood glycerol an d lacta te levels .

On the other hand, 3 hydroxyl pyruvate was maximal lysu ppr essed m axim al ly a t lowest dose an d th e a lan in e levels


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were u n chan ged a t th e h ighes t dose . So th ese m easu rementgive no discrim in at ion b etween th e in su lin s.

Human and porcine insul ins were found to be ident ical

in terns of glu cose requirem ent an d ad ju stm ent .

There is universal agreement on the equivalence of insulins and

comparisons of the extent and time courses of the changes in

blood glucos e , s erum C pep tid e , gly cerol , Alan ine an d hy d roxy

butyrate s how ed n o dif ference of any k ind .

Comp a ra tive stu dies of in su lin s in diabetic pa tien ts :- No differences were found in ei ther glucose requirement

or free ins u lin a fter S C in pr ofiles of equ a l pu rity .- No differences in peripheral glucose uptake and

iden tical m etab olic clear an ce ra te .- Solubil i ty differences between pork and human insulin

will not affect the characterist ics of intermediate actinginsulin

Com pa rison of Hu m an In su lin a n d Pork Insu lin

Much Ado About One Amino Acid?

Sir George Alberti.Clinics in endocrinologyand Metabolism 1982;11(2): 453-4 83.

There is as yet l i t t le evidence to suggest that there aremajor (or even minor) clinical differences between HumanInsulin , whether semi-synthetic or biosynthetic, andMonocompon ent Porcine Ins u lin .

Much Ado About OneAmino Acid.Markus sen J , Diabetologia(198 3) 25; 457- 45 9.

When porcine Monocomponent preparat ions are used localor systemic insulin allergy, lipodystrophy or immunologicalinsu lin resistan ce occurs very rarely.

Much Ado About OneAmino Acid.

Sonn enb erg and M Berger,Diabetologia (1983) 25;457-459 .

The presen t vogue for human insu l in i s no t matched bycomparable benefits in clinical practice. The commercial

versus scientif ic aspects of human insulin are reflected bythe t ide of commercial ly sponsored symposia, unreviewedpapers a nd reports in books are su pplemen ts to well-known

journals compared with relatively small number of originalpapers on hu man insu lin which have passed a peer rev iewsystem.

Larkins Et al.NEJ M 1986 Vol. 16 20 6-210 .

The stru cture s of hu ma n an d porcine ins u lin differ by onlyone amino acid, and that this amino acid, which l ies inposi t ion 30 of the B-chain, does n ot appea r to be direct ly


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involved in t h e an tigen itic activity of th e h ormon e.

Larkins Et al.NEJ M 1986 Vol. 16 20 6-210. Double blind trialsin newly treated diabetic

sub jects .

Human insulin was shown to be indist inguishable fromporcine insulin of comparable puri ty with respect toplasma glucose and glycosylated hemoglobin levels andinsu l in does requ i rements . Human insu l in was no less

an tigenic t ha n porcine insu lin; s ignifican t IgG-ass ociatedinsulin binding activity was detected in six of the tenpat ien ts in the human insu l in t reated group and four o f the ten pat ien ts in th e porcine insu lin t reated group .

By Acta Pediatr ScandSu ppl 270 Vol. 12.

Porcine Monocomponent insulin has therefore recentlybecome th e insu lin of choice in the long-term treatm en t of newly diagnosed diabetic children .

Differential effects of humanand an imal insu l in on theresponses to Hypoglycemia inelderly patien ts with NIDDM.Graydon s. Meneilly et al.Diabetes Care Vol. 16, 1991.

Di abetes , 1995 , 44 , 272-277 .

I t is l ikely that animal insulin cross the blood-brainbarr ier more read i ly than hu man ins u l ins , s ince th ey aremore l ipophil ic. I t has shown in animals that insulins t imulates g lucose up take the hypothalamus and thatdirect st imulat ion of hypothalamic insulin receptorsevokes behaviors consistent and hypoglycemia. If hormonal responses are mediated mainly by the glucoselevels in the central nervous system and the symptomresponses are mediated, at least in part by or directeffect of insu lin on n eu rons, th is could be an explan ationfor the differential effect of the two insulins. Animalinsulin provided a greater awareness of a

hypoglycemia beginning than h uman ins ul in.

Biologic a ctivity of BHI v/ s HPI.Diabete s Care Vol. 4, 1994 .

The amount of insulin given by the GCIIS to maintainplasma glucose levels within a normal range wasvirtu ally ident ical for BHI an d pork ins u lin s.

Diabetes, Vol. 44., March 1995,PP.257-260.

As cl inician s we m u st res pond to the experiences of thepeople using i t , especial ly perhaps because thean ticipated theoret ical advanta ges of hu ma n insu lin havenot real ly material ized. Human insulin is not markedlyless immunogenic than highly purif ied porcineequivalen ts an d , it ha s n o t become cheaper .

What are the advantages o f h u man in su l in ?Prof. S Amiel.

WWW.diabete s.org/ pu blications/ ins iderorg/ h tm l/ expertes .h tm

In retrospect , the advantages are less clear today thanwhen it was first introduced. Initially, it seemed logicalthat human insu l in would be bet ter fo r human pat ien ts.. in the event , hu ma n insu lin is not significan tly lessimmu nogenic than ne ither pu rified pork ins u lin , nor i t isless expen sive to bu y.

Hum an ins u l in gone wrong?Diabetes Medicine 1991Philip Hom eNewcastle u pon Tyne

Lessons from the cu rren t debacle are then man y , bu t i f freedom of information, just ice and medicine are toprosper in a world where the consumer is increasinglyking, then professionals wil l have to learn a degree ofself-regulat ion th at ma y clash with m ore entrepren eu rialinst incts.


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Biosynthet ic Human insu l in :Progress a nd Prospects.J ay S. Skyler et al .Diabetes Care, Vol. 4, No. 2,March -April 1981.

The plasma glucose lowering action of BHI is similar tothat of purified pork insulin (PPI). A potential problemwith BHI is contamination with protein antigens fromE.coli in which th e A and B cha ins of BHI are produced.It can not b e exclu ded comp letely.

A Prager an d G. Schern tha ne r.

Diabetologia Springer Verlag1983 .

The healthy control subject showed no stat ist ical

significan t differen ce between the binding of hu ma n an dporcine insulin at any insulin concentrat ions. Absolutereceptor number and average did not differ significantlybetween h u man and porcine insu lin e i ther .We conclude tha t th e binding beh aviors of sem isynth etichuman insulin and porcine is comparat ively identical .Patients t rea ted from th e ons et of their disease with SS Hinsulin did not differ from those treated with porcineinsu lin with regard to their ins u lin receptor statu s.

Diabetes Medicine 1995.Glycaem ic con trol.

No significant differences in the control achieved duringeach treatment and also observed within or betweengroups and glycated globin concentrat ions did notcha nge significan tly throu gh out th e stu dy.

The production of human insulin is a major scientific

achievement . There is l i t t le evidence to suggest that there aremajor (or even minor) cl inical differences between humaninsul ins whether semisynthet ic or biosynthet ic and pork

Insulin . Present ly therefore the use of human insul in mustrest largely on economical grounds. (Clinics in Endocrinology andMetabolism vol II, No 2. P.D. Home, K.G.M.M. Alberti).

- If it is s o, wh y ca n t we u se p orcin e m on ocom pon en tinsulin which is available in India at RS 65 to 85

economical than human insul ins in general diabet icpopulation (Sam Moses ).


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QUESTION 3:

What are the advantages of Bovine insulins? Should bovine

ins u lin b e retained in clin ical practice?

In 1998 ,Cost of Ins u lin therap y/ year / person $ 350

Cost of n on ins u lin therap y/ year / person $ 70

17 .5 m n diab et ics in In dia ,Total cost of diabetes in In dia $ 2.2 Bn .

Total h ealthca re bu dget for ent ire In dia $ 72 0 Mn .

Percap ita expen ditu re for al l h ealthca re $ 21- in clu din g water an d s an ita t ion.

Near ly 400 Mn In dian s live in ab solu te poverty.

When you need cost effective solutions in diabetes care,considering the above scenario, certainly the availability of

bovin e in su lin at Rs .65 / via l will pr otect th e fu n da m ent al righ tto h ealth an d righ t to l ife of th e In dian Diab etic.

