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INSULIN RESPONSE TO GLUCOSE IN PATIENTS WITH PERIPHERAL VASCULAR DISEASE, ARTERITIS, AND RAYNAUD'S PHENOMENON
1229
The lack of insulin response in patients with smallvessel peripheral vascular disease raises three questions. First, the lack of a pulsatile secretion of insulin in response to the normal physiological stimulus of a raised blood-sugar in these patients may affect peri-
INSULIN RESPONSE TO GLUCOSE IN PATIENTS WITH PERIPHERAL VASCULAR DISEASE, ARTERITIS, AND RAYNAUD’S PHENOMENON*
tissue metabolism, which is important in the xtiology of small-vessel disease. Larger arteries have vasa vasorum supplying nutrition: small vessels rely on diffusion of nutrients from the bloodstream into the vessel wall, and a relative insulin lack may hamper the passage of glucose into these arterial wall cells.
MARGARET W. GHILCHIK A. S. MORRIS
pheral
Secondly, there may be a common aetiology in the lesions in juvenile diabetes mellitus and in patients with small-vessel disease. The size of vessel involved is different, that of diabetic microangiopathy being thought to be at the precapillary and arteriole level, while in small-vessel disease the small arteries are involved; the lesions of the small-vessel-disease patient give rise to pain which suggests that, unlike the diabetic, there is no accompanying neuropathy; and patients with small-vessel disease are not diabetic as judged by carbohydrate intolerance, and their blood-glucose levels are normal. The two conditions do, however, share a refractory state of insulin secretion and resemble each other in clinical presentation. Thirdly, the poor response of the pancreatic islets stimulation by glucose or by tolbutamide might be the result of small-vessel disease affecting this organ as well as the feet and hands. Against this, no impairment of pancreatic exocrine function is apparent, and the natural history of the progress of the disease predominantly involves the limb vessels. The finding of this metabolic lesion in patients with small-vessel disease may be useful in diagnosis, to separate off a category of patients among those with peripheral vascular disease who have a distinctive site of lesion, natural history, and prognosis. Owing to the small size of the vessels involved, arterial surgery, other than lumbar sympathectomy, is not applicable. It is hoped that the finding that there is a deficient insulin secretion in response to a glucose load in patients with small-vessel peripheral vascular disease may help in providing direction for further work on Ktiology and treatment. to
We thank the British Heart Foundation for supporting this work and Prof. W. T. Irvine and Mr. H. H. G. Eastcott for allowing us to study their patients and for helpful discussion.
Requests for reprints should be addressed
to
St. Mary’s Hospital, London W.2, and St. Charles’ Hospital, London W.10
Surgical Unit,
Twenty-three patients with peripheral
Sum ary
vascular disease due to atheromatous blocks in large vessels, four patients with arteritis, and twenty patients with Raynaud’s phenomenon were tested for insulin response to glucose. (In an earlier investigation patients with small-vessel peripheral vascular disease did not secrete insulin in response to a glucose load—a previously unreported finding.) Insulin output after glucose in patients with atheromatous blocks in large peripheral arteries fell into three categories: (1) normal glucose tolerance and insulin output, the insulin rise (peak/basal ratio) comparing well with the rise in controls; (2) carbohydrate intolerance with a prediabetic pattern of glucosetolerance test, and raised circulating insulin levels both fasting insulin and after glucose, so that the insulin rise was lower than normal; or (3) the flat insulin responses after glucose that had been noted in small-vessel disease with normal glucose tolerance. Thus in these twenty-three patients with large-vessel blocks presenting with peripheral vascular disease the high and late insulin secretion after glucose reported by other workers for patients with atheroma could not be confirmed. High but not delayed insulin peaks were seen after a glucose stimulus in some patients with arteritis and with Raynaud’s phenomenon. Introduction
HIGH insulin output after glucose stimulus has been reported after myocardial infarction and in patients with ischasmic heart-disease 1-5 and after cerebrovascular thrombosis.Patients with small-vessel peripheral vascular disease were found to have a significant insulin unresponsiveness to hyperglyceemia.1 We have investigated the insulin response to a glucose load in twenty-three patients presenting with atheromatous occlusion of larger vessels, four patients with arteritis, twenty patients with Raynaud’s phenomenon, and controls.
