nm0454: er [0.3] now my name's namex i'm a consultant nephrologist which means 
i'm a kidney doctor [0.4] and i'm going to give you two talks this morning [0.
4] er both about forty-five minutes [0.5] according to your books it should be 
glomerular disease then diabetes but just to confuse you we're doing it the 
other way round [0.4] so we're going to do diabetes first [0.3] and then 
glomerular disease [1.2] and er last time i was asked to hand out handouts 
before the talk [0.4] so i'm going to submit to your er [0.4] your ways [0.3] 
if you want to spread them around [8.8] okay [0.3] right [0.2] sit down shush 
shush shush [0.6] diabetes diabetic nephropathy [4.9] actually can i have one 
of the handouts i might need to er [0.7] refresh my memory [2.9] thank 
nm0454: okay [0.6] now [0.4] why are we interested in diabetes and diabetic 
nephropathy [1.6] you know by now my talk's interactive so if you don't answer 
i'll start picking on people [0.4] so why are we interested in diabetes and 
diabetic 
nephropathy [0.5] is it just because you have an exam on the subject [3.0] okay 
come on [0.5] 
sm0455: increases 
nm0454: anybody 
sm0455: morbidity and mortality [0.4] 
nm0454: sorry 
nm0454: increases morbidity and mortality 
nm0454: yeah very good so diabetes is very bad for you it's also very common 
how common is it [0.8] 
sf0456: think it's one in five [0.4] 
nm0454: speak up [0.4] 
sf0456: one in five [1.0] 
nm0454: one in five [0.4] well [0.6] actually in some bits of the world you're 
right [0.4] in some bits of Australia [0.2] New Zealand and other countries 
it's [0.2] it is probably one in five but it's [0.2] it's probably about two 
per cent [0.5] of [0.6] the general population in the U-K [0.3] five per cent 
of blacks and Asians so it makes it [0.2] with schizophrenia rheumatoid disease 
one of the commonest chronic diseases [0.4] and therefore [0.2] er 
just by chance one or two of you in this room should have diabetes [1.4] okay 
[0.3] so it's a very common disease [0.3] er you need to know a lot about it 
and that's going to be one of the themes of this talk [0.4] the second talk is 
about rare diseases [0.3] that you ha-, know have to know a lot about because 
it's in your exam but not just [0.2] not because it's [0.4] biologically more 
common or more important [1.0] so [0.4] diabetes is very common diabetic 
nephropathy [0.3] is quite rare [0.5] why why do you think it's quite rare [0.
2] lady at the end [1.2] 
sf0457: er [1.8] 
nm0454: if you don't know guess [1.4] 
sf0457: because it takes a long time to get to that stage 
nm0454: yeah very good i mean that's exactly the answer [0.5] because it takes 
a very long time to get it [0.3] and what implication [0.4] er does that have 
for most most blacks and Asians [0.2] why why is that such [0.7] if you forget 
everything else [0.2] that i'm going to say this morning just remember what 
this lady said so [0.3] 
diabetic nephropathy takes a long time to get [0.7] and why is that so 
important [0.4] 
sf0458: 
sf0457: they tend to get it earlier [0.7] 
nm0454: well they tend to get it earlier but not that early [0.4] anybody else 
[0.7] 
sf0459: do they not get treated [0.2] 
nm0454: they're not get they don't get treated and it gets missed [0.5] and why 
does why does [0.2] chronic diabetes and diabetic nephropathy [0.5] get missed 
[2.6] it's not a trick question [0.4] why do diseases get missed in general [1.
0] 
sm0460: 'cause they're asymptomatic [0.3] 
nm0454: it's asymptomatic and that's the problem [0.4] so both diabetes and 
diabetic nephropathy and many other complications of diabetes [0.3] are 
asymptomatic these are so-called silent killers like hypertension [0.8] and 
this is the problem with them they're very common [0.2] they're very lethal [0.
2] and you'll miss them unless you look for them [1.4] so there's some facts 
there down for you on the sheet [0.3] er i've 
said at the top eighteen per cent of patients in the U-K [0.2] on dialysis have 
diabetes and that's true from the latest data [0.3] generally you go to renal-
reg-dot-com where [0.2] all British data is accumulated [0.3] fascinating for 
[0.2] us nerdy [0.3] nephrological types [0.5] er [0.4] so [0.2] it's a common 
cause of a rare disease which makes it rare [0.4] but nonetheless it's going to 
be the focus of the talk this morning [1.1] er [1.1] let's get back to basics 
as John Major once said and let's get into a few definitions [0.4] so [0.2] er 
i've got a definition of diabetic nephropathy down there for you [0.2] as you 
can see it's a rather vague one [0.5] it's i'll read it out to you [0.3] it's 
[0.3] a usually progressive renal disease [0.2] secondary to [0.4] diabetes [0.
6] and what's wrong with that definition [1.6] why is it so difficult to define 
[3.3] gentleman there why why is it so difficult to define [0.3] something like 
diabetic nephropathy [0.7] 
sm0461: 
it presents in very different forms it can present in many different ways and 
can have many different causative [0.6] 
nm0454: very good 
sm0461: 
nm0454: very good so it can present in many different ways there are many 
different forms there are many different causes and when you've got a 
complicated disease like that it's not like a myocardial infarction [0.2] which 
you can define in terms of a C-K rise dropped T [0.3] typical symptom signs [0.
3] this is a vague concept [0.4] and i'll explain a bit later on why it's such 
a vague concept [0.3] one of the more fundamental reasons why diabetic 
nephropathy is difficult to define is 'cause diabetes is difficult to define [0.
5] let's have a go gentleman here [0.4] have a go at er defining diabetes [0.3] 
sm0462: er which one do you want 
nm0454: er either [0.2] or all [0.3] speak up so everybody can hear 
sm0462: it's when the pancreas [0.2] isn't producing insulin [0.5] 
nm0454: or [0.2] 
sm0462: or when the s-, tissues aren't responsive to insulin 
nm0454: 
very good that's actually probably the best definition i've heard from a [0.2] 
a medical student it's er [0.2] almost impossible to define i mean there are 
definitions which are nice simple ones [0.4] a fasting blood sugar of over [0.
7] 
ss: seven [0.2] 
nm0454: seven [0.2] and a random of over 
ss: eleven [0.8] 
nm0454: eleven okay [0.3] so that's a nice simple one put it in the bo-, put it 
in the back of your brains useful in clinical practice [0.3] at a deeper level 
of course diabetes is very difficult to define [0.5] er and the gentleman there 
has probably come out with a pretty good one [0.3] you know [0.3] it's trouble 
with pancreas [0.5] er [0.2] you know either the pancreas doesn't make enough 
insulin or you can't respond to insulin [1.1] if you want to have another go at 
defining it [0.3] the typical group of symptoms and signs [0.4] with a variety 
of causes [0.7] associated [0.3] with [0.2] pancreatic trouble [1.2] it's 
getting a bit vague now my 
definition i'm running out of steam it's it's just impossible to define [0.7] 
er in any [0.2] concrete way because you've got gestational diabetes pregnancy-
related diabetes [0.4] is that diabetes it doesn't make you blind ten years 
later [0.2] it's diabetes while you've got it [0.8] so it is a very very 
difficult thing to define and it's quite interesting actually that one of the 
diseases that [0.3] affects your whole course [0.6] renal eyes heart everything 
is actually almost impossible to define [0.5] and we could [0.5] be defining it 
all wrong [0.8] b-, [0.2] what is the problem with the definition of diabetes 
related to absolute levels of of blood sugar [6.0] what's the problem with that 
[0.4] it's nice in a box back of the brain [1.1] simple [0.4] let us assume [0.