Insulin has been available for therapeutic purposes for over80 years since Banting & Best 1922. The earl iest

Th erap eut ic prepar at ion were obtained from Beef Pan creas -first animal insulin in clinical practice.

Clinicians are "consumer advisors" to market .


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Bovine Insulin more "Polymeric" situation for long time

(a ction of in su lin polymer dimer m onom er) &hen ce Bovine is ab le to cons titute True u ltra len te effects . No

peak ; peak less in su lin - (Hu m an u lt ra Lente two peak s, n otreal ultra Lente).

Bovine insulins are difficult to be chromatographicallypurified. But fortunately we are getting highly purified

bovin e in su lin < 2p pm in In dia for RS 65 400 u n its IU .

Bovine Insulin - Less of weight gain compared to humansynthetic insulins due to what effect? Experience based

m edicin e can an swer this .

Bovine Insulin antibodies and antigenicity? A theoreticaldiscussion: Antigenicity is largely related to purity and siteof action. Antigenicity is no longer a problem in causingiatrogenic complication of diabetes. Puri ty abolishes and

overtakes Insulin resistance. Complexing with ZN, lentetype in su lin will exacerb a te th is An tigen icity. Th is will ap ply

to all species of Insulins. Antigenicity and long term clinicaleffects are similar to any species of insulin. (Clinics inEn docrin ology an d Met ab olism Vol. II, No 2. P.D. Hom e, K. G. M. M. Albert i).

Bovine Insulins acceptable for religious perspective.Musl ims not for pork, who could not afford human insul ins

can go for bovine insulins. Thus their right to l ife and rightto health are well protected by keeping in mind their

rel igious sentiments.

Antibodies developed in response to bovine insulin have nofu n ction a l sign ifican ce:

have low affinity constant

n egligible in su lin n eu tr a lisin g power

n o clin ical in su lin resista n ce

daily insulin dose within physiological range.*Diabetes r esea rch a nd clinical Practice 49 (20 00 ) 7 15


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There is no relat ionship between Antibodies produced byinsulin and long term complications l ike ret inopathy,

neu ropa thy and nephropa thy.

Low cost b ovin e in su lin is a s effective as h u m an in su lin J AMA INDIA Physician Upd a te, April 200 1 Vol. 4, N0 4.

QUESTION 4:

Is "S pecies " of ins u lin imp ortan t or "Purity " is more importan t in

clin ical practice? Dis cus s ion.

Usu ally Th ree fold Trian gular qu estion is as ked- Pu rity

- Sp ecies of In su lin &- Du ra tion of a ction (Th ree fold) J . Sk yler form u la

The a m ino a c id s equ ence in Hum an / Porc ine / Bovine &con n ect ch ains - br iefed a s

Bovin e Porcin e Hu m an

A8 Ala TR TR

A10 Va l Iso IsoA30 Ala Ala TR

58 aminoacids are ident ical . None of the changes are a t

si tes crucial to the binding or action of insulins. Hence nosignificant difference between species of insulin in receptor

binding and action of insulin. Theoretically changes inamino acid could affect the solubility and diffusion

propert ies of insulin molecules (Clinics in Endocrinology andMetabolism Vol. II, No 2. P.D. Home, K. G. M. M. Alberti).

Receptor s tudies proved that there was complete ident i ty

between Porcine and Human insul ins employing equalpotency with bovine insulin as well . The parametersmeasured include receptor number, aff ini ty, associat ion

and dissociation kinetics, down regulation negative,com pa ra t ive an d intern al isa t ion.


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Wh y im pu re In su lin s?

If insulin was a new product marketed for first t ime thisyear there is no doubt that product ion insul in free from

signif icant hormonal contaminants would be an obl igatoryrequirement and there is no known benefi t in inject ing the

contaminants . We now have porcine monocomponentin su lin , i.e. only in su lin an d n o conta m in an ts .

Antigenicity is largely related to purity and site of action .Antigenicity is no longer a problem in causing iatrogenic

complication of diabetes. Puri ty abolishes and overcomesInsulin resistance. Complexing with ZN, lente type insulin

will exacerbate this Antigenicity. This will apply to allspecies of Insulins. Antigenicity and long term clinical

effects are similar to any species of insulin. (Clinics inEn docrin ology an d Met ab olism Vol. II, No 2. P.D. Hom e, K. G. M. M. Albert i).

There seems to be no reason to bel ieve that human insul in

preparation made by biotechnological or chemicaltechniques wi l l be any less contaminated by such

derivatives (desamido insulin, arginyl insulin, insulinethylesters), and indeed the yield figures would seem toindicate problems of contamination with previously

unencountered insul in l ike compounds in the biosynthet icprocess. These may well be more difficult to separate from

the insul in than the contaminants found in pancrea t icextracts .

Purity a void s an tibodies & local in su lin pr oblem s.

Purification process involves almost 14 steps and variousmethods of purification includes Gel filtration &

Chr oma togra ph ic p u rificat ion. Sin gle ch roma togra ph y aims

at rem oval of A an d B com pon ent s of crystal lin e in su lin .Thus offering C or Singlepeak insulins which will have Pro-in su lin conta m in at ion of


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Highly purified insulin available in India is thechromatographically purified insulin which contain < 10

PPM and other hormonal contaminants do present .Antibodies cross-reacting with insulin are induced by

proinsulin, insulin derivatives (desamido insulin, arginylin su lin , in su lin eth ylesters ) a n d comp lexes in su lin .

Monocomponent insul in means Insulin alone and nothingelse (no contaminants) . I t requires several radio immuno

assays to dec la re tha t each contaminant such as g lucagon,somatostat in, pancreatic polypeptide, VIP etc. are below the

level of detection.

QUESTION 5:

Bovine ins ulin v/ s ins ulin an tibodies an d their clinical problems

w hat are all the idea s ?

Essentially all patients who receive Insulin for long periodsdevelop antibodies to Insulin - (Even antibodies to

endogenous Insul in is known) (IAA) - even if completelyPurified insulin is available - some Antigenicity will exist.

Antigenicity is the fundamental problem and property ofpolypeptide hormone.

I t may be t rue that pat ients wi th large Insul in requirements

have antibodies - overall correlat ion of Insulin requirementto an t ibodies is n ot cons tan t (Ku rtz & Naba rro).

Clinical insulin antibodies, theoretically have some

"ad van tages" an d "disa dvan tages"

Advantages - Insulin reservoir effect - smoother insulin

effects - r edu ces Brit t len ess .


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Disa dvan ta ges - in su lin + an tibody com plexes.

- It is disputed whether insulin antibodies exert a stabil izingeffect on glycem ic control, a ss u m in g tha t d iss ociat in g an tibody

complexes would help mimic basal insulin secretion, orwhether they cause hyperlabile state of glycemic control . VanHaeften et al (Timon W. Van Haeften Diabetes Care 1989; 12

(9)) have described a slower rise in free insulin levels afterinjections of short-acting insulin preparation in insulin

antibody posit ive as compared with insulin antibody negativepat ients . Al though some reports can doubt on the c l inical

relevance of this observation, this delay in insulin availabilitymay contribute to post-prandial hyperglycemia, conversely

high levels of insulin antibodies can also cause an increase inthe half l i fe of plasma free insulin with resultant prolongation

of post-prandial and night t ime hyperinsul inaemia andconsequent hypoglycemia. However very high levels of insulin

antibodies can certainly produce post-prandial hyperglycemiaand night t ime hypoglycemia. Whether human insul in

analogues are useful candidates for short -act ing insul int reatment under this part icular condi t ion s t i l l needs wide

clin ical con firm a tion . (Medicin e u pda te 200 2 Page n o:289 ).

Few Syndromes associated with insulin antibodiesrecognised- (circulatory insulin Reservoir syndrome) isinteresting. (Congenital Temporary Diabetes of newborn) etc

are kn own.

Now Insulin Antibodies are measurable - Also at AIIMS,Kochu pillai et al, worked over Bovine Insulin & antibodies.Antibodies developed in response to bovine insulin have no

fu n ction a l sign ifican ce:

h ave low affin ity cons ta n t (2 m agn itu de less t h anth e n at ive liga n d)

n egligible in su lin n eu tr a lisin g power

n o clin ical in su lin resista n ce daily insulin dose within physiological range. *Diabetes r esea rch a nd clinical Practice 49 (2000 ) 7 15


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There is no relat ionship between Antibodies produced byinsulin and long term complications l ike ret inopathy,

neuropa thy and nephropa thy.