M. W. G.
REFERENCES
1. Yudkin, J. Lancet, 1964, ii, 4. 2. Cohen, A. M., Bavly, S., Poznanski, R. ibid. 1961, ii, 1399. 3. Stout, R. W., Vallance-Owen, J. reviewed by Lancet, 1969, i, 1078. 4. Peters, N., Hales, C. N. ibid. 1965, i, 1144. 5. Nikkilä, E. A., Miettinen, T. A., Vesenne, M. R., Pelkonen, R. ibid. 1965, ii, 508. 6. Tzagournis, M., Seidensticker, J. F., Hamwi, G. J. Ann. intern. Med. 1967, 67, 43. 7. Hoffman, W. S. J. biol. Chem. 1937, 120, 51. 8. Hales, C. N., Randle, P. J. Lancet, 1963, i, 200. 9. Bagdade, J. D., Bierman, E. L., Porte, D. J. clin. Invest. 1967, 46, 1549. 10. Meade, R. C., Kneubuhler, M. A., Barboriak, J. J., Schulte, W. J. Diabetes, 1969, 18, 397. 11. Yalow, R. S., Goldsmith, S. J., Berson, S. A. ibid. p. 402.
Patients and Methods Twenty-three patients with peripheral vascular disease who had atheromatous occlusions of large vessels (iliac, femoral, and popliteal arteries) were investigated. There All were eighteen men and five women, average age 60. except two were smokers. Their symptoms of claudication or ischxrnic pain in the feet were severe enough to have caused their presentation and investigation in a surgical vascular clinic. Fifteen had undergone arterial surgery and five had come to amputation. *
presented at a British Heart Foundation at the Royal Postgraduate Medical School on Dec. 4, 1970, and at the Vascular’and Surgical Research Societies at St. Mary’s Hospital on May 14, 1971, and at the University of Birmingham Medical School on July 17, 1971.
Based
on a
paper
symposium held
1230 The four
patients with arteritis investigated were: a with true Takayasu arteritis (pulseless disease of the upper limbs) who subsequently showed a good clinical response to cortisone; a middle-aged man with a symptomless abdominal aortic aneurysm of which the histology was a Takayasu type arteritis; a young woman presenting as small-vessel disease with rest pain in the feet and all peripheral pulses present and in whom histology of a biopsy of a painful nodule on the leg was giant-cell arteritis; and an elderly woman with collagen disease, pregangrene of the toes, and all her peripheral pulses present. woman
young
with an abdominal aneurysm and the young with giant-cell arteritis were smokers. Twenty patients with Raynaud’s phenomenon were studied (seventeen women and three men). Their ages ranged from 14 to 73, and the symptoms had been present for 1-28 years. Four patients had irreversible isch2emic lesions at the fingertip pulp; the remainder had attacks which were fully reversible. Three patients had evidence of acrocyanosis and one of these had also erythromelalgia. Profuse sweating of the hands accompanied the Raynaud attacks in two patients. Eleven of the patients were smokers. The controls were those of the previous paper,7 where they were compared with twenty-five patients with smallvessel disease. The serum-immunoreactive-insulin and blood-glucose levels were estimated as described previously on the fasting resting patient throughout a 50 g. oral glucose-tolerance test. The response of blood-sugar and serum-insulin to the glucose ingestion was estimated for each patient over a 2-hour time course, and the ratio of peak insulin value over the basal fasting level was called the insulin rise. The
man
woman
Results
The insulin response to a glucose load in twentythree patients with peripheral vascular disease due to atheromatous occlusion of large arteries fell into three distinct patterns (fig. 1):
(1) Nine patients (40%) curves
had normal glucose-tolerance and normal insulin responses throughout the test.
(2) Eight patients (35%) had prediabetic glucose-tolerance
Fig. 2-Insulin rise in patients with large-vessel atheroma, arteritis, or Raynaud’s phenomenon, and controls. > 120 mg. per 100 ml. 2 hours after The absolute insulin output at peak response was in many cases high, and on average higher than the group with a normal response, but the fasting levels were also raised. These patients had an abnormal insulin response to the glucose stimulus, the insulin rise being only 3,2. (3) Six patients (25%) had the flat insulin unresponsiveness to a glucose stimulus that we had come to recognise as characteristic in the small-vessel disease patients. Their glucose-tolerance curves were normal. Circulating insulin was normal in the fasting basal state and remained at the same level throughout the glucose-tolerance test, failing to rise to a peak on the stimulus of hyperglycsmia.