2] demonstrate it [0.2] in the exams [0.6] 
sf0463: there's lots of variation in the range anyway [0.3] 
nm0454: yeah there's a lot of normal variation very good so [0.4] by now you 
should realize that all normal ranges are a load of rubbish they're 
all based on [0.5] er [0.2] the standard normal distribution so this could be 
height blood sugar [0.2] et cetera et cetera and all normal ranges [0.3] we 
take usually are two standard deviations from the mean [0.3] so we say a normal 
blood sugar [0.3] is what four to six [0.3] and diabetes [0.8] is a fastingness 
of seven [0.2] or a random of over eleven [0.2] but there's always going to be 
tail end Charlie who's quite normal who doesn't have diabetes [0.6] but is has 
diabetes by a number definition [0.9] and the other reason why it's so 
difficult to define of course [0.3] is that the complications of diabetes [0.3] 
are really the complications of what [2.8] 
sm0464: persistent hyperglycaemia [0.3] 
nm0454: speak up [0.2] 
sm0464: persistent hyperglycaemia [0.3] 
nm0454: er yeah yeah okay you're right but but [0.2] what what [0.6] what 
constellation of diseases [1.0] large vessel diseases [1.7] is [0.9] the main 
[0.3] problem [0.8] with diabetes or one of the main problems with [0.5] 
ss: 
nm0454: speak up 
sm0465: 
ischaemic heart disease 
nm0454: yeah ischaemic heart a part of atheroma [0.6] and there is a danger [0.
2] of course that the large vessel complications of diabetes [0.3] today we're 
going to talk about a small vessel complication of diabetes diabetic 
nephropathy [0.7] but the large vessel complication of diabetes are atheroma [0.
5] and it's not impossible of course [0.3] that we've all got our Venn diagrams 
mixed up [0.7] and [0.2] the [0.3] atheroma Venn diagram [0.3] is [0.2] 
overlapping with the diabetes Venn diagram and of course it does 'cause 
diabetes [0.2] does this but it's also possible [0.3] that people with 
ischaemic heart disease people with disease [0.2] who happen to have [0.3] a 
blood sugar of eight what's eight it's in the middle [0.3] are labelled as 
having diabetes [0.3] causing atheroma [1.1] and i think [0.4] there is so much 
overlap in what we now call Syndrome X which is this loose constellation of 
diabetes [0.3] ageing hypertension atheroma [0.2] eating 
chips et cetera et cetera [1.1] it is very very grey now [0.5] nonetheless [0.
5] i've [0.2] hopefully laid out a few rules for you a few simple rules but [0.
3] don't think about it's like most things in medicine if you think about it in 
too much detail [0.6] it's all wrong [0.5] and it's too complicated so just 
think about it simply [1.4] okay [0.2] so diabetes is difficult to define [0.4] 
and therefore diabetic nephropathy is difficult to define but [0.2] we have to 
[0.2] work on some definitions [0.3] we've talked a bit about [0.4] er the 
prevalence already [0.4] now [0.9] how common is diabetic nephropathy on the 
sheet there [0.2] i've put a few numbers for you [0.3] i've said that [0.2] 
forty per cent of people with IDDM [0.8] and five per cent of people with NIDDM 
[0.6] get diabetic nephropathy [1.0] er [1.3] again [0.6] there's a lot of 
problem with all these numbers [0.4] who's heard of hea-, of of linear bias [1.
2] any mathematicians in the room tell me about linear bias [2.4] come on [0.9] 
there's one of you deep down there [0.4] [laughter] i know [0.5] you read maths 
textbooks every night [0.8] [laughter] 
this thick you love it [0.3] [laugh] [0.5] come on [0.3] linear bias [1.6] well 
linear bias [0.4] this is i wasn't going to talk about it this morning but [0.
2] i was thinking about it in the car on the way here [0.4] and i s-, [0.5] er 
[1.0] almost certainly decided to destroy my own talk [0.4] linear bias affects 
the whole of medicine [1.6] particularly chronic diseases but there are [0.2] 
er some important there is some importance for [0.2] acute diseases too [0.4] 
okay so we've got these numbers we say [0.3] X per cent of the population have 
Y A per cent of the population have B [0.7] ten years later fifty per cent have 
cancer fifty per cent are dead [0.7] where do these numbers come from [0.5] 
where do they come from how do we develop these numbers [0.8] lady on the end 
here [1.4] 
sf0457: er [0.3] 
nm0454: it's not a trick question [0.8] if we said you know if i said to you [1.
4] fifty per cent of the population have [0.5] diabetes [0.3] where do you 
think that number comes from [2.1] 
sf0457: 
observing population 
nm0454: very good yes observing population [0.2] cross-sectional analysis [0.2] 
okay so taking a large population [0.6] a hundred people a thousand people and 
and finding out who has diabetes [1.0] but that's wrong isn't it because that's 
a snapshot [0.5] it doesn't really tell you about the disease in the community 
[1.3] and what you need to know [0.5] in terms of [0.2] how common is the 
disease now how common the disease was and how common the disease will be [0.3] 
is actually nearly impossible to define [0.3] so for example diabetes [0.7] we 
could take time X in the past [0.6] nineteen-sixty-one when i was born [0.3] 
long time ago [0.6] er [0.4] we define diabetes in a certain way [0.2] and at 
that point we do a cross-sectional study and we say that one per cent of the 
population has diabetes [1.4] time goes on [0.2] and we say diabetes is bad 
for you and leads to complications [0.3] it leads to [0.3] X per cent of people 
getting diabetic nephropathy that's why i was thinking about it in the car on 
the way here [0.3] X per cent of people forty per cent of IDDMs five per cent 
of NIDDMs [0.3] getting the complications which [0.2] must be over ten years by 
definition that's also on your sheets [0.6] and so they're getting the 
complications there so that's bad for you because [0.2] if you wait long enough 
you'll get the complication of diabetes [0.4] then something else might happen 
you may get [0.3] away from small to large vessel complications then you may 
die [0.9] and then [0.2] people can't do studies on you when you're dead [0.9] 
but from that [0.2] passage of time [0.3] we draw all the conclusions that 
based all of our knowledge [0.5] but remember most of the analysis is done at 
various times [0.4] it's cross-sectional data [0.2] about a linear disease [0.
2] and it could all be wrong [0.3] these are not the same patients [0.4] 
society has changed [0.2] the 
planet has changed the universe has changed in that time [0.6] and our 
definitions of chronic disease so [0.2] the definition of rheumatoid arthritis 
might be quite different then [0.2] from then [1.4] and if you think about it 
most chronic diseases have this problem with linear bias [0.5] and [0.4] the 
bias leads to what wh-, what does it make researchers do [2.9] lady there in 
the blue [0.9] researchers who don't understand linear bias [0.5] what do they 
what what what [0.3] is the danger that they do [2.7] 
sf0466: 
nm0454: what happens as you get older [1.0] hair falls out go grey [0.3] 
everything goes floppy [0.8] what happens [1.1] to your brain as you get older 
[1.0] what do old what do me and namex talk about when [0.2] when we're out of 
here we're sick of you lot [laughter] you're always 
late [0.5] moaning your mobiles are on [0.3] what are we mo-, [0.4] what are we 
[0.5] what do we moan about [2.6] anybody [1.9] 
sm0467: how it used to be [0.5] 
nm0454: how things used to be yeah [0.2] the golden age [laughter] [0.2] when 
things were better [0.2] when medical students wore [0.2] ties and had 
briefcases [0.5] the good old days when we were good at football [0.2] we won 
the World c-, ah yeah we won a World Cup earlier [laughter] [0.6] i hope you 
all watched it [0.4] er [1.8] yeah we talk about the good old days the bygone 
era the golden age when things were good [0.6] and it's all claptrap isn't it 
[0.2] it's all claptrap it's just me and namex getting older it's your and 
you're getting older too [0.2] and it's linear bias again [0.2] we're talking 
about some [0.4] bygone era which never existed [0.4] you know [0.2] because 
time moves on [0.4] and all of our conclusions that we draw about ourselves and 
society and 
diabetes and diabetic nephropathy [0.4] have the problem of linear bias in them 
[0.7] 'cause all you need to do is change the definition [0.8] from say four to 
six [0.3] for diabetes to four to seven or rheumatoid arthritis in another way 
[0.2] to completely change [0.5] the whole of [0.2] Western medicine and and 
the knowledge that we [0.3] pass on to you [1.7] how do we get rid of it we 
can't get rid of it actually because it's it's it's part of time it's part of 
the course of the universe and it it is impossible to get rid of [0.4] and so 
the best we can come out with is generalizations made from cross-sectional 
studies [0.6] the important thing from your perspective is to know that it goes 
on [0.4] and therefore you should be nice and cynical about any form of i-, [0.