Low cost bovin e in su lin is as effective a s h u m an in su lin J AMA INDIA Ph ysician Upd a te, Ap ril 200 1 Vol. 4 , N0 4.

QUESTION 6:

Are there any special advantages of porcine insulins in clinical

practice? S hou ld porcine ins ulins be s till retained in clinical

usage? Comments about humanised porcine insulin; Its

an atomical and clinical referen ces an d d ifferen ces ?

Porcin e In su lin & Hu m an In su lin ar e in one Boatfor over 30

years & hence m ost popu lar ized.

Among animal Insulins porcine Monocomponent Insulin issupreme & has stood the Test of t ime - In India i t is st i l la vailab le at h alf th e price of Hu m an Synth etic.

The Big advantage is that Porcine is capable of extreme

puri f icat ion & porcine monocomponent is same as HumanInsul in.

As a lread y s ta ted Hu m an ised Porcin e In su lin is s emi

synthe t ic & many companies a re us ing Human Insul inlab elled as s u ch an d call it Hum an .

Chemical recombinat ion of the chains loses the advantage

of the natural folding of molecule that occurs with porcineinsul in product ion and hence the curvature of insul inPept ide is m ainta in ed with it s ad van tages.

Sometimes the question is raised. Are there any differencesbetween Humanised Porcine (semi synthet ic human insul in)

or Hu m an In su lin produ ced b y Genet ic Engin eerin g.


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S.No Sem isynthe t ic Insul in Synthe t ic Insul in

1. Sou rce Porcin e In su lin Sou rce Non biologica l

2. C pept ide presen t C pept ide ab sen t3. Less a n tigen ic Th eoretica lly leas t a n tigen ic.

4. Monocom ponen t produ ct Claimed to be

Monocomponent .E.coli (Pr otozoa ), s till a n

animal .

Comparison of Efficacy of Human and Porcine insulin inTrea tm en t of Dia bet ic Ketoacidosis.

Between these two groups there were no significant

differences in sex, state of consciousness, age duration ofinsulin therapy before DKA. Basal levels in venous blood of

glucose. B-OHB, acetoacetate, creatinine, calcium, phosphate,sodium, potassium and IRI. No difference were found inarter ia l pH, bicarbonate and base excess . (Diabetes Care 10: 49-55,198 7) (Fred E. M. G. Strom s MD. J os A. Lu tterm an MD)

Th ere is a n ad van tage with porcin e in su lin , i.e ., sm al l ar m s

of Glucagon are a lso extracted - (newer Human Insul ins donot contain glucagon) Glucagon in very small doses may

avoid Hypoglycemia. (Profes sor Am iel - Wolff 1998 , Lan cet)

QUESTION 7:

The synthetic genetic engineered human insulins - are there any

d is ad van tages ? From theory to practice?

The terminology appl ied to insul in and the s t ructure of insul in appears to have been agreed internat ional bydefault .

Truly human insul in i s only produced by human pancreasand has been divided by Deckere t and others 1981 in toendogenous human insul in secre ted by the pancreas in

si tu, and exogenous homologous human insul in derived by


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pancreat ic extract ion or cul tured is le ts . Normal humaninsul in thus best br ief ly described as endogenous,

pancreatic or islet cultured.

Human insul ins a re only human in the sense of having the

amino ac id sequence and te r t i a ry s t ruc ture of na tura lhuman insulin. They are fully synthetic (i .e . derived fromaminoacids)

Ph ilip Cor fm a n , MD. Is s ynthet ic Ins u lin bet ter tha n Natu ral Ins u lin ?

When Humulin was approved in 1982, the FDA declared

tha t the synthe t ic produc t had not been shown to have anytherapeutic improved over animal insulin. The Agency

m aintains th is posit ion toda y.

Is Synth et ic in su lin not a s s afe as Natu ral Ins u lin?

La belin g wa s r equ ired by Lilly at t im e of a pp roval

A few patients who have experienced hypoglycemicreact ions af ter t ransfer from animal-source insul in to

human insul in have repor ted tha t the ear ly warning

symptoms of hypoglycaemia were less pronounced ordifferent from those experienced with their previousinsulin.

This labeling mak es one w onder about s afety. .

These words, required by Lily to be in the label of

Humulin one year af ter approval in 1982, demonstra tesvery well that the company was aware of the problem of

hypoglycemia unawareness from the very beginning.

The Kinetics of natural Insulin is longer and softer than

synthetic insulin. Indeed, Dr. Galloway of Eli Lilly published these findingin 1982. Diabetes Care.

And in 1988 Galloway l isted these differences between natural and syntheticinsu l ins .


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- Human insul in is more rapidly absorbed from the

injection site.- Hum an ins u lin is s hor te r ac t ing tha n an im al ins u lin s

- For optimal treatment of children: different dosageregimens.

- Hypoglycem ia is m ore likely.

Diabete s Mellitus 198 8 J . A. Galloway.

Pos s ible problems w ith hu man ins ulinBM frier et a l, Hypoglycaem ia in clinical diabetes 199 9.

More h ypoglycem ic ep isod es

Redu ced h orm onal respon ses Differen t s ymp tom s of h ypoglycaem ia

Impaired hypoglycaemia awareness

More deat h s from h ypoglycaem ia.

* Human insulin reduced brain signal activity during near-

normoglycaemiaRoth c, Landolf HP, Achermann P, Teuscher A, Bordely A, SLEEP 1996.

- We took EEGs in-pat ients on natural insul in, found that

brain signal activity was reduced when they switched tosynth et ic in su lin a n d re tu rn ed to n orma l when s witched ba ck.

- We postulated that this effect may relate to hypoglycaemiaunawareness seen with synthet ic insul in.

* All n ight EEG power sp ectru m in nonREM sleep

Roth O et al. SLEEP 19 98 .

- Synth etic in su lin redu ced sign al activity in n on-REM sleep.

Patients on Porcine insulin experience sound sleep longer andfeel m ore relaxed t h e n ext d ay, (Hu ma n Vs Porcine Ins u lin in pat ients withIDDM Roth C et.al, Sleep 21, 1 998 ).


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* Different Effects of human and animal insulin on the

responses to hypoglycemia in elderly patients with type 2

diabetesMen eilly GS et al, Diabe tes 1 99 6.

- We con clu de th at beef/ pork in su lin resu lts in greaterawareness of hypoglycemic warning symptoms than does

h u m an in su lin in elderly pa tient s with NIDDM.

* Hum an ins ulin a nd Pregna ncyKuhl C. Diabetic pregnan cy stud y Group, Copenh agen 19 96 .

- Ou r cu rr ent kn owledge of h ypoglycem ia in pr egn an cy can besummarized as follows: As many as 71% of IDDM pregnancies

may be complicated by severe hypoglycemia which seems todevelop more quickly and often without warning signs during

gestat ion.

* Hum an ins ulin an d traffic(Canton of Zurich, S w itzerland )

- Hypoglycemia unawareness has a lso become a problem with

traffic accidents, as demonstrated in these findings fromSwitzerland. Insulin hypoglycemia was a rare event before

in trodu ction of syn th etic in su lin .

* Unex plaine d d eaths of ty pe1 d iab etic patientsTattersa ll RB, Gill GV, Diab etic Med icine 1 99 1.

- Most were diabetics a ged 1 2-43 year s wh o ha d gon e to bed inap pa rent ly good h ealth an d were foun d dea d in th e morn in g.

- Al l was taking human insul in a t the t ime of death but most

ha d b een switched from a nimal ins u lin be tween 6 m onths an d2 years ear lier.

- Finally, I want to mention the dead-in-bed syndrome, firstdes cribed in s ome deta il by Tat ters a lkl in 19 91 .


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QUESTION 8:

How does the anatomy, structure, curved chains & c peptides

etc differ with human genetic engineered insulins - and theirclinical applications if an y ? Is this k nowled ge imp ortant?

Insul in is a prote in wi th 51 aminoacids. There are twomethods of analysis . One is X-ray analysis , which must be

con du cted with a crysta l and th e crysta llin e s t ru ctur e of th emolecule. NMR is the second manner of analysis, where the

st ructure is determined from, and a molecule in solut ion.Here one can only derive informat ion on the number of

a tom s, which com pose th e m olecu le .

