Slide 1

Thank you Mr President. Ladies and Gentlemen allow me to thank ERA-EDTA for this invitation. It’s really a great pleasure and honor to be here today. My topic today, as you can see, is insulin resistance and hypertension in kidney disease.

Slide 2

Although I’ve been working in this exact field for about 10 years now, my lectures become more and more difficult. The reason for this is that data are continuously accumulating and more and more complex associations come to light, so it’s very difficult to pack all this information within the small period of a lecture. Nevertheless, I will try to show you as much information as I can on epidemiology, data from population studies, on pathophysiology, data from background and human studies, some data from genetic studies and also some data from clinical studies also to make you at least believe, if you don’t believe the diagnosis of the metabolic syndrome, at least believe that insulin resistance is a very important factor and that we should go and try to lower insulin resistance also for patients with CKD. So this slide that you have already seen from Professor Alvestrand I included it to make a tribute to this famous doctor Kylin, as we are in Stockholm, but what I want to stress is that these very early observations of the coexistence of various factors we now term as components of the metabolic syndrome were made long before these factors were recognized as risk factors for cardiovascular or CKD. The essence of this coexistence which is what we call syndrome has never been debated even some years ago when the heavy debate was on.

Slide 3

The syndrome emerged in our collective thinking about 20 years ago when this gentleman here, Gerald Reaven, described his ‘Syndrome X’. The great contribution of Gerald Reaven was that he put resistance to insulin-stimulated glucose uptake at the centre of the syndrome saying that perhaps it’s the underlying factor, the causal factor.

Slide 4

A year after that Norman Kaplan added obesity to the clustering but from then on, whether you name it metabolic or insulin resistance syndrome it doesn’t really matter, the pattern was something like this; insulin resistance is predisposing to all this disturbances, with one obvious exception, obesity, which in the great majority of individuals in the Western world is a cause of insulin resistance and predisposes through insulin resistance to the other disturbances.

Slide 5

So it has been described that insulin resistance is linked to a bunch of abnormalities here. Others are traditional risk factors and others are emerging risk factors for cardiovascular disease. Insulin resistance per se is associated with cardiovascular disease.

Slide 6

The question is, what’s going on with CKD? Again, somebody could say that we know these are well known factors for CKD. Some of them can be emerging factors and what I’m trying to show you is that insulin resistance and hyperinsulinemia can be associated to CKD and predispose to renal injury.

Slide 7

So I would like first to remind you what is insulin resistance because many diabetologists really don’t know what we term as insulin resistance. So by the formal definition is the defect of biological response in the action of endogenous or extragenous insulin. So the problem here is when we refer to insulin resistance, most of the time we refer to insulin-mediated glucose uptake. This is fine because this is the main action of insulin and this is the action responsible for the homeostatic circuit and so on and so on. But there are two things that one must have in mind, first this is not the only action of insulin in the body, insulin has many other actions. Second, not all these actions are resistant to insulin in the presence of resistance to insulin-mediated glucose uptake. This is a matter of intracellular signalling pathways and this is a very solid concept, the concept of selective insulin resistance which is central to all these associations.

Slide 8

So I would also like to say a few things which are crucial to the understanding of all these things. This is the natural history of type 2 diabetes. I always use this slide because type 2 diabetes is not type 1 diabetes. They have many similarities but they also have many differences, in fact, they have more differences than similarities. So in the vast majority of individuals in the Western world today due to obesity, due to low physical fitness, due to aging things start somewhere here with decreasing insulin sensitivity and then the β cells will try to compensate for that and for a period of time we will have hyperinsulinemia and normal glucose control. After again some period of time the β cells will not be able to compensate and then overt type 2 diabetes will develop. The thing that most diabetologists neglect is that you have a period of time here when you have insulin resistance and hyperinsulinemia and this period of time can extend from a few months to years or even decades or even forever in some people. Within this time this hyperinsulinemia is very bad, it predisposes to several problems including hypertension and early renal injury and this is why when you have the diagnosis of type 2 diabetes here in most of the cases of type 2 diabetes you will also have hypertension and in some cases you will also have signs of early renal injury which is not happening in type 1 diabetes.

Slide 9

So if I may go on with some data of epidemiology.

Slide 10

I know this slide is very bad I just put it here to show you how many studies have tried to examine these associations. We know now that both insulin and insulin resistance from cross-sectional and prospective studies are associated with prevalent or incident hypertension.

Slide 11

This is one of the very first studies in the field, prospective data from the Atherosclerosis Risk in Communities studies. 6 years of follow up, 5000 people, showing that insulin is associated with future development of hypertension. The problem is that these associations are mostly evident in Caucasian or Asian populations and they are not equally evident in other populations. In this case this was not evident in African-American people.