2] information any form of statistics [0.3] that anybody puts in front of you 
[1.6] so [0.7] let's er [0.3] throw away the rule book [0.6] and er [0.8] move 
on [0.6] so we've got to give you some numbers er [0.5] we've said er that [0.
3] er diabetic nephropathy does 
exist it's a small vessel complication of diabetes [0.4] it's much more common 
in IDDMs but IDDM is a much rarer disease than NIDDM so [0.4] by definition 
therefore far more people with NIDDM [0.5] and that's where the problem lies 
get diabetic nephropathy [0.3] and most of our patients in namex [0.2] the 
typical namex [0.3] patient [0.2] is a late middle-aged fat Asian or black [0.
3] NIDDM [0.3] [laughter] who presents late and that is the problem they 
present late as the gentleman [0.2] said earlier [0.2] it is an asymptomatic 
disease [1.7] okay [0.5] onset of the disease er most of the small vessel 
complications of diabetes come on after ten years [0.6] so tell me some small 
vessel complications [0.2] gentleman on the end there other than diabetic 
nephropathy [0.4] small vessel [1.8] 
sm0468: don't know [0.6] 
nm0454: lady next to him [1.1] 
sf0469: er is retinopathy 
nm0454: 
retinopathy okay [0.2] there's another one which is usually classed as a small 
vessel any anybody else know [3.6] neuropathy [0.5] neuropathy [0.5] er [0.3] 
anything small [0.2] is a usually a small vessel complication large vessel are 
com-, are complications of atheroma [0.5] brain [0.2] peripheral vascular 
disease of the heart [0.8] er [0.4] cu-, that's all rubbish though isn't it [0.
8] i mean [0.3] i mean it doesn't take a a rocket scientist to work out that 
big blood vessels [0.4] get smaller don't they [1.9] and branch off in 
capillaries et cetera [0.4] so er [0.2] the whole classification of the 
complications of diabetes of small and large vessels is completely arbitrary 
'cause what's small and what's large [0.2] but nonetheless we do attempt to 
classify it in that way [0.4] clearly most patients will have problems with 
both [0.6] and that's very important for diabetic nephropathy because [0.3] as 
well as having diabetic 
nephropathy [0.3] a small vessel complication [0.3] lady there with the 
baseball cap [0.4] what else do you think might affect the kidney [1.5] as well 
as [0.7] problems with the small vessels [2.6] 
sf0470: [0.6] [0.4] 
nm0454: speak up sorry [0.3] 
sf0470: [0.8] 
nm0454: i can't hear you sorry [0.6] 
nm0454: i don't know [laughter] 
nm0454: okay lady next to her [0.2] what else might affect the kidney [0.3] in 
diabete-, other than the small vessel complications [3.9] 
sf0471: large vessels 
nm0454: large vessels such as the [0.9] 
sf0471: renal artery 
nm0454: renal artery okay and so [0.3] er if you've had diabetes for over ten 
years [0.3] you've usually got trouble in the large vessels [0.3] 
and trouble in the small vessels [0.4] er [0.3] so [0.4] diabetic nephropathy 
pure diabetic nephropathy [0.3] is extremely unusual and most people have both 
[0.9] and in fact [0.2] there are other [0.4] renal complications of diabetes 
[0.2] they're listed down there for you just to [0.3] er read a few of them out 
[0.2] papillary necrosis which has other causes [0.3] anyone like to tell me 
some other cause of papillary necrosis [3.3] not fair as i'm sure you don't 
have a lecture on papillary necrosis [0.6] fascinating disease actually [0.3] 
[1.9] the [0.4] the papilli remember are part of a drainage system of the 
kidney these are the papilli [0.7] and they can fall off [0.4] papillary 
necrosis [2.1] sickle cell disease okay [0.3] sickle cell disease and diabetes 
are [0.2] two of the most important causes of [0.4] of [0.3] er papillary 
necrosis in this country but worldwide probably analgesic nephropathy are 
probably [0.2] er as important in the developed country [0.8] okay [0.2] so 
diabetes can affect the kidney in many ways renal vascular diabetic nephropathy 
papillary necrosis [0.2] 
recurrent urinary tr-, [0.2] tract infections are more likely to get [0.2] 
contrast nephropathy [0.3] after [0.2] er an angiogram of any type [1.4] one of 
the fascinating things about diabetic nephropathy [0.5] and in fact all the 
complications of diabetes [0.4] is [0.4] the W question [0.8] why [1.0] 
followed by the H question [1.2] which is how [2.2] so [0.4] you tell me [2.1] 
how [0.2] does diabetes damage the eyes [0.3] the kidneys [0.3] the nerves [1.
2] lady with the blue there [0.2] third from the end [1.8] 
sf0472: er [0.8] 
nm0454: if you don't know give me a can you give me a calculated guess what [0.
2] what do you think the metabolic abnormalities in [0.6] in diabetes might be 
[3.4] 
sf0472: there's lots of under pressure if you're going to have cirrhosis 
nm0454: very good i'm glad you said that actually 'cause [0.4] the obvious 
thing to say is what you're obviously not a a lady of the obvious [0.9] 
[laughter] what is 
what is the obvious thing to say [0.9] diabetes is characterized by [0.8] quite 
[0.5] 
ss: 
nm0454: hyper [0.2] 
ss: glycaemia 
nm0454: glycaemia [1.1] and so the most likely cause of all the [0.2] trouble 
[0.3] is hyperglycaemia but [0.3] there's a lot of research going on into the 
and of course nobody knows [0.2] and the whole research department i don't know 
if it's a particular interest of of of [0.2] 
nf0473: me 
nm0454: of er namex or or or [0.5] er [1.0] research all over the U-K in 
physiology departments [0.4] er is obviously is is i-, to these questions the 
why and the how questions [0.4] how does diabetes do it [0.8] of course nobody 
knows [0.3] and [0.2] a lot of research is now orientated towards pressure [0.
2] and it may be [0.2] that the effects of blood pressure on small vessels are 
probably more important than hyperglycaemia [0.2] there's lots of other 
theories [0.2] insulin growth hormone [0.2] cytokines just goes on and on and 
on [0.3] 
Brian Williams who's a professor of medicine in Leicester [0.2] his whole 
research is oriented towards this area but it is quite interesting [0.3] er [0.
2] that we haven't actually come that far since er Banting and Best [0.3] who 
who were Banting and Best [0.9] let's pick on somebody else lady in the black 
top there who were Banting and Bess [1.1] 
sf0474: they 
nm0454: have you heard of them 
sf0474: discovered insulin [0.3] 
nm0454: very good okay [0.3] so even if you didn't know good [laughter] 
calculated guess [0.4] er [0.7] and er [0.3] they they discovered well [0.9] i 
don't know if they d-, discovered insulin they they they refined it perhaps [0.