Looking a t the molecula r s t ruc ture human and pork insulins are almost identical . However the structure ofinsul in receptors is unknown, so the microscopic pic ture of

how insul in works in the body i s unknown. St ruc ture andactivity can not be easily inferred.

In short , insulin is flexible, i ts structure is not froze.Microscopic function cannot be derived from the structure;

for this, the crystal l ine structure of the insulin receptors inthe body must a lso be known. In general i t i s found that

muta t ions in the aminoac id sequence can lead toconsiderable changes in the s t ructural propert ies in porcine

insulin solution. However functional implications of suchchanges can only be assessed by more deta i led l igand

bind in g stu dies of n at ive an d m u ta ted ins u lin s (Dr.Meu wly).

Insulin is injected in microcrystal form. The solubility of

microcrystal form was therefore different from the solubilityof microcrystal form of Porcine insulin. The beta cells in thehuman body do not produce c rys ta l s but ra ther ac t ive or

precursor forms - this means a greater di fference.Researchers are working now only on this aspect . The bigpharma when they s ta te that synthet ic insul in is exact ly the

same as natural insul in was fa lse . I t was a lso a fact that


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recombinant insulin produced by E.Coli bacteria, at firstdoes not form properly; it is linear. Every beginners

bioch emist ry h an dbook d escribes th e di fferent p h ysical an dbiochemical process (heat, pH etc.) required to fold the

insulin molecules thus produced. So there is a differencean d th is proven - (Romen Leist, Bioch em ist).

C pep tides exact fu n ction is n ot kn own - ( C Peptide ca n besynthetically manufactured by Genetic Engineering if

wanted).

The fundamental insul in property & i ts accompanying

solubility - Lipid solubility etc are all maintained by thecurved nature and diffusion into t issues - (or else i t behaveslike a straight hormone) - If straightened as a straight chain

the amino acid sequences may also have different effects(as an example the Growth hormone is a s t ra ight hormone -

191 am in o acids ).

C Peptide also varies in different animals. C peptide havenow be understood to have an influence on micro

albuminuria correct ion and other fr inge act ions. C Pept ideis abs ent in exogenou s in su lin ad m in ist ra t ion & m ay n eedsupplementation. This subject of "C Peptide" & connecting

Peptides (why th ey ar e ther e in in su lin s) & th e cur vat u re of

the molecule etc & various significances have to beper iodically u pd a ted by clin icia n s & Dia bet ologist s.

QUESTION 9:

"Insulin hypoglycemia" versus human insulins and Animal

insulins - and the nocturnal hypo etc and sleep rhythms - do

they ma tter in clin ical practice - clin ical expe rien ces ?


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* Human insulin reduced brain signal activity during near-

normoglycaemiaRoth c, Landolf HP, Achermann P, Teuscher A, Bordely A, SLEEP 1996.

- We took EEGs in-pat ients on natural insul in, found that

brain signal activity was reduced when they switched tosynth et ic in su lin a n d re tu rn ed to n orma l when s witched ba ck.

- We postulated that this effect may relate to hypoglycemia

unawareness seen with synthet ic insul in.

* All night EEG pow er s pectrum in n onREM s leepRoth C et al. SLEEP 19 98 .

- Synth etic in su lin redu ced sign al activity in n on-REM sleep.

Patients on Porcine insulin experience sound sleep longer and

feel more relaxed the next day, (Hu ma n Vs Porcine Ins u lin in pat ients withIDDM Roth C et.al, Sleep 21, 1 998 ).

Possible problems with h u m an in su linBM frier et a l, Hypoglycemia in clin ical diab etes 199 9.

More h ypoglycem ic ep isod es

Redu ced h orm onal respon ses Differen t s ymp tom s of h ypoglycem ia

Impaired hypoglycemia awareness

More dea th s from h ypoglycem ia.

* Be llagio Report 1996 .

S cien tific in formation for Bellagio Rep ort April 19 96 .

Huma n Ins ulin Hyp oglycemia Una w arenes s :

Accum ulated Evid ence on the Phen omenon

Conclus ions of Be llagio Rep ort:

- Human insul in i s a useful insul in formula t ion and many

people with diabetes can happily use i t . However, asubstantial minority of people with diabetes feel safer, have


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been hypoglycemic warning symptoms with animal insulinan d fewer ab ru pt h ypoglycem ic episodes .

- A transfer back to animal insulin brings rel ief in most

instances from severe hypoglycemic events due to loss ofwarn in g sym ptom s *.

- Pat ients who have a lways been on human insul in may f ind

advantages if they are al lowed to change to animal insulin(Bradley C, Report to WHO Regiona l Office for Eu rope, J u n e 1 992 ).

- At the Liverpool Symposium of human insulin andh ypoglycem ia (19 92 ) th ere was gen era l agreemen t for car efu lly

designed large field studies. Until such scientific evidence can

be a vailab le, th e sim ple pr actical ad vice mu st b e tha t pa tien tswho wish to use animal insul in should be able to have thein su lin of th eir ch oice (Diabetic Medicin e 19 92; 9: 57 9-80).

- The balance of scientific data confirms that there aredifferences between human and animal insul in. Several show

advantages with animal insulin in controlled studies also inthe e lderly despi te an intact counter-regulatory response and

in numerous case his tories . No studies show any cl inical

advantages of human compared to animal insul in (Alberti KGMM,Brierley EJ , Reduced awaren ess of hypoglycemia in th e elderly despite an intactcoun ter-regulatory respon ses . QJ Med 1995; 88: 439-445).

- Review of literature shows altered cognitive function and

reduced autonomic nervous s t imula t ion wi th human insul in .Th ese observat ions ar e in agreem ent with th e recent s tu dies of

brain glucose uptake in well controlled diabetic patients (BoylePJ, Brain glucose uptake and unawareness of hypoglycemia in-patients with IDDM.

New Engl. J Med 1995; 333: 1726-31) and offer an explanation for

reduced awareness in some pat ients experiencinghypoglycemic events from human insul in t reatment . Thisexplanat ion comes as a re l ief to many doctors and pat ients .

Adding to this the many case reports from pat ients or theirfamilies who have experienced to witnessed practical problems

with human insul in (Insul in Dependent Diabetes Trust , DraftRepor t , Feb. 1996 ) m eans tha t th e cas e for sa ying tha t hu m an


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insulin should not be the automatic first l ine choice insulin formost insul in-dependent or insul in-requir ing diabet ic pat ients

is proven beyond reasonable doubt . (The International Team Residency,Rockefeller Foun dat ion Cen ter Bellagio, April 1996 ).

* Different Effects of human and animal insulin on the

responses to hypoglycemia in elderly patients with type 2

diabetes

Men eilly GS e t al, Diabe tes 1 99 6.

- We con clu de th at beef/ pork in su lin resu lts in greaterawareness of hypoglycemic warning symptoms than does

h u m an in su lin in elderly pa tient s with NIDDM.

* Hum an ins ulin a nd Pregna ncyKuhl C. Diabetic pregnan cy stud y Group, Copenh agen 19 96 .

- Ou r cu rr ent kn owledge of h ypoglycem ia in pr egn an cy can be

summarized as follows: As many as 71% of IDDM pregnanciesmay be complicated by severe hypoglycemia which seems to

develop more quickly and often without warning signs duringgestat ion.

* Hum an ins ulin an d traffic(Canton of Zurich, S w itzerland )

- Hypoglycemia unawareness has a lso become a problem with

traffic accidents, as demonstrated in these findings fromSwitzerland. Insulin hypoglycemia was a rare event before

in trodu ction of syn th etic in su lin .

* Unex plaine d d eaths of ty pe1 d iab etic patients

Tattersa ll RB, Gill GV, Diab etic Med icine 1 99 1.

- Most were diabetics a ged 1 2-43 year s wh o ha d gon e to bed in

ap pa rent ly good h ealth an d were foun d dea d in th e morn in g.


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- Al l was taking human insul in a t the t ime of death but mostha d b een switched from a nimal ins u lin be tween 6 m onths an d

2 years ear lier.

- Finally, I want to mention the dead-in-bed syndrome, firstdes cribed in s ome d etail by Tat ters all et al in 19 91 .

* 4 th J u ly 2000 .

Hum an an d a nimal ins u lin s compa red.

