- Email: [email protected]
Peripheral microvascular disease in diabetes
150
Discussions/Diabetes Research and Clinical Practice 30 Suppl. (1996) S13 7-S I 60
question. Did I understand you to say that syndrome X is a benign disease? H. Tomoike: I understand from the cardiological field. Question continued: Cardiology. Do these people not go into heart failure? In other words, if they have angina for many years, you imply that there is no myocardial change so that they don't go into heart failure or have any decrease in cardiac function. H. Tomoike: Well, it's possible. I'd like to say, the number of these patients with syndrome X is very small. Question continued: I understand. H. Tomoike: And as far as I know or I experienced, prognosis is very good. But how to manage chest pain is very difficult. Question continued: No, no. I understand about the chest pain. I was interested in the other, the longterm aspect. Thank you. Comment: My understanding of the cardiac syndrome X is that it's probably made up of many different functional causes, and I was interested in the way that you specifically dissociated cardiac syndrome X from the metabolic syndrome X. I ' m interested because there have been two or three groups now who have suggested that the metabolic syndrome X, or glucose intolerance or hyperinsulinemia, may be one of the reasons why there is microvascular dysfunction, perhaps through endothelial cell dysfunction or precapillary resistance changes. H. Tomoike: Well, I'd like to take your comment, because previous studies didn't measure insulin level or glucose tolerance tests to patients with cardiac syndrome X. Probably we should consider the role of microvascular syndrome X in these capillaries. But from the reported cases, I think these diseases are quite different. We should think about it and test the hypothesis to coronary patients, I think. Y. Goto: Thank you very much, Dr. Tomoike.
Peripheral microvascular disease in diabetes J. Tooke Y. Goto: Thank you very much, Dr. Tooke. Now Dr. Tooke's presentation is open for discussion. Anybody else with comments? Question: John, I have two questions. You've
shown us the capillary pressure in subjects with nephropathy in comparison with non-diabetic subjects and non-complicated subjects. There is always the question whether retinopathy and nephropathy are related in their pathogenic mechanisms. Do you have data on capillary pressures in subjects with retinopathy but no nephropathy? That's one question. The second question is, you showed us in the nephropathy subjects an increased capillary pressure and as one of the arguments for the hemodynamic hypothesis. But in the early diabetes, you have an increased flow. And several people, including our group, have shown that when you have nephropathy, then the increased flow is back to normal. Isn't it possible that the increased pressure in the nephropathic subjects is not due to increased flow, just a consequence of the sclerotic changes in the vascular bed? J. Tooke: In answer to your first question, we haven't looked at a large group of patients with marked retinopathy but no evidence of nephropathy, and I agree that would be an interesting study. In the nephropathic patients, I think one would have to assume that, given the fact that the flow at that stage is normal or reduced, that the predominant change has been an increase in post-capillary resistance. And I think we've actually concentrated far too much attention on the precapillary vasodilatation that seems to occur early in diabetes, and forgotten that capillary pressure is a function also of postcapillary resistance, and it may well be that relative vasoconstriction in nephropathic patients is one of the more fundamental mechanisms separating that high-risk group from the other subjects. F.A. Gries: Dr. Tooke, usually nitric oxide is supposed to be one of the most important regulators. Do we have any evidence that in your experiments this might be a factor of importance? J. Tooke: The only data we have to date is the last data I showed you on the iontophoresis of acetylcholine in patients with non-insulin-dependent diabetes, which suggests that the release of all response to nitric oxide is impaired. However, what I didn't show you is that if we look at the response in those patients to iontophoresis of a direct nitro donor, such as sodium nitroprusside, we also see an impaired response, which suggests that there is also a failing at the level of the smooth muscle. Now, we don't know
DiscussiotL~/Diabetes Research and Clinical Practice 30 Suppl. (1996) S 137-S 160
the nature of that failure. It could be due to quenching of a normal amount of nitric oxide that's released by, for example, glycation products. One piece of evidence in support of that is the fact that early studies in patients with impaired glucose tolerance but not diabetes suggest that their smooth muscle response is r~latively well preserved but they do, even at that stage, demonstrate a problem with their endothelial cell response. Question: I would have two questions. It's certainly a very fascinating story. But can we assume that the numbers of capillaries and the width of the capillaries is the same in controls compared to diabetic patients, would be my first question. J. Tooke: Right. The numbers of capillaries, I think we can safely assume that that is the case, because there have been both video and microscopic studies of the living anatomy and there have also been histological studies which have shown similar capillary numbers, certainly at these stages of the disease. As for the dimensions of the capillaries, there is evidence that the capillary lumen is reduced in size, particularly in complicated patients. So that may well be part of the resistance change at a postcapillary level that's contributory. Question continued: So the increase in pressure could be some mechanism to overcome narrowing of the capillaries in diabetics? J. Tooke: That's possible; on the other hand, the fact that would argue against that is that we see changes, increased capillary pressure, within the first year of insulin-dependent diabetic life, and it seems unlikely, intuitively, to me that you will have structural remodelling of the capillary bed that early in the disease process. Question continued: My second question would be, nail fold capillaries are in some way also very specific capillaries. Is it really a very good surrogate marker, so to speak, for all capillaries in the organism? J. Tooke: Yes, that's a good question, and I think, as I've said at the beginning of my talk, that we have to be careful that we don't over-extrapolate findings from one vascular bed to another. However, I think that the idea that the nail fold is particularly different from the rest of skin is an overworked argument. The nail bed is different, but the nail fold is simply an anatomical, if you like, redistribution of the skin. It
151
doesn't have particularly high numbers of arteriovenous shunts or other unusual characteristics. And the skin in that area exhibits the same range of physiological responses that we see in skin in other areas. But I take the point, we have to be guarded about the degree to which we extrapolate from one vascular bed to another. Y. Goto: OK, thank you very much, Dr. Tooke.