(blood-sugar glucose load).
curves
the
Individual
insulin ratios for all fortyshown in fig. 2. The patients with atheromatous blocks in large vessels have already been discussed. Of the four patients with arteritis, three had normal glucose-tolerance curves and one, the 53-year-old woman with collagen disease, had a prediabetic curve. The basal fasting insulin level was a normal low value, and they all produced high insulin peaks after a glucose load-at the upper limit of normal in three patients and well above normal in the patient with true Takayasu disease. The twenty patients with Raynaud’s phenomenon had normal glucose-tolerance curves and normal basal circulating insulin levels. After glucose six patients produced insulin peaks higher than any value in the normal range; five of these patients were under 40, though the sixth patient was aged 60. seven
patients
peak/basal are
Discussion
Of the twenty-three patients with peripheral vascular disease due to large-vessel atheromatous block, none had the high insulin response to glucose which other workers have
Fig. I-Insulin rise in twenty-three patients with peripheral vascular disease and normal controls.
reported. Among our patients with atherosclerotic occlusive large-vessel peripheral vascular disease 35% had glucose intolerance-a finding that accords with Kingsbury’s39% for atherosclerotic peripheral vascular disease 8-a figure of 48% for patients with ischaemic
1231
heart-disease,4and 29% after myocardial infarction.a Our patients had raised fasting insulin levels, but the peak/basal insulin response was not high. Although
the term hyperinsulinism is sometimes applied because of the large amount of circulating insulin, in fact impaired insulin secretion is often seen in these patients. As with obesity 9,10 or maturity-onset diabetes mellitus,"," the basal fasting insulin may be high but there is no increased secretion in response to a
glucose load.
In all but one3 of six papers 1-6 the high insulin response to glucose reported in patients with atheroma referred, not to an increase in insulin output over the basal level after a glucose load, but to raised absolute values for circulating insulin both in the basal and stimulated state. The data show that the insulin response to glucose, as measured by peak/basal ratio, was, in fact, within the normal range or lower than normal. Tzagournis et al.did show a true high insulin peak response to glucose in patients 1 month after myocardial infarction. However, their basal fasting insulin level seems to be obtained from the combined data for patients and controls, so we cannot calculate the separate insulin rises for patients and controls; the mean basal level might be higher for the patients, thus giving similar peak/basal ratios in each
their metabolism is impaired by lack of glucose and insulin. In this respect it is of interest that the patients with the completely flat curves of insulin unresponsiveness are those whose occlusive lesions are in small arteries, vessels whose intimal cells are dependent for nutrients on diffusion from the circulating bloodstream and which are not nourished as well from the vasa vasorum.
We thank the British Heart Foundation for supporting this work and Prof. W. T. Irvine, Mr. H. H. G. Eastcott, and Mr. E. J. Williams for referring patients for study and to Dr. Claude Andre for useful discussion.
Requests for reprints should be addressed
to
M. W. G.
REFERENCES 1. 2.
3.
4. 5. 6. 7. 8. 9.
Peters, N., Hales, C. N. Lancet 1965, i, 1144. Nikkilä, E. A., Miettinen, T. A., Vesenne, M-R., Pelkonen, R. ibid. 1965, ii, 508. Tzagournis, M., Seidensticker, J. F., Hamwi, G. J. Ann. intern. Med. 1967, 67, 42. Christiansen, I., Deckert, T., Kjerulf, K., Midtgaard, K., Worning, H. Acta med. scand. 1968, 184, 283. Devlin, J. G., Stephenson, N. Metabolism, 1968, 17, 999. Leetma, H. E., Gentler, M. M., Saluste, E., Whiter, H. Circulation, 1968, 37/38, suppl. VI, p. 124. Ghilchik, M. W., Morris, A. S. Lancet, 1971, ii, 1227. Kingsbury, K. J. ibid. 1966, ii, 1374. Bagdade, J. D., Bierman, E. L., Porte, D. J. clin. Invest. 1967, 46,
1549. 10. Phear, D. N. Lancet, 1962, ii, 955. 11. Berson, S. A., Yalow, R. S. Am. J. Med. 1961, 31, 874.
group.
40% of our patients handled glucose normally and had normal insulin release. There remains a small group (25%) who, as with patients with small-vessel disease,’ have normal glucose tolerance but a striking insulin unresponsiveness to a glucose load. These patients’ case-notes did not suggest that their disease had started with small-vessel lesions and progressed to large-vessel atheroma, and they were clinically indistinguishable from the other two groups of largevessel-disease patients. We have seen very high peak/basal ratios in patients with arteritis and in younger patients with Raynaud’s Neither disease process involves phenomenon. atheroma. In general, our findings indicate that patients with atherosclerosis do not have an excessive insulin secretion in response to a glucose load. The idea that individuals who respond to carbohydrate intake by pouring out insulin, shunt their glucose into fat under insulin overstimulation, and are at high risk of having fatty atheromatous plaques on their vessel walls, does not, therefore, accord with our findings: on the contrary, our patients with atheroma manifested as occlusive peripheral vascular disease often had a poor insulin response to glucose. Some are normal; some, like the obese or like patients with maturity-onset diabetes mellitus, have raised fasting insulin levels but respond inadequately in response to a glucose load; some, notably all the small-vessel-disease patients7 and a few of the large-vessel atheroma patients, have a flat insulin response to glucose. The explanation of the connection between inadequate insulin secretion and the development of atheroma may lie in the need for insulin to carry glucose into cells. Poor output of insulin in response to metabolic need may result in deprivation of the supply of glucose for cell metabolism. The cells constituting the intimal lining of arteries may be more vulnerable to fatty infiltration when
Preliminary Communications EXTERNAL METHOD FOR DETECTION OF FETAL BREATHING IN UTERO
K. BODDY
J. S. ROBINSON Nuffield Institute for Medical Research, University of Oxford for detecting has been developed using chronic fetal lamb preparations, and has been used successfully in pregnant women.