A repor t com m iss ioned by t he Bri t i sh Diabe t i c Assoc ia t ionRhys Williams , Mark Airey, Cath y Benn ett, Pau l Martin , Pat Spoor.

Division of Public healthNuffield In stitu te for Hea lthUn ivers ity of Leed sUnited kingdom

Conclusions :

In our view the following conclusions can be drawn from the

ab ove synth esis :

The small numbers of trials that do suggest an effect ofh u m an in su lin requ ire explan at ion .

Th e explan at ion cou ld b e:

Stat is t ical: these resu lt h ave occu rred by cha n ce a lone

Biological: difference in response to human insulin existbetween populations (ei ther due to genetic factors,environm ent factors or gen et ic / environm ent in teract ion) so

that research carried out in different population (of

different nationalities, for example will show differentconclusions.

The evidence does not support the content ion thattrea tm ent with h u m an in su lin p er se affects th e frequ ency,severi ty or symptoms of hypoglycemia. However, a number

of studies, mainly those of less rigorous design, describe an


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effect when people are transferred from animal insulin toh u m an in su lin . It is n ot possible to sta te how comm on th is

is or wh eth er th e ph enom enon is s pecific to h u m a n in su linor an effect resulting from stricter glycaemic control

(perhaps compounded, in some cases , by neurologicalcomplications in long-standing diabetes). This remaining

uncerta inly makes i t essent ia l that insul in from animalsources cont inues to be avai lable so that c l inic ians and

pa t ients m ay re ta in th is ch oice of t reatm ent

The evidence summarized in this report is clearly anunsatisfactory in many ways. It is l ikely that not al l of theeviden ce availab le is in th e pu blic dom ain.

For example, the largest double blind RCT (Anderson 1990)is a vai lab le on ly in ab st ra ct from. Oth er im portan t da ta m ayexist but only as unpubl ished scient i f ic reports or as

documents kept confidential by commercial organisations.Fur ther work in th i s a rea needs to bui ld upon the above

an alyses as m ore in forma t ion becom es a vai lab le .

Progress in th e s ta t is t ical aspects of m eta-an alysis m ay tak e

it possible to combine the results of the double blindcros sover RCTs a vaila ble in th e litera tu re will be va lid.

Qualitative description of patients experiences followingchangeover from animal to human insulin is almost

completely lacking in this body of evidence. Some casereports and case series come close to this but , in general ,

this is a largely unexplored area. Such investigations couldbe incorporated into a well-designed crossover Rct with

three periods of intervention to explore the effect of changeba ck from th e secon d interven t ion to a fu rth er period on th e

first intervention.


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S TATEMENT FROM IDDT

Jenny Hirst , Co-chairmanJ u ly 7 2000 .

In September 1999 Novo Nordisk, one of the three majorsuppl iers of insul in in the world issued a press s ta tement

that included the following:

Novos Ad mis s ion

Historically improving Glycaemic control with solubleHum an Ins u lin ha s b een as socia ted with an increased r isk

of Hypoglycemia

So Now you know

But of even greater concern is a statement from Aventi 's ,

another large insul in manufacturer , dated Apri l 24 th 2000that includes the following:

Aventis Admission

Human Insul in therapy may be associated withHypoglycemia, worsening of diabetic retinopathy,

Lipodystrophy, skin reactions (Such as Injection si tereact ions, pruri tus and rash) , a l lergic react ion, sodiumretent ion a n d edem a.

The sta tements were put in the publ ic domains by the

insul in manufacturers and not by IDDT. These s ta tementscause us concern because the adverse reac t ions tha t may

occu r with h u m an in su lin th era py, as listed b y Aven tis a n dNovo Nordisk, are very much in line with the evidence from

a large number of pat ients in various countr ies . Theserea ctions lar gely regress with a ch an ge to an im al in su lin s.


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National Institute of clinical excellence (NICE). The final

draft guideline on Type 2 diabetes glycaemic control, iscurrently on the NICE website 2002 April . Page 59 in the

sect ion on the use of insul in in the t reatment Type 2 s ta testhe following:

Despi te the lack of an evidence-base to support current

pract ice , the group recognized that usual insul in therapyboth for people wi th diabetes s tar t ing and cont inuinginsul in now ut i l ized human species insul in ra ther than beef

or p ork. However t h e pu rified form s of th ese lat ter s pecies ofinsulin are appropriate options for cl inical and patient

choice.

Professor Albertis statement

Personally I care less about what sort of insulin is available,

an d m ore th at it is a ccess ible, afforda ble, of rea son ab le qu ality a n d works . (IDDT, Sum mer Newslet ter , Iss u e no 33 J u ly 2002)

In general Hypoglycemia can easily occur in synthetic

Human Insul in & Hypo unawareness & Warning Syndromesmay be absent - because Human synthe t ic Insul in sa id tobe less Lipophil ic - & does not reach the Hypothalamus

easily. "Silent Hypo" common.

Hypoglycemic symptoms were fewer in number in patients

taking human insul in , meaning pa t ients on Human insul inare at higher risk of suffering from hypoglycemic

unawareness (Science 1 2001, Elphinstone Conference, UBC).

Nocturnal Hypo - Dead in Bed syndrome at night. Dead inundisturbed Bed syndrome (BMJ) - sa id to be common in

1980- 90 period. Tight control cases of IDDM mostly.


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Addendum (SGPM). In Indian scene severe Hypo is notobserved as major problem with human insul in. Broadly

becau se we a re u s ing lower doses of h u m an in su lins an d n ot ast r ic t control regimen and many sleep laboratory reports have

not been s tu died.

At this juncture we should not forget , af ter 80 years usagewith animal insul ins there were no reports on Hypo-

unawareness. When we are gett ing highly purified Bovine atRS. 65 and monocomponent Porcine a t RS. 135 Why we

should not provide this cost-effective solution to our diabetics(SGPM).

QUESTION 10 :

Insulin & weight gain human insulin - versus animal insulin ? It

is ap pa ren t or rea l in clin ical experien ces ?

In gener al in su lin is a n "an ab olic horm one".

Insul in is a growth hormone in foetus - Foetus has i t s ownGrowth hormone & also foetal insulin - (Hyper insulinaemia

in foetus can produce Macrosomia).

Insulin weight gain in IDDM & NIDDM. Is it different? InIDDM weight gain is only proportion to weight loss - In

Type2 weight gain can occur - (obese Type2 Probably moreweight gain) - some small controversy exists. Many agree on

this weight gain even some of the Sulphonylurea cancause weight gain in NIDDM - Lean NIDDM - No weight

gain.

Th e su bject of weight gain requ ires a differen tial st u dy.

"Spontaneous Hypoglycemia" in non-diabetes: Healthy non-diabetes can develop hypo glycaemia episods after an

early breakfast . Postbreakfast Hypo sett les well after asecond break fas t .


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In general weight gain is more with synthetic Human

Insul in - ra ther then animal Insul ins - wi th Bovine Insul inmuch less - no weight gain (experience based) not evidence

based).

QUESTION 11 :

S elective clin ical s itua tion e xa mp le (pregn an cy ) etc (allergy to

one or other s pe cies ) are all s elective s ituations - ind ivid ual id eas

w ith ind ivid ua ls expe riences ?

Pregnancy - an exclusive si tuation with Diabetes - knownDiabetic going through Pregnancy as well as Gestational

Diab etes , m ay need short term Insu lin th erap y.

Many considerat ions are taken into account - Insul in doesnot cross the placenta - But Insul in ant ibody complexes(Water-soluble) can cross & produce Macrosomia. Even

minimal ant ibodies can cause problems unl ike in Nonpregna n t (n on-pregn an cy n o problems ).

Th e rea lity- Animal insulin Vs Human insulin

N = 170 m others 39.Macrosomia (>90 percentile) & ponderal index similar

Obs t Gyn ecol 19 91 78 (4), 59 0-3.Even in pregnancy, no difference has been observed in terms

of neonatal Macrosomia and ponderal index between users of bovine and synthetically produced insulins (Koch u Pillai, AIIMS).

Fifty insul in dependant pregnant diabet ic women weretreated from p resenta t ion a t an an tena tal clin ic a t th e Royal

Maternity Hospital , Glasgow. The data presented in thepa per b y J .M. Lieper et al clear ly sh ows th at th ere is n o

difference in the group treated with highly purified porcineinsulin as regards to blood glucose, control birth weight or

n eon ata l com plicat ions as sh own in Tab les .