4] er [0.3] and er this story which [0.2] i'm sure you're all familiar with of 
a medical student and a [0.2] and a surgeon [0.3] who were put on the task of 
finding out 
what was the trouble in diabetes [0.4] was it insulin could they refine insulin 
[0.4] one of them i can't remember which one does anybody know [1.2] Banting or 
Best one of them developed diabetes knew they were going to die 'cause in the 
the States they couldn't get a patent on insulin [0.2] went off on a world tour 
[0.4] er [0.2] there were no mobiles no texting no e-mails [0.3] he just 
assumed he was going to die on his world tour and then the other one refined 
insulin [0.2] so had to have a ring round [0.3] all the bars of [0.3] Vienna 
and Paris you know find this drunken medical student [laughter] [0.4] er [0.2] 
and er [0.2] just get them back get him back and say [0.5] actually we've 
cracked it we've got insulin and here's an injection and they lived happily 
ever after no [0.2] he lived for many years [0.3] er [0.2] n-, anybody know [0.
5] anybody know which one it was can't remember okay look it up Banting and 
Best [0.6] er [0.4] but we haven't actually come that much further since 
Banting and Best because we haven't answered [0.4] the the W and the H 
questions for 
diabetic nephropathy or any of the complications of diabetes [0.7] and [0.9] 
these are incredibly important questions because [0.2] it's pretty unlikely 
we're going to be able to [0.3] get at the factor that causes diabetes [0.4] 
but we might be able to turn off some of the complications of diabetes if namex 
can crack it in her in in in her lifetime [0.9] okay [1.5] bit of pathology [0.
4] er [0.6] i know your course doesn't emphasize pathology [0.2] and certainly 
i'm not going to emphasize it either because when i was a medical student they 
axed the pathology course which i thought was one of the best things they ever 
did [0.5] er [0.3] but you do need to know a little about it [0.3] and er [0.2] 
there are some characteristic findings of diabetic nephropathy [0.6] we don't 
to be honest normally [0.6] do a kidney biopsy on somebody with suspected 
diabetic nephropathy so in other words if they have [0.3] renal problems and 
diabetes we assume [0.3] by and large that it is diabetic nephropathy [0.5] er 
and that can 
be a dangerous assumption [1.3] if you were to do a renal biopsy at the 
earliest stages you do see some characteristic abnormalities you see expansion 
of the mesangium you see [0.3] er [0.2] enlargement of the glomerular basement 
membrane [0.3] but these are really non-specific and can be seen in other 
nephropathies such as membranous nephropathy [0.7] there is a more specific 
lesion [0.3] which all medical students know called the Kimmelstiel-Wilson 
lesion [0.8] er [0.3] and this is part of a [0.2] so-called nodular 
glomerulosclerosis [0.3] and it has a characteristic [0.4] er lumpy appearance 
[0.3] er i deliberately haven't brought any slides of it along [0.4] er [0.2] 
because that's going to be one of your tasks after this talk [0.4] to go out 
and find out what a Kimmelstiel-Wilson lesion looks like [0.4] and er if you're 
really interested find out who Kimmelstiel and Wilson were [0.4] but 
again [0.2] it's not that specific to diabetes [0.2] and there are other renal 
diseases such as light chain [0.4] deposition disease and other causes of these 
lumps [0.4] of [0.3] er sclero-, of nodular glomerulosclerosis [0.9] okay [0.5] 
so i've talked a bit about the pathogenesis we don't know the answers to the 
the how and the why question [0.9] er [0.4] having [0.3] destroyed all your 
ideas [0.3] of diabetes diabetic nephropathy linear bias the definition of 
disease statistics et cetera [0.4] er i've put a nice little table in there for 
you 'cause then you can go away [0.3] and assume that is completely correct [0.
3] and you can er [0.2] regurgitate that [0.3] the so-called Mogensen 
classification [0.4] of diabetic nephropathy [0.4] er [0.5] i don't know how 
useful it is but it is something that i would expect you to know about [0.3] er 
[0.4] and [1.0] it [0.2] Mogensen in nineteen [0.3] can't remember when it was 
[0.3] eighty-two came up with this classification of four stages of diabetic 
nephropathy [0.4] and i just want to go through those [0.2] 
briefly with you [0.6] er [0.5] the first stage is perhaps one of the most 
interesting one [0.9] and [0.3] er i i've got no idea how they found this 
information out [0.4] but apparently at the early stage of diabetic nephropathy 
[0.2] you go through a hyperfiltration stage which is very similar to the [0.2] 
first trimester of pregnancy [0.5] er [1.0] do you know namex [0.4] [0.3] 
nf0473: no 
nm0454: does anybody know [0.2] have you done any research into diabetes [0.3] 
for previous degrees [1.5] no [0.7] ah yes you do [0.5] one of you knows you're 
just not telling me [0.4] the the er [0.4] i d-, [0.3] i don't know how they 
found out and obviously they they had a very accurate way of measuring G-F-R in 
the earlier stages of diabetes and we're talking [0.3] you know [0.2] the first 
couple of years of diabetes [0.5] er and if you measure G-F-R at this stage 
apparently it is increased 'cause the kidney [0.2] hyperfiltrates and 
apparently actually enlarges [0.3] there are very few causes of [0.2] of renal 
enlargement does anybody know any others [2.3] apart from 
diabetes [1.6] 
sm0475: removal of the other kidney [0.3] 
nm0454: yeah very good actually yeah [0.3] absolutely removal of the other 
kidney [0.2] any any any [0.2] any other that's about the only guaranteed thing 
[0.3] course nobody knows the mechanism of how your body knows you've lost a 
kidney and [0.2] how it knows to enlarge the other one [0.4] other causes of er 
of of a lar-, l-, enlarging kidneys [0.7] 
sf0476: tumour [0.4] 
nm0454: speak up [0.2] 
sf0476: tumour [0.3] 
nm0454: tumour yeah no [0.2] yes a bit [0.2] i mean you get a big lump [0.2] 
the whole kidney itself doesn't enlarge 
sf0477: cysts [0.3] 
nm0454: cyst yes polycystic kidney disease but it c-, [0.3] the actual renal 
tissue doesn't enlarge [0.2] but sort of and sort of [0.3] 
sm0478: hypertension [0.2] 
nm0454: hyper-, no [0.3] no [0.2] [0.9] ameloid ameloid is a characteristic 
cause of so-, enlarging kidneys [0.3] and some 
you were half right [0.2] lymphoma and leukaemia [0.3] er if they directly 
infiltrate the kidney can cause the kidneys to enlarge [0.4] but there are 
relatively few causes er of of a large kidney [0.4] er [0.2] and most of them 
are impossible to detect as the changes are so small [0.4] and you need very 
accurate [0.3] er ultrasound technology [0.9] okay [0.3] the second stage it 
starts to get a bot-, bit more interesting [0.5] the glomerular [0.2] disease 
that i've described [0.4] the if you were to do a biopsy at that point [0.3] 
the mesangial enlargement [0.3] the thickening of the glomerular basement 
membrane [0.3] er starts happening [0.3] er the patient is unaware of this [0.
4] the G-F-R is still more than it was [0.3] there's still no protein in the 
urine they still have normal blood pressure [0.4] and er the creatinine is is 
still normal [0.8] er [0.5] this is er a very important stage [0.3] and er and 
and i think that [0.2] we we very often or or too often maybe this is what 
Mogensen was getting at in his classification [0.4] think about stage three [0.
3] as the starting point in diabetes 
diabetic nephropathy which is the micro [0.2] albin-, albuminuria stage [1.3] 
tell me about microalbuminuria gentleman at the back there with the green [0.5] 
on the on the right tell me about microalbuminuria [1.2] or microalbuminuria [0.
3] can't say it [0.2] 
sm0479: er [1.3] 
nm0454: have you heard of the concept [0.6] 
sm0479: no [0.4] but it's [0.8] er [1.8] 
nm0454: i'll tell you what it is and this when i was a student i thought it was 
small albumin molecules [0.2] 
sm0479: that's what i said as well 
nm0454: yeah [laughter] [1.0] ah it's not actually [0.4] ask somebody else [0.