An ultrasonic
technique
Summary fetal breathing in
utero
INTRODUCTION
IN chronic
preparations of fetal lambs and rabbits episodic breathing occurs normally in utero, 1,2and work in sheep has indicated that such breathing is a good indicator of fetal health.33 Observations of fetal lambs delivered into a warm saline bath have shown that breathing movements are associated with alterations in the shape of the fetal chest 1; we describe here the detection of these changes using an ultrasonic A-scan. MATERIALS AND METHODS
diagnostic sounder (Hewlett Packard model 7214A) used on four chronic fetal lamb preparations and seven pregnant women. The ultrasonic source had a 2 mW per sq.cm. average power and a 500 Hz pulse repetition-rate delivered via a 2-5 MHz frequency transducer within. A water(12-5 mm.) lead-zirconate-titanate crystal. soluble transmission gel (’Aquasonic 100’) was used to form the coupling medium. Recording periods varied from 30 to 120 minutes. The techniques for the chronic sheep preparations A
was
The lack of insulin response in patients with smallvessel peripheral vascular disease raises three questions. First, the lack of a pulsatile secretion of insulin in response to the normal physiological stimulus of a raised blood-sugar in these patients may affect peri-
INSULIN RESPONSE TO GLUCOSE IN PATIENTS WITH PERIPHERAL VASCULAR DISEASE, ARTERITIS, AND RAYNAUD’S PHENOMENON*
tissue metabolism, which is important in the xtiology of small-vessel disease. Larger arteries have vasa vasorum supplying nutrition: small vessels rely on diffusion of nutrients from the bloodstream into the vessel wall, and a relative insulin lack may hamper the passage of glucose into these arterial wall cells.
MARGARET W. GHILCHIK A. S. MORRIS
pheral
Secondly, there may be a common aetiology in the lesions in juvenile diabetes mellitus and in patients with small-vessel disease. The size of vessel involved is different, that of diabetic microangiopathy being thought to be at the precapillary and arteriole level, while in small-vessel disease the small arteries are involved; the lesions of the small-vessel-disease patient give rise to pain which suggests that, unlike the diabetic, there is no accompanying neuropathy; and patients with small-vessel disease are not diabetic as judged by carbohydrate intolerance, and their blood-glucose levels are normal. The two conditions do, however, share a refractory state of insulin secretion and resemble each other in clinical presentation. Thirdly, the poor response of the pancreatic islets stimulation by glucose or by tolbutamide might be the result of small-vessel disease affecting this organ as well as the feet and hands. Against this, no impairment of pancreatic exocrine function is apparent, and the natural history of the progress of the disease predominantly involves the limb vessels. The finding of this metabolic lesion in patients with small-vessel disease may be useful in diagnosis, to separate off a category of patients among those with peripheral vascular disease who have a distinctive site of lesion, natural history, and prognosis. Owing to the small size of the vessels involved, arterial surgery, other than lumbar sympathectomy, is not applicable. It is hoped that the finding that there is a deficient insulin secretion in response to a glucose load in patients with small-vessel peripheral vascular disease may help in providing direction for further work on Ktiology and treatment. to
We thank the British Heart Foundation for supporting this work and Prof. W. T. Irvine and Mr. H. H. G. Eastcott for allowing us to study their patients and for helpful discussion.