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Table: Clinical Characterist ics and progress of Mothers and

Babies Stu died.

Human Insulin Treated Pork Insulin Treated

Age (Years) 26.9 + 5.1 27.9 + 4.8

Duration of diabetes (years) 9.1 + 5.7 10.4 + 8.5

Gestation of presentation (weeks) 12.0 + 6.6 11.5 + 6.5

Gestation of delivery (weeks) 37.3 + 2.1 37.4 + 1.7

Maternal HbA1, at presentation (%) 9.8 + 2.1 10.0 + 2.9

Maternal HbA1, at 26 weeks gestation (%) 7.7 + 1.5 7.8 + 1.0

Maternal HbA1 at delivery (%) 7.3 + 1.4 7.5 + 0.8

Birth Weight ratio 1.04 + 0.2 1.07 + 0.2

Macrosomia (cases) 4 5

Neonatal hypoglycemia (cases) 4 4

Major congenital abnormalities Pyloric stenosis, congenital heartdisease

Anencephaly, neonatal hyperthyro

Results are expressed as mean + S D

No difference between the groups at tained stat ist icalsignificance.

Table: Insulin Dose (mean S.D.) at 20 Weeks Gestation, Pre-

delivery (Mean Gesta tion 3 7 weeks) an d 5 Days Post-Partu m .

Human Insulin Pork insulin20 weeks gestation n = 19 n = 18

Morning Soluble 14.5 + 2.6 14.3 + 3.0 NSIsophane 25.2 + 1.7 24.7 + 2.8 NS

Evening Soluble 8.0 + 1.9 8.7 + 1.7 NS

Isophane 26.5 + 1.8 17.0 + 2.8 p


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insul in on human insul in. Otherwise morning and eveninginsulin doses were similar. Two women receiving human

insulin had to change to a thrice-daily regimen (bedtimeIsophane insul in) in the thi rd t r imester to avoid nocturnal

h ypoglycem ia an d fas t in g h yperglycem ia.

A comparat ive shorter t ime act ion of human Isophaneinsul in was suggested by the increased requirement forIsophane insulin in the evening injection (to maintain

fasting normoglycaemia) and the necessity in two cases todelay the evening Isophane injection unti l bedtime. These

findings are consis tent wi th the known characteris t ics of biosynthet ic Isophane insul in, both in formal

pharmacokinet ic s tudies and in c l inical t r ia ls in non-pregnant diabet ic subjects . This informat ion was not

avai lable a t the t ime the s tudy was carr ied out . Increasingthe dose of evening Isophane insulin in order to control

fasting blood glucose levels carries the risk of includingnocturnal hypoglycaemia. These problems might be avoided

by the us e of longacting hu ma n insu lin p repa ra t ions .Medicin e u pd ate 2 002 Dr. An il S. Bhora sk ar .

In practice if for any reasons if i t is not possible to use

porcine Monocomponent or human, any insul in have highlypurified may be suitable to correct the metabolism.

In al lergy - also one or other variety may be changed -al lergy to any insulin is noted. Even Genetic EngineeringHuman insul in can produce a l lergy. (any therapy with

in su lin al lergy is u su ally n ot perm an ent ).

Allergic Rea ctions to Anima l In s u lin

Allergic reactions including urt icaria and anaphylaxisoccurred with early insul in preparat ions, but as these were

very impure, the ant igen may not have been insul in.Immediate-type systemic hypersensit ivi ty reactions toinsulin are rare now and they will virtually disappear once

patients switch over to highly purified insulins. In insulin


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allergic patients insulin specific IgE values are often 10-20fold higher than in-patients without al lergy. A major

problem is the cross-reactivity that occurs between anti-insul in ant ibodies and the var ious animal and human

insulin preparation in-patients presenting with al lergy toanimal insulin. In non-allergic cases posit ive skin test to

human insul in do not necessari ly have any cl inicals ignif icance, because as many as 40% to 50% pat ients

receiving conventional insulin therapy showed wheal-and-flare responses and int ra-dermal test ing. (Guntram Schern t ianerDiabetes Care, 1993 ; 16.)

Another manifestat ion of insulin al lergy, which is also nowrelatively rare, is a delayed local injected insulin which is

seen as t ender subcutaneous lump tha t deve lops a t theinjection si te 30 minutes after injection and lasts for 12-24

hours. This is local Arthus-type reaction, mediated by IgGrather than by IgE and is a t t r ibutable to the compliment

activation by insulin IgG immune complexes. The exactfrequency of allergic reactions to animal insulin

preparations is unknown. However, after reviewing theent i re litera tu re on this s u bject one can sa fely conclu de th atthe f requency has been reduced 30% to < 5% in the pas t

h alf cen tu ry.

Allergic Reaction to Human Insul ins

In view of the wide spectrum of immune-mediatedcomplicat ions of insul in therapy, much at tent ion has been

directed to the reduced immunogencity of highly purifiedforms of animal insulins and more recently available

recombinant and semi-synthet ic form of human insul in.Delayed-type insulin allergy and especially immediate-type

were extremely rare in type1 and type2 diabetic patientswho were t reated exclusively with human insul in in many

centers .

As human insul in preparat ions are not tota l ly non-immunogenic , local and acute systemic responses to


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exogenous human insul in have occasional ly been reported.Th ere are occas ions where a pa t ient with a kn own h is tory of

anaphylaxis to animal insulin may also develop similarreact ion to human insul in. Recent ly Ganz et a l described a

type 2 diabetic patient who manifested both severe insulinresistance and persistence systemic al lergy despite

t reatment wi th recombinant human insul in. However, inth is cases symp toms of in su lin a l lergy ha d a lready em erged

several months after ini t iat ing therapy with mixed bovine-porcine insulin. After switching to recombinant human

insulin, generalised urt icaria with pruri tus, significanteosinophi l ia , and diffuse lymphoadenopathy reminiscent f

seru m sickn ess l ike resp onse occu rred. Th is ca se illu st ra testhat a wide array of clinically significant responses to

human insul ins occurs when i t i s used in insul in a l lergicpat ients (Timon W. Van Haeften Diabete s Care 198 9; 12 (9)).

Pat ients who are intermit tent ly exposed to insul in becauseof irregular administration appear to be a t a higher r isk

for m ore pers isten t a n d s evere al lergic reaction s.

Lipoatrophy

The phenomena of l ipoatrophy, in which there is a loss of

fat at insulin injection si te was previouslyquite common,being reported in 10% - 55% of pat ients t reated with

convention al bovin e/ porcin e in su lin . Patients withlipoatrophy usually have high circulating insulin antibody

t i t ters . An immune basis for this condi t ion has beensuggested by the immunehistochemical demonstra t ion of

both insul in and IgG subcutaneous t issue biopsied fromlipoatrophy areas . Lipoatrophy is now very rare with highly

pu rified porcine ins ulin s . (Guntram Scherntianer Diabetes Care, 1993; 16.)


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Thus individual ideas & individual experiences may prevailin th ese s itu at ion s.

QUESTION 12 :

The so-ca l led "Ava i labi l i t y of a nim a l Insu l in cry s t a l s" - a s

a s u b je c t w h a t i s t h e r e a l it y i n an i m a l i n s u li n s ac r os s t h e

Globe?

The problem of shortage of animal insulins in U.S. wasraised even over 20 years ago (Podalsky et al). The problem

of Limited Insulin supplies Globally. 15000 pigs & 18500cows 800 pou n ds of Pan creas, yie ld one pou n d of

insul in, to serve 750 pat ients one-year supply. But theconcern is the increase in the number of pat ients year af ter

year.

Th e big Ph ar m a h as with dra wn bovin e in su lin s in India an dtheir long term st ra tegy to discont inue animal insul insremains unchanged. Their exis t ing product ion of animal

insulins will gradually be converted to the production ofsem isynth et ic hu m an in su lin . E.g. biobras / NN produ ct ion

in Brazi l . What this means that they wil l make humaninsul in from animal insul in. Hence the name semisynthet ic .

Th at is how hu m an in su lin was firs t m ad e in 198 0s .