3] two ladies at the back there [0.8] what what do you think micro-, have you 
heard of the phrase microalbuminuria [1.3] 
sf0480: is it just an amount of [0.2] protein [0.6] 
nm0454: 
speak up yep 
sf0480: it's amount of protein in the blood [0.7] 
nm0454: yeah yeah [0.2] anybody want to expand on that [0.5] 
sm0481: does it mean you can see it in a microscope but not [0.4] 
nm0454: no no i mean that's what i used to think isn't it it's not such a silly 
answer [1.0] 
sm0482: 'cause there's some albumin in the bl-, in in the blood [0.7] 
nm0454: no it's microalbuminuria so it's in the urine [0.5] 
sm0483: is it just small quantity of small amounts of microalbumin 
nm0454: very good small amounts of albumin in the urine [0.2] and [0.3] very 
small amounts which cannot be detected by stick-, dipstick testing [0.4] are 
present in the early stage of diabetic nephropathy [0.9] er [0.2] in my second 
talk i'm going to talk more about dipstick testing and the [0.2] reliability 
and unreliability of dipstick testing [0.5] er [0.3] and [0.8] the importance 
of it is it's said to be the forerunner [0.2] of [0.3] full-blown diabetic 
nephropathy but it's more important than that because [0.4] it's possibly the 
forerunner [0.2] of [0.2] all the small and large vessel complications of 
diabetes and possibly [0.3] also [0.3] the complications the large 
vessel complications of diabetes [0.7] in a non-diabetic [0.3] in other words 
atheroma [0.2] in somebody who doesn't have diabetes and there is evidence from 
the [0.3] the Framingham study [0.2] that microalbuminuria is one of the most 
important [0.7] things you can measure in a human being when they're twenty [0.
2] if you want to find out whether they're going to be alive when they're forty 
[1.0] er [0.2] and [0.2] it seems that the kidney can in some way [0.2] show [0.
3] you know what's going to happen in the rest of your life [0.5] er [0.2] and 
so if you have significant amounts of microalbuminuria yours at your earlier 
stage [0.2] you know [0.2] smoke [0.3] you might as well enjoy it [0.3] it's 
very bad news microalbuminuria [0.6] just [0.3] anybody tell me about the 
Framingham study what's the Framingham study lady at the front [0.6] have you 
heard of it 
sf0484: no [0.4] 
nm0454: lady next to her [0.4] very important study landmark study still going 
on [1.1] i'm going to pick on you again [0.4] what [0.4] 
sf0485: i don't know either 
nm0454: any anybody anybody Framingham study 
sm0486: 
it's a big study in America where 
nm0454: yep 
sm0486: it s-, started since nineteen-sixty-four or something like that and it 
nm0454: yes 
sm0486: it's been following [0.4] a group of people living in Framingham [0.2] 
nm0454: yes 
sm0486: for different diseases 
nm0454: yes [0.3] absolutely okay [0.3] so there's a small study [0.3] er [0.2] 
does he know all the stuff this bloke [1.3] [laughter] well [0.9] er er proud 
of you [0.4] er and [0.2] it it's an attempt to get rid of linear bias i mean i 
don't think they realized that when they set i-, set it up [0.2] small town [0.
3] on the east coast shush [0.2] east coast of the United States in Framingham 
[0.3] where they took a cohort of people [0.3] who traditionally didn't tend to 
move too much from Framingham a bit like Coventry people [0.3] [laughter] they 
just stay there basically miserable might as well stay here and nowhere else to 
go and the train's rubbish [0.3] 
but the [0.2] er [0.2] and f-, for the people of Framingham tend to stay around 
[0.2] it's not that large a group it's in the tens of thousands of people 
rather than hun-, and that's [0.2] maybe also one of the reasons why the study 
worked and is still ongoing [0.2] and they've been followed since the sixties 
[0.4] and and and a lot of what we teach you [0.3] about [0.3] er the [0.2] 
pathogenesis [0.3] and the cause of atheroma and diabetes all comes from the 
Framingham study there's a massive website that's all about the Framingham 
study [0.3] they're publishing papers every week [0.4] er and and and and much 
o-, o-, of [0.3] of traditional Western medicine actually comes from Framingham 
[0.2] i don't think the people of Framingham realize that [0.9] and what we 
know about microalbuminuria i don't know [0.5] how they had the foresight in 
the early sixties [0.3] to start looking for very small amounts of protein in 
the urine but they did [0.5] and er and and this is a a very er clever idea [0.
8] the reason i emphasize the 
first two stages is that i think [0.2] that if we're going to do anything about 
diabetic nephropathy and anything about the other complications the retinopathy 
[0.2] it's before Framingham [0.3] it's before microalbuminuria it's when 
they're normal [0.5] it's when they are [0.2] the IDDMs [0.2] are [0.6] four [0.
5] are six [0.2] are ten years old [0.4] then you start them on an ACE 
inhibitor [0.2] then you do what you need to do [0.2] to stop them from getting 
any complications not when they're twenty not when they're thirty [0.8] but 
there lies the rub [0.2] because the majority of patients i said are NIDDMs and 
they present late [0.4] they've had a blood sugar of eight for five years of 
nine for another five years [0.2] then it's picked up on routine testing [0.4] 
and it's all over by then [0.3] the eyes are starting to go they they're in 
stage three more likely stage four of diabetic nephropathy [0.2] there's 
nothing you can do [0.3] so if you want to really help diabetics i think it's 
[0.2] it's premicroalbuminuria or at least at microalbuminuria stage [1.1] and 
this is 
true for the not just for the kidneys but for the eyes and all the other 
complications [0.9] okay [0.2] so can we isolate specific patients to focus on 
[0.6] well [0.5] not really er [0.3] race [0.3] er black and Asian people are 
more likely to get the small vessel complications that [0.2] they're more 
likely to get diabetes and they're more likely to get the bad diabetes [0.8] 
there are strong genetic factors which [0.3] er [0.2] are probably polygenic 
and haven't really been worked out but [0.2] there are certainly [0.2] patients 
who are born with a predisposition to develop bad diabetes [1.0] and this is 
one this is the counter-argument [0.4] for being a touchy-feely person going 
out in the community [0.2] starting all black and Asian people [0.2] on an ACE 
inhibitor as soon as they're born [0.3] a-, and that studies [0.2] such as that 
have been done there were some islands on the north coast of Australia [0.3] 
where [0.4] people just couldn't get away and they put entire communities with 
and without [0.4] er diabetes on ACE inhibitors [0.2] and this is one of the 
few things you 
can do for a diabetic [0.4] and they've dramatically reduced the dialysis rates 
[0.4] the mortality cardiac mortality [0.4] er [0.6] look it up [0.6] northern 
Australia islands [0.3] diabetic nephropathy [0.3] er you'll find [0.2] loads 
and loads of papers [0.3] er [0.2] and they're actually fascinating studies 
where you take an entire community [0.4] and reduce their glomerular capillary 
pressure and see what happens [0.2] and a lot happens [1.1] the reason i 
emphasize this is i think that [0.4] racial and family [1.0] er predisposition 
to developing bad diabetes [0.2] is probably the most important factor [0.2] 
and that of course we can do nothing about you can't change your parents [0.6] 
and it does seem that forty per cent or so of diabetics [0.5] get [0.7] bad 
diabetes including the eyes the kidneys et cetera and so if you were a cynic 
you'd say well why bother for those forty per cent 'cause they're [0.2] 
buggered anyway [0.3] er but nonetheless i think we have to er adopt a positive 
approach and try and treat [0.2] the hundred [0.3] er not not just the sixty [1.