Slide 12

With regards to insulin resistance these are baseline data from very big cohorts from the RISC-EGIR study where Ferrannini and associates have shown that when you measure insulin sensitivity with the best method available now, the hyperinsulinemic-euglycemic clamp, even if you adjust for several factors including BMI or even insulin, you have a significant associations with blood pressure levels. We also have some prospective studies in the field.

Slide 13

This is the first one, a small cohort from Japan 6 or 7 years of follow up showing that HOMA in the highest quartile was associated with a 7-fold increase in hypertension incidence. There are also some other studies in the field.

Slide 14

This is a study from the Insulin Resistance Atherosclerosis Study - again 5 years of follow up. Insulin sensitivity was measured with the minimal model which is a reliable technique showing that for each unit increase in insulin sensitivity you get a 10% decrease in the incidence of hypertension.

Slide 15

So with regards to the kidney disease I would say that things are much more consistent and actually the first studies were studying the association of insulin sensitivity with microalbuminuria and as you can see here, again data from the IRAS study as insulin sensitivity goes up, the odds ratio of microalbuminuria goes down.

Slide 16

Again, during the past few years we’ve had some quite important studies in the field. These are data from the NHANES studies. Here are the data Doctor Alvestrand showed you just a few minutes before showing that increasing quartiles of HOMA for insulin resistance or insulin are associated with increased risk of CKD. Whereas increasing quartiles of blood glucose, within normal values of course, are not.

Slide 17

Again, we have also prospective data in the field, Atherosclerosis Risk in Communities study, 9 years of follow up, over ten thousand people and again insulin resistance with HOMA is associated to the future risk of chronic kidney disease no matter how many adjustments you made. So these were the epidemiology data.

Slide 18

I would like to show some data from genetic studies also. I’m a clinician and I don’t fully understand all these kinds of things but these are very good examples of what can happen in the case of extreme forms of insulin resistance.

Slide 19

I’m sure you all know the PPAR-gamma receptors. They belong to this super family of ligand-activated hormone receptors.

Slide 20

They’re considered to be the master regulator of adipogenesis and they’re present in various tissues including the human kidneys.

Slide 21

There are some studies in the field and this is one of the first studies where the investigators were searching for mutations in people with heavy forms of insulin resistance. These investigators here have managed to find 3 individuals with these two new mutations leading to non-functional PPAR gamma.

Slide 22

If you look at the paper, the phenotype is something like this which is to my point of view what we call metabolic syndrome. This subject is not obese, she’s not even overweight with strict BMI criteria, BMI 24.9, but she has abdominal obesity and no fat depots in the gluteal region or the periphery.

Slide 23

If you see the biochemical and other characteristics; extreme insulin resistance followed by early onset of type 2 diabetes, early onset of high hypertension in early 20s with problems in pregnancies and so on and again the rest disturbances.

Slide 24

What is even more interesting, these is from the same investigators, these are the 2 children of this gentleman here carrying exactly the same mutations and as you see all the characteristics are within normal limits except for insulin. So increased insulin resistance is the primary defect and this is an indirect proof of what Reaven said that insulin resistance comes first and is the underlying factor. We have also some data on kidney disease. There was a nice paper published in JASN a couple of years ago in subjects with extreme insulin resistance, PPAR-gamma mutations, lipodystrophy showing also heavy proteinuria that is decreasing with decreasing insulin resistance and when renal pathology was studied, diabetic nephropathy was almost at no time evident - I think it was only in one case or something like that.

Slide 25

So if we ask what is going on with background mechanisms, are there any?

Slide 26

The answer would be yes and as we have said and others have said this increasing amount of insulin which is, of course, essential for normal glucose homeostasis, they act on other tissues that preserve their insulin sensitivity for example, the kidneys enhancing sodium reabsorption and as we and Doctor Fujita from Japan say this is critical in salt sensitivity. They affect the central nervous system by increasing sympathetic activity, they affect the vascular smooth muscle cells increasing growth and all these actions are preserved, whereas in contrast the beneficial action of insulin on vasodilation is impaired because the intracellular signalling pathway is the same with the action of insulin on glucose uptake. So the net effect of all this is a contribution towards a blood pressure increase.

Slide 27

If you look further there are also some other mechanisms – in states of insulin resistance we have some alterations in the pumps of the cellular surface. I’m not going to go into the details.

Slide 28

We have stimulation of endotheilin production, we have upregulation of the renin-angiotensin system in various tissues and so on.

Slide 29

Again, with regards to the kidney there are also several mechanisms. I would love to go into the details but we don’t have the time. Insulin directly increases glomerular permeability to albumin without affecting systemic vascular permeability and, of course, increases urinary albumin excretion. It also increases IGF1 levels and both directly and indirectly increases mesangial cell proliferation and extracellular matrix protein synthesis. Of course, it increases the level of TGF-β which is very important. It causes upregulation of intrarenal RAS, increasing AT1 receptor expression, the action of angiotensin II, upregulation of ET-1 production induction, increased oxidative stress, increased inflammation, increased PAI-1 and so on.