In reality American National Advisory Board 1978, WHO1980 feels that there would not be any insul in shortage and

no such problems wil l ar ise . Insul in manufacturers ownstudies are bel ieved to confi rm that most pig pancreases

remain u nh arvested (Teu sch er an d Diem 19 80, DECKERT et .al 1981) an d pigpan creases a lone can m eet the cu rrent dem an d. Chemica lly

modified human insulin (enzyme modified pork) depends onanimal pancreat ic insul in as i t s s tar t ing materia l . Assured

product ion thus cannot be a reason for a development of th is in su lin (K.G.M.M. Alberti).


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Animal insulins are freely available in India at mostaffordable prices. These extensive promotional activities like

th is, will certa in ly reas su re th e pr acticin g diab etologisi ts th ea vailab ility of an im a l in su lin s in th e In dian m ar ket .

QUESTION 13 :

Are there an y extra e nvironm en tal inf lue nces " - lik e "ma d cow

d is eas es " Prion d is eas es - pig enceph alitis viru s es etc - are

they real imp ed imen ts - or created id eas etc w ha t is the problem

an d w ha t is the reality? Dis cus s ion?

Defin in g CJ D:

Cla ss ical Cretzfeldt -J a kob Disea se (CJ D) is a ra re(< 1:

1,000 ,000:yr) an d fa ta l brain d isorder cha ra cterized b y rap idlyprogressive dement ia and associated neurological

dis turbances. The disease produced microscopic vacuoles inneurons that appear sponge-like and is often referred to asspon giform enceph alopa th y.

Origin al ly thou gh t to be cau sed b y a viru s , recent r esearch

has pointed to a new type of pathogen called a proteinaceousinfectious particle (prion), which is capable of transforming

n orm al ben ign p rotein m olecules in to in fectiou s, d ead lyprotein s by a lter in g their s h ap e an d cons equen t ly, th eir

function. There is currently no evidence that personsdiagnosed with an y form of CJ D carr y in fectiou s p rion s in

their blood.

Sometimes the other aspects of disease in animals havebeen invoked as problems (Mad cow disease, Spongiformencephalopathy & pig encephalitis Virus etc).

Generally Viruses reaching the Pancreas is protected (RSGLeslie) unless it is pancreatotrophic - (in general virus

Diseases have a tropism). In general in medicine the virus


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disease have a Big Tropism like skin Tropism ParotidTropism Hepatic or Pancreatic or Brain Tropism. Thus we

are shut up with Mumps breakdown with Measles orJ au n dice with Hepat it is e tc with out Tropism u su al ly the

organs are not affected. Hence no possibility of BSE inpanc reas .

In general animal meat Beef is so highly processed that i tis h ighly un likely th at th ey con tain a n y pr otein .

In general the manufacturing process of Insul in fromanimals involves several elaborate steps of purification,

steri l ization and cert ifications. The large 254 BSE aminoacids would be fi l tered out by the 4 th of 14 th filter steps in

manufac tur ing.

Scientist: Mad Cow May Not Cause Human Illness 1 0/ 2 4/ 0 1

Mad cow diseas e an d th e illn ess th ought to be its h u m an

equ ivalent m ight n ot be l in ked after a ll.

George Vent ers, a n expert in pu blic hea lth m edicin e inHamilton, Scotland, believes the rogue prion brain protein that

cau ses m ad cow diseas e , or b ovin e spon giform enceph alopa th y(BSE), does n ot cau se n ew varian t Creu tzfeldt-J ak ob Disea se

(vCJ D) a degenera t ive bra in diseas e foun d in h u m an s.

Bu t Vent ers s a id th ere is n o direct eviden ce tha t th e prionresp ons ible for BSE an d oth er a n im al disea ses is infectiou s in

h u m a n s .

Pr ions in an im als a nd hu m an are d iffe rent , h e a rgu es , and

hu m an s do not ge t other an im al pr ion d iseases su ch as sc rape fou n d in s h eep from eating lam b.

BSE is n ot a t ra n sm iss ible diseas e .


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It is a lso in corr ectly described as an in fection. Th ere can be n oin fection with out a viru s or b acteria, a s th ere ar e neither i t is

clear ly a p oison in g. A poison in g can n ot prod u ce at ran sm iss ib le d isease bu t it can be t ran splan ted from one

an im al to an other an d m ade to appear t ra ns m iss ib le .

Transmission is an i l lusion.

Proof that al l spongiform diseases are produced endogenouslyh as b een confirm ed by an im al research .

When cats, mice, sheep, pigs, goats, monkey, etc. , are

experimentally inoculated with BSE (2), yet all naturallyoccu rr in g form s of sp ongiform s diseas e when m icroscopically

exam in ed h ave a sp ecies sp ecific recon gnisab le pat tern . Wh ena d ifferen t gen otype is u sed t o dona te th e feed or in ocu lu m s i t

pr odu ces wha t is r eferred to by SEAC as th e Donor s pecieseffect (2) a m ou se with in du ced BSE for exam ple (2) pr odu ced

a m u tan t form of BSE as th e in du ced p oison is s im ply bein gtra n splan ted from th e donor to the recipient a s th ese ar t icles(3)(4) clear ly d em on st ra te. Bradley R., Experimen tal Tran sm ission of BSE,199 6, Elsevier, Paris. TSE, SEAC. Lond on HMSO. Sep tem ber 1 994 . P 62. Brown P.,Carleton Gajdus ek D. , et al . The New Englan d J ourn al of Medicine, Sep t 19, 19 85, p728 .

To su ccessfu lly reprodu ce the t r u e diseas e th e in du ced genet ic

m ateria l mu st come from s am e species as th e recipient .

Th is Don or Sp ecies effect (2) visibly dem on st ra tes th e disea secan n ot be t ran sm it ted to oth er species . New var ian t CJ D was

n ever n ew an d n ever var ian t . It h as a lways been s im ply CJ D.If a n ew disea se was im m ergin g in Brita in relat ed to eatingBritish beef th e sp ecies effect wou ld r evea l from wh a t a n im a l

th e disea se origin a ted. Th e m iss in g Donor sp ecies effect, inall form s of sp ongiform enceph alopa th y n ot in du ced by

scient is ts , pr oves th e diseas e did n ot breech th e sp eciesbarr ier .

Th e end ogenou s origin s of sp ongiform enceph alopa th y.


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Spongiform diseas es occu r in both an im als a nd hu m an s . Thediseas e is given a differen t n am e according to the s pecies,

su ch as CJ D in h u m an s , Scrap e in s heep, BSE in ca t t le , an dCWD (chr onic was tin g disea se) in deer a n d elk. The d isea se in

vegeta rian elk or deer, th erefore eatin g m eat ca n n ot cau se it incows, sh eep, h u m an s, or an y oth er species . Eat in g Brit ish beef

can n ot poss ibly cau se n ew var ian t or an y oth er form of CJ D.We can also prove th at it was n ever experim ent ally, wha t

ap pear ed to be t ra n sm it ted was in r eality in du ced pu tr idprotein poisoning. Bio-accu m u lated n eu rotoxic residu es th at

su rvived in th e fat com pon en t of th e newly in trodu ced solven t-free fat extraction pr ocess .

End ogen ous Origins of SEs

Dioxins

Dioxin s for jus t on e exam ple refers to a grou p of ch em ical

com poun ds th a t sh are cer ta in s im ila r ch emica l s t ru c tu res an dbiological cha ra cterist ics. Dioxin s ar e pr esen t in th eenviron m en t a ll over th e world. Dioxin s ar e releas ed into th e

air from combu st ion process es su ch as waste in cin erat ion an dfrom bu rn in g fu els. Dioxin s ca n also be form ed when

h ous ehold t ra sh is bu rn ed forest fires . An im als can tak e updioxin s d eposited on plan ts an d concentr a ted in th e food

cha in s o th ose an im als ha ve high er concentra t ions th atplan ts , dioxin s ten d to accu m u late in fa t . Abou t 95 % of

exposure to dioxins occur through consumption of food,especially food containing animal fat.

Conclusions

Our proposit ion could a gain be tested a n d p roven b ycon du ctin g a s im ple experim ent which wou ld involve trea tin g

two sa m ples of organ s from a cow. Dry clean an d p rocess onesa m ple with a s olvent u sed in th e feed m an u factu rin g process

i.e. t richloroeth ylene a n d com pa re th e toxic residu es of each .


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On ly th e non -solven t trea ted s am ple will conta in th e pred ictedneurotoxic residue.