0] er [1.5] glycaemic control [0.6] 
oh God [0.4] i've got to tell you about this haven't i [0.5] this is one of the 
things that i've i've i i have to tell you about [0.3] because you you'll be 
expected to regurgitate it but i don't particularly believe in myself [0.5] er 
[3.2] what's the Judaeo-Christian [0.2] method of controlling people [laughter] 
[1.8] 
sm0487: [0.9] 
nm0454: Islamic as well [1.7] come on [0.3] bit of politics [1.4] how lady here 
[0.6] how do we control people in the [0.6] Judaeo-Christian [0.2] way [0.3] 
sf0488: you have [0.7] one partner [0.6] 
nm0454: yeah [0.3] yeah [0.3] okay [0.7] fair enough yeah [0.2] i'm talking 
more about [0.2] society how do we control society 
sf0488: well you don't marry your cousin you don't [0.6] have children family 
[laugh] 
nm0454: mm yeah but a bit broader [0.3] politics [laughter] cynicism i want [0.
7] 
sm0489: 
indoctrination [0.2] 
nm0454: sorry 
sm0489: indoctrination 
nm0454: indoctrination [0.6] 
sm0490: fear [0.4] 
nm0454: fear ah fear [cough] that's how we control people [0.2] in the Judaeo-
Christian way isn't it fear [0.4] the stick and the carrot [0.5] er [0.6] and 
[0.2] if you're a good boy [0.9] what happens [0.4] 
sm0491: you're rewarded [1.1] 
nm0454: you go to heaven [1.1] [laughter] good things happen [0.3] if you're a 
bad boy or girl [1.0] it's very bad isn't it [0.6] so [0.2] if you're a good 
boy you get rewarded by stuff you do good things you don't eat chips you don't 
go to McDonalds you don't smoke you don't have [0.3] God it's boring isn't it 
[1.7] [laughter] and if you're a bad boy you do all those things and then bad 
things happen you have diabetes you get fat you eat chips and you go to 
McDonalds [0.4] and it all goes horribly wrong [1.3] and [0.6] the problem [0.
6] with the Judaeo-Christian-Islamic [0.3] method of controlling people is we 
extended it to medicine of course because you know 
we're part o-, [0.2] of this culture we can't get away from it [0.4] so [0.2] 
and this is true of all chronic diseases whether it's rheumatoid arthritis 
schizophrenia [0.3] you're a bad boy you didn't take your tablets you didn't 
have electric shocks to the head you didn't have injections once a month so 
what's going to happen you go out you go kill people [0.3] that's bound to 
happen [0.4] er [0.5] and [0.5] we have linked it to diabetes as well and the 
classic way we've linked it is glycaemic control [1.5] and for years decades it 
has been assumed [0.3] that if [0.5] the blood sugar is the bad thing in 
diabetes which it probably isn't it's probably the blood pressure [0.7] er [0.
2] then if you have tight diabetic control you can prevent the complications [1.
2] and this was dogma in Western medicine for for decades [0.3] er until what 
what landmark study [4.2] not many studies you need to know about in detail but 
there are a couple in diabetes [0.3] anybody [2.6] 
the D-C-C-T [0.4] in nineteen-ninety-one New England Journal of Medicine [0.8] 
the U-K-P-D-S [1.6] B-M-J the Lancet look these up [0.4] very important studies 
[0.6] if you ever get me in a viva i'll ask you about them the reference the 
page number [0.2] [laughter] the exact number of [0.3] patients in each study 
[0.2] i will not forget [0.2] okay [0.3] so don't come across me in a viva and 
don't know both studies sideways those are landmark studies [0.7] er [0.6] and 
the bottom line is that the first study [0.6] attempted to address [0.6] the 
Judaeo-Christian concept [0.3] of [0.2] tight diabetic control [0.5] leads to 
good result [1.2] in IDDMs and the U-K-P-D-S done in the U-K [0.2] did the same 
in NIDDMs [0.4] and both studies i'm not going into them in detail today [0.2] 
have been interpreted or [0.3] misinterpreted as being [0.2] positive [1.5] er 
[0.3] in that the patients who achieved tight diabetic control [0.2] had less 
complications [1.0] and they did [0.4] to an extent [0.4] but the end points 
were all soft [0.6] such as [0.6] can anybody think of a soft end point in 
diabetic nephropathy or [0.3] eye disease [0.9] let's pick on somebody else 
gentleman there [0.2] if you were do a s-, design a study [0.5] of [0.3] does 
[0.5] tight diabetic control prevent the complications [0.4] and you wanted to 
look at the complications of [0.7] diabetes such as nephropathy or eye disease 
[0.4] what what would be a possible soft end point [0.8] that you could look at 
[0.4] er i i [0.6] wishy-washy [0.3] end point [0.8] difficult to [0.5] define 
and prove [2.6] anybody else [0.4] ladies up lady in the white there soft end 
point diabetes [0.3] 
sf0492: disturbance in vision [0.4] 
nm0454: yeah disturbance in vision would be a good one [1.2] proteinuria [0.3] 
rate of decline of [0.2] renal failure [0.3] lots just think about it there's 
lots of soft end points [0.5] and the soft end points [0.2] were affected by 
tight diabetic control [0.2] so there is some evidence of tight diabetic 
control [0.5] but er if you look at the studies [1.1] and i stress i will ask 
you about them if i ever meet you in a viva [0.4] er [0.5] and i will 
create hell if you don't know about them [0.8] er [1.6] the hard end points 
weren't there [0.4] death [0.3] dialysis chop your legs off blindness they 
weren't there there was no significant improvement [0.4] in the hard end points 
[0.2] now you can say er back to linear bias well what does that [0.3] what 
does that matter that you don't stop people from from dying [0.4] er [0.4] er 
and you don't [0.4] er chop their legs off if you can delay chopping their legs 
off [0.9] by a year [0.5] then that's a good thing [0.2] obviously [0.6] but 
that wasn't proven either [0.8] er [0.2] because the study didn't really 
incorporate this problem of linear bias into it [0.3] now but these are the 
best studies that we have and they are landmark studies [0.4] and and you 
should know about them [2.4] okay [0.4] er [1.0] they well probably [0.5] 
several hundred people's life work [0.2] so i shouldn't knock them too much [0.
3] er [0.3] you know these were tens of thousands of patients putting them in 
in into into both studies [0.4] and they are the the best data that we have [0.