Insulin and insulin-like growth factors: their role in the development of diabetic cardiovascular disease B. G~ke Y. Yazaki (Chairman): Thank you very much for your nice overview of the role of insulin and IGF on atherogenesis. Now, Dr. Gt~ke's lecture is open for questions or comments. Is there any comment? Yes, please. Dr. Goerpe, lstanbul: I thank you for this brilliant and more on a cellular level lecture. And I am a clinician and I want to ask you two questions. Do you recommend us to prescribe sulfonylureas with a very short half-life, and this is the first question. And the second one, are there human studies comparing the insulin delivery, subcutaneous or intraperitoneal or portal insulin delivery, and the effect of these two types of insulin delivery on the cardiovascular events? Thank you. Dr. G~ke: Well, to answer the second question first, I ' m not aware of studies like these comparing circulating insulin levels with portal insulin levels. The only studies I know of focused more on the glucagon business. And it seems like when you treat patients with insulin pumps, you are able to sufficiently increase circulating insulin, but the ratio between glucagon and insulin in the portal vein is not being changed very much. So these patients, this is all stuff published by Unger twenty years ago or something in dogs, and later on was published in humans. This relation comes down to a hyperglucagonemia in the experimental animals and in the patients, and some of the effects regarding hyperglycemia and so on I explained by this. But as far as I remember, as far as I recall, there is no literature answering your second question. And the first question is, I myself in the clinical
Discussions/Diabetes Research and Clinical Practice 30 Suppl. (1996) S13 7-S I 60
question. Did I understand you to say that syndrome X is a benign disease? H. Tomoike: I understand from the cardiological field. Question continued: Cardiology. Do these people not go into heart failure? In other words, if they have angina for many years, you imply that there is no myocardial change so that they don't go into heart failure or have any decrease in cardiac function. H. Tomoike: Well, it's possible. I'd like to say, the number of these patients with syndrome X is very small. Question continued: I understand. H. Tomoike: And as far as I know or I experienced, prognosis is very good. But how to manage chest pain is very difficult. Question continued: No, no. I understand about the chest pain. I was interested in the other, the longterm aspect. Thank you. Comment: My understanding of the cardiac syndrome X is that it's probably made up of many different functional causes, and I was interested in the way that you specifically dissociated cardiac syndrome X from the metabolic syndrome X. I ' m interested because there have been two or three groups now who have suggested that the metabolic syndrome X, or glucose intolerance or hyperinsulinemia, may be one of the reasons why there is microvascular dysfunction, perhaps through endothelial cell dysfunction or precapillary resistance changes. H. Tomoike: Well, I'd like to take your comment, because previous studies didn't measure insulin level or glucose tolerance tests to patients with cardiac syndrome X. Probably we should consider the role of microvascular syndrome X in these capillaries. But from the reported cases, I think these diseases are quite different. We should think about it and test the hypothesis to coronary patients, I think. Y. Goto: Thank you very much, Dr. Tomoike.