We prove the diseas e is n ot tra n sm iss ible. A poison in g is n ot a

t ran sm iss ible diseas e it is an in ju ry. Th e prion is a symp tomnot the cau se .

MAD COW DISE ASE

http://www.suite101.com/article.cfm/4866/71780

Au th or: J u an C. MendiblePublish ed on : J u ne 12, 2001

Prions ar e protein s , a n d in order for th e ones from cows tocau se diseas e they ha ve throu gh go your gas t roin test in al t ract ,your blood s t ream an d cross wha t is called th e to bloodba rr ier, whos e fu n ction is to stop b ig molecu les from goin g

in to the bra in .

Now, in th e GI ar e pr oteases, en zymes th at dest roydigestm ost of th e protein s th at you ea t . Th is is on e of th e reas ons it

h as n ot been p ossible to design a way to take ins u lin orallyit

is d est royed in th e GI. In su lin is a m u ch s m al ler prote in th anprions.

Even if th e prions s h ould ma ke it thr ough th e GI system a n din to the blood, they sh ould be dest royed by your im m u n e

system ; an d if th ey su rvive al l th at , th ey st i ll h ave to cross th eblood-bra in ba rr ier , en ter th e cells , fin d th e n orma l prion s an d

con vert th em to pa th ogenic. Aren t th ey stretch in g it toom u c h ?

In their s ta tement of 16 Apri l 1996, The EuropeanMedicines Evaluation Agency (EMEA) concluded inter alia

that for al l active ingredients or reagents used in themanufacturing process , the measures deta i led in exis t ing

European guidel ines guarantee that medicinal productscontaining bovine t issue are safe. There are no recorded


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cas es of varian t Creu tzfeldt J acob Disea se (vCJ D) th at h avebeen lin ked to the u se of ph ar m aceu t icals conta in in g bovin e

derivatives.

However, i t is important to note that after rigorous survil lanceefforts and scientific scrutiny by leading scientific investigators

as well as government and regulatory agencies, a large body ofevidence demonstra tes that there is no credible support for

t ra n sm iss ion of CJ D, in clu din g vCJ D, from person to personth rou gh blood or plasm a-derived pr odu cts . Th erefore , an y r isk

m u st b e considered as th eoret ical.

QUESTION 14 :

If all the insulins are available and if their action are more or

less the same - is the cost important? Or the marginal

advan tages a nd dis ad vantages matters ??

If al l insulins are available - mono species and Purity arethe Supremes - no doubt insul in act ion wil l be the same -Th ey all will sit on recep tor s & act well.

Analogues of insulins sit well & act - when syntheticanalogues act wel l - why not natural Insul in analoguesBovin e / Porcin e & Hu m an .

In that case, of course cost wil l be the important factor -a l though som e ma y not car e for the cost - a t least s ay so.

Marginal disadvantages & advantages between the insul insa lways were th ere even ear lier.

But Physicians & Diabetologists must be aware of al l theaspects of Bovine, Porcine & Human & apart from these


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clinical animal Insulin. "Animal Insulinology" - has becomea big su bject in Bas ic Dia betological scien ces-

When animal Insulinology is progressing this question isinevitable.

QUESTION 15 :

Some of the synthetic insulin analogues have serious potential

problems . Mitogene s is & Carcinogen icity e tc - even if incid en ce

is not h igh can it be tak en into accoun t. For ins tance "Pro

ins u lin" - clin ical trials - my ocardial toxicity - with d raw n etc -

many other instances also. What are the collective ideas -

enthus ias tic idea s and non enthus ias tic idea s ?

Replace Hum an Ins u lin by hu m an ins u lin was the m otto inth e newer In su lin Er a -

Now because Genet ic Engineering has been advancing, thefocus on Insul in analogues began & pharma companies &

In su lin Resear chers go on specu lat ing on var ious an alogu es- sh ort a ctin g & long acting an a logu es.

Pro insulin for cl inical usage was produced as an earl ieranalogue & now with drawn quickly owing to myocardial

Toxicity.

Now many short acting & Long acting Insulin analogues aredevised - Insulin Aspart , Insulin Lispro, Insulin Glargien -

Lan tu s In su lin & so on -

Discover a n an alogue & th en fin d & Bu ild u p a u sa ge for it -is the u su a l pa th way.

Regarding Clinical trials of analogues - various

contradict ing ideas can occur - as an example Insul in


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"Lisp ro" in 19 98 etc. New En g. J ou rn a l of Medicin epu blish ed so m an y pr oblem s in u sa ge of "Lisp ro" "in

pregnancy" - so many frightening foetal anomalies etc &again las t year 20 01 sa m e NE J ourn al of Medicin e

publ ished and announced resul ts wi th Lispro as safe inpregna n cy even sa m e repor ted au thors (Jovanochic) - Probably

one will lose confidence in "evidence Based Medicine" -across U.S.

Bren t Hoad leys In su lin Pa ten t Resea rch a n d Fin dings:Feb 2 8, 20 01 Hoadleygold, inc, Bren t h oadley PhD.

In his book 1984, George Orwell wrote about newspeak.This is now the language used by the pharmaceut icals to

create billions of dollars in profit from geneticallyengineering insulin-like molecules.

Pharmaceuticals will tell you the foreign protein insulinsource is the pancreas of a pig or cow. When given names

such as humalog, l antus or novorapid by giantcorp ora tion s, a foreign p rotein b ecomes a won der a n a log of

human insul in . The t ru th i s a l l three of these subs tancesare foreign proteins in some cases not even an insulin

molecule. All could be considered new growth hormoneswith very little being known about long term effects.

Dia betics n eed to app ly for long-term guinea pig sta tu s.

QUESTION 16 :

In ma ny in s u lin - Blood glucos e controls & comp lication trials noanalogues were used and the available Routine Insulins also

good en ough? Wh at are the commen ts ?

In Insul in analogues - the usual quest ion Basic asked is Dowe need the various analogues? The straight answer will be


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- No - Not necessary - round about answer may be - yes inselective areas of Insulin practice.

Many of the given classical Trials DCCT or UKPDS - or

Kumamoto - did not use the Insul in analogues - There wasno necessity and Tight control of Blood glucose can bea chieved with ou t i t .

So i t looks as if Insulin analogues are for "Coined usuage"

(again a coined Terminology) not absolutely essential - (stillm ay h ave its own u sa ge in selective ar eas ).

QUESTION 17 :

In general what are the individual ideas and final opinion and

concluding messages in this subject of animal insulins versus

hum an ins ulins and GE ins ulin.

As daunting as the over al l costs of diabetes care the day today challenge for individuals with diabetes and policy

m ak ers re la tes to choices in diab etes care . Wh at ben efits d ovarious choices of insulin provide and at what cost .

Whether these quest ions are asked at an individual ornational level , knowing the answer is fundamental to cost

effectiveness.

In dia presen ts c las sic exam ple,In 1998 ,

Cost of Ins u lin therap y/ year / person $350Cost of n on ins u lin therap y/ year / person $ 70

17 .5 MN diabetics in In dia,Total cost of diabetes in In dia $ 2.2 Bn .Total h ealthca re bu dget for ent ire In dia $ 72 0 Mn .

Percap ita expen ditu re for a l l h ealth cares $ 21- in clu din g water an d s an ita t ion.


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Near ly 400 Mn In dian s live in a bs olu te p overty.

Th e a vaila b ility of cost effective a n im a l In su lin s ismandatory in the Indian Sene. (Nearly 400 Mn Indians l ive

in absolute poverty) and in developing countries (where80% of the populat ion consumes 20% of world product ion

of in s u lin ).- Sin ce Pur ity - Pur ity h as been con qu ered in an im al

in su lin s th ey m ay be otherwise equa ble - why n othave all of them. Cost effectiveness is important for

regu lar an d con t in u ed u se of in su lin especial lybecause there is no medical insurance coverage in

Indian Medical Sene.

- Th e debate on th ese differences h as con t in u ed s in ce th eint roduc t ion of t rea tment wi th human insul in and,

u n fortu n at ely, very often th e pat ien ts experien ces h a vebeen classed as only anecdotal and of little value.

- Research h as a lready demonst ra ted tha t hu m an in su linh as n o clin ical ad van ta ges for pa tien ts. Wh en ins u lin is

n eeded a n im al in su lin sh ould be con sidered as firs t

ch oic

Documents

Bovine Porcine