4] 
but look at them critically [1.4] as just out of interest apart from [0.3] get 
away from my ideas of [0.3] the Judaeo-Christian method of controlling people 
what [0.2] what wh-, why why do you think [0.4] who do you think set up the 
studies and why [2.1] lady there the in the black jumper [0.3] who do you think 
[0.4] 
sf0493: er [0.4] 
nm0454: would an old cynic like me set up a study [1.5] 
sf0493: er 
nm0454: who would set up such a study and why [0.8] 
sf0493: i guess people that [0.3] can er [0.3] didn't believe that er [0.7] it 
had a difference [0.5] 
nm0454: so either the [0.2] the the knockers [0.3] like me [0.5] or more likely 
[0.6] 
sf0493: people trying to prove it [0.2] 
nm0454: the believers 
sf0493: yeah 
nm0454: and who are the believers [0.2] 
sf0494: drug companies [0.8] 
sm0495: 
pharmaceutical companies 
nm0454: pharmaceutical companies yeah ah there's a cynic [0.3] that's what i 
like to hear [0.8] [laughter] excellent i know i know where to get the cynical 
pharmaceutical companies yeah [0.6] diabetologists [0.4] it's their raison 
d'être [0.4] you know [0.2] if tight diabetic control doesn't lead to good 
outcomes what's the point of a diabetologist don't tell other people [0.3] 
don't tell [0.4] all these professors Professor and everybody [0.4] don't tell 
them don't even mention my name i didn't exist [0.4] don't exi-, i wasn't here 
[0.3] but you know it's their raison d'être [0.2] and it may not be true [0.9] 
now you can s-, you can be just as cynical about kidney medicine as well renal 
units well i've come back from Australia drop it in the conversation [0.2] 
[laughter] i visted a a renal unit in in north-west Australian [0.3] there were 
no nephrologists there they don't need one [0.2] they worked it out themselves 
[0.2] and a forty-bedded [0.2] 
dialysis is run by nurses and G-Ps so you know [0.4] do we need nephrologists 
maybe not [0.7] and it's quite interesting actually slight aside i i asked one 
of the G-Ps [0.3] er [0.2] h-, how how she knows so much about er [0.6] er 
dialysis and kidney transplantation [0.3] she said well mate i've got a bit of 
paper [1.1] and she showed it's absolutely brilliant she showed so we had a bit 
of paper on the wall [0.4] and the whole of nephrology was [0.3] er summarized 
on one single bit of paper and it was absolutely brilliant you know [0.2] 
creatinine goes up put them on the whirly they've got oedema put them on the 
whirly [0.3] diabetes it's probably diabetic nephropathy put them on the whirly 
[0.5] and [0.3] [laughter] er [0.3] and it was all there one bit of paper [0.6] 
and i thought my whole specialty [laughter] on one bit of paper this is 
terrible [0.6] er but the same 
can be said of of of of most specialties you know what is the the point of us 
[0.3] er i don't know [0.2] that's not for for for me to judge [0.8] okay [0.5] 
er [1.8] treatment [0.2] treatment so we talked about some treatments that er 
might work [0.4] could work should work [0.3] in fact [0.5] let's [0.2] be a 
bit less cynical [0.8] and think about what we can do [1.3] well we can only do 
what we can do we can only do what what what [0.4] powers are given to us what 
drugs are given to us [0.5] and the important [0.2] thing in diabe-, diabetic 
nephropathy is to rationalize the problems [0.4] to rationalize the problems in 
an early stage and attempt to do something about it [0.2] even if it's all 
claptrap [0.3] at least it gives the patient something to do [1.1] the sort of 
things you can do [0.2] you can achieve [0.2] tight diabetic control that's 
what the D-C-C-T and U-K-P-D-S [0.2] that's what i think they really showed [0.
3] they showed it was possible and nobody had ever shown it was possible [0.9] 
tight diabetic control as shown by H-B-A-one-C [0.6] you can get the blood 
pressure down [0.3] 
you can favour ACE inhibitors and ACE antagonists [0.2] these things do work [0.
2] they do affect [0.2] soft end points [0.9] at the later stages if you have 
people with advanced [0.7] complicated diabetes diabetic retinopathy [0.5] it's 
going to get a bit vague [0.2] later [0.7] diabetic nephropathy [1.0] prepare 
them for dialysis [0.7] diabetic legs [0.8] not much you can do [0.3] send them 
to Mr namex [0.4] er [0.3] but [0.5] there are things we can do at these 
earlier stages and wi-, to those of you who are going to be G-Ps it's very 
important to recognize these early stages and do something about them [0.5] 
don't be a cynical Dr namex don't wait till their legs fall off go blind [0.4] 
try to prevent that stage if you can [1.8] okay [0.2] so i don't particularly 
want to talk about the the treatment [0.3] of end-stage renal failure which is 
the final stage of diabetic nephropathy in any great detail today [0.3] other 
than to say that it exists [0.4] the treatment's for them really the same as 
for [0.2] non-diabetic diseases [0.3] dialysis peritoneal dialysis 
haemodialysis 
transplantation [1.2] kidney alone transplants [0.4] what i would like to leave 
you with is some thoughts for the future [0.3] in terms of the treatment of of 
diabetic nephropathy [0.3] until [0.8] namex can crack it and we can sort out 
the the how and the why question [0.3] we have to go back to a bit of our old 
agricultural medicine [0.7] which is [0.2] chopping things out of other people 
[0.4] and putting them into other people [0.6] and [0.3] the modern treatment 
for diabetic nephropathy in an IDDM [0.4] wh-, wh-, why would it not work in a 
NIDDM [0.4] it's a kidney pancreas transplant why would that not work in a 
NIDDM [1.2] 
sf0496: because the tissues will have been [1.1] 
nm0454: what's 
sf0496: 
nm0454: what's the difference between IDDM and NIDDM in terms of [0.6] the the 
the the the the the underlying problem [0.5] shush listen [0.4] 
sf0497: 'cause in a NIDDM it's more of the tissues being non-receptive 
nm0454: very good okay so in [0.4] IDDM you don't make it in NIDDM you can't 
respond to it [0.3] and 
therefore if you put a new kidney pancreas into somebody it won't it work won't 
make any difference they won't respond to it [1.3] and [0.2] it can sometimes 
[0.2] be quite difficult to tell the difference between IDDM and NIDDM because 
[0.4] younger people are getting fatter linear bias again the things aren't as 
good as they used to be [0.3] but you know [0.4] people are getting fatter 
actually [0.2] and er and er even even if you chuck out linear bias [0.3] and 
with it diabetes is getting more complicated [0.2] so we now see people in 
their thirties fat people [0.3] with diabetes and it's sometimes quite 
difficult to tell whether they're [0.3] a new IDDM [0.3] er [0.3] or an insulin-
requiring NIDDM [0.5] er you can measure [0.3] what can you measure [1.1] one 
[2.2] biochemical test which is useful [0.2] 
sm0498: insulin [0.3] 
nm0454: yes C-peptides are quite good at at er differentiate them so we don't 
normally do it because usually [0.3] er it it is it is clinically obvious [1.1] 
so the problem with combined kidney pancreas 
transplantation [0.3] is [0.4] it's only good for a few fit usually white IDDMs 
[0.2] so it isn't [0.5] the saviour of the free world it isn't the saviour [0.
2] o-, of diabetes [0.3] and in Coventry i've established a link with Guy's 
which is one of the units in the U-K which [0.3] does kidney pancreases [0.3] 
and we have [0.2] er a couple of patients on their waiting list and one has [0.
3] has er received a kidney pancreas transplant [0.4] er [0.3] about six months 
ago and she now has [0.5] a normal blood sugar [0.2] and normal kidney function 
[0.4] hoorah [0.6] er her hair's falling out due to tacrolimus [0.3] her face 
is fat [0.3] due to prednisolone [0.4] and she was beautiful [0.3] and now she 
isn't but she's got normal kidney function [0.3] and er she doesn't have 
diabetes [0.5] she's also oh yeah she's had to spend six [0.2] months living in 
London [0.3] which she didn't want to do [0.4] but er [0.6] the the it is 
possible [0.2] er they are being done not in any great numbers i mean Guy's 
last year did about twelve and you know they're covering a lot of the [0.2] a 
lot of the United Kingdom so [0.3] in statistical 
terms it's [0.2] as important [0.4] er or less important than a heart 
transplant about two-hundred heart transplants done in the U-K every year [1.4] 
er [0.3] so what about the future future er pancreatic islet transplantation 
has been tried in the U-K before [0.3] er [0.3] didn't really work i was in in 
the early nineties and we tried it and it all went horribly wrong [0.6] er [0.
3] so we we aborted a programme quite early [0.3] er s-, there's a group in 
Canada who's come up with a new protocol [0.2] and er various units in the U-K 
are starting to copy that now [0.2] and the idea is you graft pancreatic islet 
cells in the laboratory [0.3] and [0.2] inject them into where does anybody 
know where we inject them into [0.2] 
sm0499: liver 
nm0454: into the liver [0.2] and er [0.3] they spread through the liver and 
other organs and form little [0.3] er pancreases little islets of of Langerhans 
[0.6] er [0.8] so [0.2] that may be the future of stem cell research [0.3] 
there 
are some [0.2] advances in the near future which i think will come through 
things like inhaled insulin [0.6] er [0.3] but there are some small things [0.