Peripheral microvascular disease in diabetes J. Tooke Y. Goto: Thank you very much, Dr. Tooke. Now Dr. Tooke's presentation is open for discussion. Anybody else with comments? Question: John, I have two questions. You've
shown us the capillary pressure in subjects with nephropathy in comparison with non-diabetic subjects and non-complicated subjects. There is always the question whether retinopathy and nephropathy are related in their pathogenic mechanisms. Do you have data on capillary pressures in subjects with retinopathy but no nephropathy? That's one question. The second question is, you showed us in the nephropathy subjects an increased capillary pressure and as one of the arguments for the hemodynamic hypothesis. But in the early diabetes, you have an increased flow. And several people, including our group, have shown that when you have nephropathy, then the increased flow is back to normal. Isn't it possible that the increased pressure in the nephropathic subjects is not due to increased flow, just a consequence of the sclerotic changes in the vascular bed? J. Tooke: In answer to your first question, we haven't looked at a large group of patients with marked retinopathy but no evidence of nephropathy, and I agree that would be an interesting study. In the nephropathic patients, I think one would have to assume that, given the fact that the flow at that stage is normal or reduced, that the predominant change has been an increase in post-capillary resistance. And I think we've actually concentrated far too much attention on the precapillary vasodilatation that seems to occur early in diabetes, and forgotten that capillary pressure is a function also of postcapillary resistance, and it may well be that relative vasoconstriction in nephropathic patients is one of the more fundamental mechanisms separating that high-risk group from the other subjects. F.A. Gries: Dr. Tooke, usually nitric oxide is supposed to be one of the most important regulators. Do we have any evidence that in your experiments this might be a factor of importance? J. Tooke: The only data we have to date is the last data I showed you on the iontophoresis of acetylcholine in patients with non-insulin-dependent diabetes, which suggests that the release of all response to nitric oxide is impaired. However, what I didn't show you is that if we look at the response in those patients to iontophoresis of a direct nitro donor, such as sodium nitroprusside, we also see an impaired response, which suggests that there is also a failing at the level of the smooth muscle. Now, we don't know
DiscussiotL~/Diabetes Research and Clinical Practice 30 Suppl. (1996) S 137-S 160
the nature of that failure. It could be due to quenching of a normal amount of nitric oxide that's released by, for example, glycation products. One piece of evidence in support of that is the fact that early studies in patients with impaired glucose tolerance but not diabetes suggest that their smooth muscle response is r~latively well preserved but they do, even at that stage, demonstrate a problem with their endothelial cell response. Question: I would have two questions. It's certainly a very fascinating story. But can we assume that the numbers of capillaries and the width of the capillaries is the same in controls compared to diabetic patients, would be my first question. J. Tooke: Right. The numbers of capillaries, I think we can safely assume that that is the case, because there have been both video and microscopic studies of the living anatomy and there have also been histological studies which have shown similar capillary numbers, certainly at these stages of the disease. As for the dimensions of the capillaries, there is evidence that the capillary lumen is reduced in size, particularly in complicated patients. So that may well be part of the resistance change at a postcapillary level that's contributory. Question continued: So the increase in pressure could be some mechanism to overcome narrowing of the capillaries in diabetics? J. Tooke: That's possible; on the other hand, the fact that would argue against that is that we see changes, increased capillary pressure, within the first year of insulin-dependent diabetic life, and it seems unlikely, intuitively, to me that you will have structural remodelling of the capillary bed that early in the disease process. Question continued: My second question would be, nail fold capillaries are in some way also very specific capillaries. Is it really a very good surrogate marker, so to speak, for all capillaries in the organism? J. Tooke: Yes, that's a good question, and I think, as I've said at the beginning of my talk, that we have to be careful that we don't over-extrapolate findings from one vascular bed to another. However, I think that the idea that the nail fold is particularly different from the rest of skin is an overworked argument. The nail bed is different, but the nail fold is simply an anatomical, if you like, redistribution of the skin. It
151
doesn't have particularly high numbers of arteriovenous shunts or other unusual characteristics. And the skin in that area exhibits the same range of physiological responses that we see in skin in other areas. But I take the point, we have to be guarded about the degree to which we extrapolate from one vascular bed to another. Y. Goto: OK, thank you very much, Dr. Tooke.
Insulin and insulin-like growth factors: their role in the development of diabetic cardiovascular disease B. G~ke Y. Yazaki (Chairman): Thank you very much for your nice overview of the role of insulin and IGF on atherogenesis. Now, Dr. Gt~ke's lecture is open for questions or comments. Is there any comment? Yes, please. Dr. Goerpe, lstanbul: I thank you for this brilliant and more on a cellular level lecture. And I am a clinician and I want to ask you two questions. Do you recommend us to prescribe sulfonylureas with a very short half-life, and this is the first question. And the second one, are there human studies comparing the insulin delivery, subcutaneous or intraperitoneal or portal insulin delivery, and the effect of these two types of insulin delivery on the cardiovascular events? Thank you. Dr. G~ke: Well, to answer the second question first, I ' m not aware of studies like these comparing circulating insulin levels with portal insulin levels. The only studies I know of focused more on the glucagon business. And it seems like when you treat patients with insulin pumps, you are able to sufficiently increase circulating insulin, but the ratio between glucagon and insulin in the portal vein is not being changed very much. So these patients, this is all stuff published by Unger twenty years ago or something in dogs, and later on was published in humans. This relation comes down to a hyperglucagonemia in the experimental animals and in the patients, and some of the effects regarding hyperglycemia and so on I explained by this. But as far as I remember, as far as I recall, there is no literature answering your second question. And the first question is, I myself in the clinical