Slide 30

So what about clinical data?

Slide 31

Just to have a small look. I’m sure you all know the 3 TZD compounds that have been used, troglitazone is no longer available, it was withdrawn about 8 years ago. I’m not sure what will happen with rosiglitazone.

Slide 32

Anyway we have several studies now from animals showing that these drugs are associated with blood pressure lowering.

Slide 33

And we also have several studies in humans with pioglitazone

Slide 34

 and rosiglitazone

Slide 35

 and if you put them in a formal metanalysis, you will see the fact that the most reliable studies in the field had a small but consistent reduction of about 5 mmHg for systolic

Slide 36

and 4 mmHg for diastolic

Slide 37

and the question is ok are there any mechanisms for this action? The answer is, it’s rather yes.

Slide 38

In fact these compounds reverse all the mechanisms I was talking to you about that connect insulin resistance with blood pressure elevation with one exception - and the exception is sodium retention because they do cause sodium retention and this was very nicely shown a couple of years ago - but they do reduce sympathetic activity, they do improve endothelium-dependent vasodilation, this was also evident in human studies. They reverse the problems of cellular surface pumps, they inhibit the proliferation of vascular smooth muscle cells, they inhibit endothelin production, they downregulate tissue renin-angiotensin systems and so on.

Slide 39

With regards to the kidney, there were also animal studies in the field showing decrease in urine albumin excretion and when renal pathology was studied prevention of glomerulosclerosis.

Slide 40

There were also human studies in the field and in most of the cases these agents were reducing urine albumin excretion in normo or microalbuminuric subjects.

Slide 41

It’s impressive to see, this is a study comparing four anti-diabetic agents; pioglitazone, glimepiride, voglibose and nateglinide and urine albumin excretion was only reduced with pioglitazone with equal blood glucose control and it’s impressive that insulin was also reduced only with pioglitazone and blood pressure levels were slightly but only reduced with pioglitazone.

Slide 42

This effect is also evident from larger clinical studies this is data from the QUARTET study – urine albumin difference should be about 15-20%- this is pioglitazone compared to metformin both added to sulphonylurea.

Slide 43

This is again about 20% difference in urine albumin excretion, rosiglitazone compared to sulphonylurea this time both added to metformin.

Slide 44

The question that somebody might have is what is going on with proteinuria? The answer is we don’t know yet. This is the first study in the field by Dr Agarwal and colleagues. Pioglitazone was compared to glimepiride in patients with about 3 g of proteinuria due to diabetic nephropathy and again a 20% reduction on top of ACE inhibitor or ARB but this study was short in duration and included only 44 subjects. So, at least this thing reserves further investigation. 

Slide 45

As I was looking at the literature during the past few days I discovered something last but not least these are the results from the DREAM trial. For those of you who don’t know the DREAM trial was a two times two factorial trial comparing the effects of rosiglitazone versus placebo and at the same time of ramipril versus placebo on the incidence of diabetes. The primary endpoint was new-onset diabetes or death. Rosiglitazone did very well but ramipril did nothing at all in subjects with IGT. They also had pre-specified secondary outcomes one composite cardiovascular outcome and one composite renal outcome which you see here. In contrast to ramipril, rosiglitazone decreased the composite outcome, decreased albuminuria progression and also almost decreased the rate of GFR reduction. Of course, this study cannot answer if this was due to the drug per se or this was due to the huge reduction in the incidence of diabetes but again, it needs further investigation.

Slide 46

Before closing, are there any mechanisms for renal protection with these agents? The answer is yes again, we have several studies ON THIS; blood glucose lowering, blood pressure lowering, insulin lowering, improvement of endothelial function, reduction of inflammation, of oxidative stress, down-regulation of RAS, attenuation of endothelin levels, reduction in trophic mechanisms and so on and so forth.

Slide 47

So to conclude we have data from population studies showing that insulin resistance and hyperinsulinemia are associated with both hypertension and CKD. We have some data from studies with genetic mutations showing that individuals with extreme forms of insulin resistance present early and heavy onset of the metabolic syndrome as well as renal injury. We have data showing that there are a number of mechanisms that can explain how insulin resistance and hyperinsulinemia promote blood pressure elevation and renal injury.

Slide 48

Again we have data with drugs that reverse insulin resistance showing that they can improve both blood pressure and microalbuminuria and background studies in this field showing explanatory mechanisms for these actions. So it seems that future studies should further delineate these associations and fully clarify the importance of insulin resistance reduction towards prevention and also delayed progression of both CKD and cardiovascular disease.

Slide 49

So it seems that we’re not in the dark - actually we have bright light coming from the roof of the cave, from a small hole, so what we have to do in the future is to uncover the roof to be in the open air. Thank you very much.