2] which which are coming through [0.3] i don't personally feel that we're 
going to [0.2] er [0.2] be treating diabetes much better than Banting and Best 
[0.4] until [0.2] somebody clever [laugh] [0.5] like namex [0.3] er [0.2] 
actually cracks the the how and the why question [0.2] i think our our 
treatments are still er agricultural [0.9] okay that's it on diabetes have a [0.
3] ten [0.6] minute break before you go any questions on diabetes and then w-, 
when you come back it'll be glomerular disease [0.6] any questions diabetes [0.
2] 
sm0499: yes 
nm0454: diabetic nephropathy [1.3] if you're shy come down the front okay 
sf0470: er i just want to know like why would you give insulin to a type two 
diabet-, diabetic patient 
nm0454: do you know i i i thought that when i was a student i couldn't work it 
out 
sf0470: i don't understand it 
nm0454: why you'd give insulin 
sf0470: i don't see how 
nm0454: 
why you'd give insulin no wh-, why would [0.6] er [0.2] i suppose because [0.6] 
somebody tried it once and it worked [0.3] i mean conventionally NIDDMs we 
start off [0.4] on agents such as sulphonylureas as you know [0.2] biguanides 
[0.3] there's this new group called the glitazones we're using acarbose [0.5] 
but [0.3] it seems to me that the [0.3] that the the pancreas sort of gets worn 
out [0.3] and you you you keep stimulating it you know [0.4] er [0.3] some of 
the drugs work by stimulating the pancreas some [0.3] by er er reducing the [0.
4] insensitivity to insulin [0.6] but eventually it seems to [0.2] you know you 
you're you're bashing away at the pancreas and then it [0.5] wears out then we 
don't have anything else to do 'cause the blood sugar's still rising [0.5] a-, 
and and so a somebody somewhere along the line [0.4] tried insulin but you're 
right it shouldn't work really [0.3] all i c-, 
sf0470: but typically you do 
nm0454: yeah 
sf0470: you do do that 
nm0454: i mean i all i can think of is it's some supersaturated system [0.5] 
and if you you know give 
enough [0.5] i mean some NIDDMs need large doses [0.5] er 
sf0470: yes 
nm0454: that that that it you can break through the lack of responsiveness to 
[1.0] it's not a very good answer 
sf0470: but you still do that practically you do do that 
nm0454: yeah practically [0.3] so you know [0.2] if you achieve good diabetic 
control and by that i mean a an H-B-A-one-C of less than eight say [0.4] and 
you know [0.5] er most blood sugars [0.3] you know [0.3] in the normal range or 
just above the normal range [0.4] with tablets then that would be fine [0.8] er 
if you didn't [0.2] few patients are just controlled by diet alone [0.3] if you 
didn't you'd add insulin [0.3] 
sf0470: yeah [0.4] 
nm0454: and [0.2] 'cause quite a few patients are on both actually [0.4] 
sf0470: yeah 
nm0454: we just don't know i mean you know we can say that if you you know you 
do biopsies you 
see this thickening of the glomerular basement membrane you see [0.4] er [0.5] 
proliferation in the mesangium [0.4] but you know [0.3] but [0.3] but [0.6] 
what leads to that and why that leads to [0.5] er [0.2] proteinuria [0.7] we 
don't know [0.3] i mean i'm going to talk about it a bit in the second talk 
about [0.2] there are some various theories about [0.4] why [0.4] er [0.3] 
proteinuric diseases [0.3] happen [0.6] er [0.3] well it isn't obvious is it 
really [0.7] you know [0.4] 
sm0500: it's all about glycosylation of the basement [0.8] 
nm0454: yeah 
sm0500: 
nm0454: i mean you you you [0.4] you you may know more about it than than i do 
but i i i [0.4] er [0.2] i [0.8] er and you know chip in in the second talk [0.
3] i don't think we know but [0.3] all you can say is that [0.5] a high blood 
sugar does seem to be associated [0.4] reason we don't understand [0.5] with 
proteinuria [0.7] and and and that [0.3] eventually if untreated leads to renal 
failure [1.3] 
nf0473: the photocopier's broken so i think that's 
nm0454: okay 
nf0473: 
so i'll come back [0.3] when i've done them so 
nm0454: okay right 
nf0473: we'll do them [0.4] 
sm0500: so 
nm0454: right so 
sm0500: you could just say [0.5] 
nm0454: in simple terms i mean what i tell a patient what i m-, is is is that 
[0.3] that i-, is is the high blood sugar somehow damages [0.4] er and i i draw 
them diagrams o-, o-, of glomeruli and things and [0.3] and if they the more 
articulate patient i i i would actually [0.4] i think in one of my previous 
talks i talked about the kidney being a tube [0.3] i'll i'll talk about that in 
in in the second in my second talk [0.2] you know and i'd actually do like draw 
glomeruli and and draw [0.3] er the the capillary the the the [0.4] 
intraglomerular capillary [0.4] and say somehow the blood sugar damages the 
wall [0.3] and makes sort of [0.2] holes in the wall [0.3] and protein [0.3] 
which normally passes through the kidney then falls out you know i wi-, [0.3] 
i'll talk about a bit in that second talk [0.5] er [0.5] but somehow [0.4] you 
know [0.5] the high blood sugar 
somehow leads to proteinuria and that eventually 
sm0501: 
nm0454: yeah that's going to be [0.3] er 
sm0501: 
nm0454: er [0.4] that's the spare one that's yours yeah okay [1.6] i've not 
really answered your question but [laughter] it's it's because we don't it's 
'cause we don't know 
sf0502: do you get a decreased G-F-R [0.4] does it 
nm0454: eventually yeah that's the stage f-, oh it's on the previous as-, 
that's the stage four [0.3] it's when the G-F-R goes down and then your 
creatinine starts to rise 
sf0502: so first it affects [0.2] the [0.5] er [0.2] the nephron and then it 
affects [0.4] the vessels [0.4] 
nm0454: well it it it affects really [0.3] diabetes affects the large vessels 
[0.2] in simple old old [0.4] bog standard atheroma [0.3] 
sf0502: yeah 
nm0454: and the small vessels in this other way which we don't understand [0.4] 
sf0502: oh yeah 
nm0454: and and and both lead to the renal impairment [1.5] traditionally 
you're not told [0.3] that 
renovascular disease is part of diabetic nephropathy [0.3] 
sf0502: mm-hmm 
nm0454: but i think it must be i don't because you can't [0.2] define the size 
[0.4] of a blood vessel [0.2] you know the big ones the small one [0.6] 
sm0503: yeah 
nm0454: do you want to ask a question or 
sm0503: i've actually [0.7] i think first of all [0.5] do you know who actually 
published er 
nm0454: er no the i think they were both published without authors [0.2] 
sm0503: right [0.2] 
nm0454: so er and and so if you look up D-C-C-T on the Internet you get hun-, 
thousands of of of of er papers [0.4] i think it was nineteen-ninety-one New 
England Journal [0.6] and the the the [0.2] nineteen-ninety-one i think or 
could be three [0.4] er the the the er [0.6] U-K-P-D-S was about nineteen-
ninety-nine and two-thousand [0.5] and that was published in several stages [1.
2] er and it and then [0.5] you know i mean i know i'm cynical about it but it 
it is [0.2] the best information we've got [0.5] and er [0.7] which is er [0.2] 
why we [0.3] and er when i'm even 
though i'm cynical with you lot i'm not [0.5] completely cynical with patients 
because if you [0.2] if you give them my old [0.2] linear bias spiel and [0.3] 
and [0.2] Judaeo-Christian [0.5] model of controlling the world [0.3] you know 
that [0.2] basically removes all hope [0.4] from the patient [0.4] 
sm0501: yeah 
nm0454: and that i wouldn't recommend you know because [0.3] you mustn't ever 
remove hope from a patient [0.4] 'cause their only hope is that you [0.4] 
either get rid of their diabetes or or or or at least you control it