Requests for reprints should be addressed
to
St. Mary’s Hospital, London W.2, and St. Charles’ Hospital, London W.10
Surgical Unit,
Twenty-three patients with peripheral
Sum ary
vascular disease due to atheromatous blocks in large vessels, four patients with arteritis, and twenty patients with Raynaud’s phenomenon were tested for insulin response to glucose. (In an earlier investigation patients with small-vessel peripheral vascular disease did not secrete insulin in response to a glucose load—a previously unreported finding.) Insulin output after glucose in patients with atheromatous blocks in large peripheral arteries fell into three categories: (1) normal glucose tolerance and insulin output, the insulin rise (peak/basal ratio) comparing well with the rise in controls; (2) carbohydrate intolerance with a prediabetic pattern of glucosetolerance test, and raised circulating insulin levels both fasting insulin and after glucose, so that the insulin rise was lower than normal; or (3) the flat insulin responses after glucose that had been noted in small-vessel disease with normal glucose tolerance. Thus in these twenty-three patients with large-vessel blocks presenting with peripheral vascular disease the high and late insulin secretion after glucose reported by other workers for patients with atheroma could not be confirmed. High but not delayed insulin peaks were seen after a glucose stimulus in some patients with arteritis and with Raynaud’s phenomenon. Introduction
HIGH insulin output after glucose stimulus has been reported after myocardial infarction and in patients with ischasmic heart-disease 1-5 and after cerebrovascular thrombosis.Patients with small-vessel peripheral vascular disease were found to have a significant insulin unresponsiveness to hyperglyceemia.1 We have investigated the insulin response to a glucose load in twenty-three patients presenting with atheromatous occlusion of larger vessels, four patients with arteritis, twenty patients with Raynaud’s phenomenon, and controls.
M. W. G.
REFERENCES
1. Yudkin, J. Lancet, 1964, ii, 4. 2. Cohen, A. M., Bavly, S., Poznanski, R. ibid. 1961, ii, 1399. 3. Stout, R. W., Vallance-Owen, J. reviewed by Lancet, 1969, i, 1078. 4. Peters, N., Hales, C. N. ibid. 1965, i, 1144. 5. Nikkilä, E. A., Miettinen, T. A., Vesenne, M. R., Pelkonen, R. ibid. 1965, ii, 508. 6. Tzagournis, M., Seidensticker, J. F., Hamwi, G. J. Ann. intern. Med. 1967, 67, 43. 7. Hoffman, W. S. J. biol. Chem. 1937, 120, 51. 8. Hales, C. N., Randle, P. J. Lancet, 1963, i, 200. 9. Bagdade, J. D., Bierman, E. L., Porte, D. J. clin. Invest. 1967, 46, 1549. 10. Meade, R. C., Kneubuhler, M. A., Barboriak, J. J., Schulte, W. J. Diabetes, 1969, 18, 397. 11. Yalow, R. S., Goldsmith, S. J., Berson, S. A. ibid. p. 402.
Patients and Methods Twenty-three patients with peripheral vascular disease who had atheromatous occlusions of large vessels (iliac, femoral, and popliteal arteries) were investigated. There All were eighteen men and five women, average age 60. except two were smokers. Their symptoms of claudication or ischxrnic pain in the feet were severe enough to have caused their presentation and investigation in a surgical vascular clinic. Fifteen had undergone arterial surgery and five had come to amputation. *
presented at a British Heart Foundation at the Royal Postgraduate Medical School on Dec. 4, 1970, and at the Vascular’and Surgical Research Societies at St. Mary’s Hospital on May 14, 1971, and at the University of Birmingham Medical School on July 17, 1971.
Based
on a
paper
symposium held
1230 The four
patients with arteritis investigated were: a with true Takayasu arteritis (pulseless disease of the upper limbs) who subsequently showed a good clinical response to cortisone; a middle-aged man with a symptomless abdominal aortic aneurysm of which the histology was a Takayasu type arteritis; a young woman presenting as small-vessel disease with rest pain in the feet and all peripheral pulses present and in whom histology of a biopsy of a painful nodule on the leg was giant-cell arteritis; and an elderly woman with collagen disease, pregangrene of the toes, and all her peripheral pulses present. woman
young
with an abdominal aneurysm and the young with giant-cell arteritis were smokers. Twenty patients with Raynaud’s phenomenon were studied (seventeen women and three men). Their ages ranged from 14 to 73, and the symptoms had been present for 1-28 years. Four patients had irreversible isch2emic lesions at the fingertip pulp; the remainder had attacks which were fully reversible. Three patients had evidence of acrocyanosis and one of these had also erythromelalgia. Profuse sweating of the hands accompanied the Raynaud attacks in two patients. Eleven of the patients were smokers. The controls were those of the previous paper,7 where they were compared with twenty-five patients with smallvessel disease. The serum-immunoreactive-insulin and blood-glucose levels were estimated as described previously on the fasting resting patient throughout a 50 g. oral glucose-tolerance test. The response of blood-sugar and serum-insulin to the glucose ingestion was estimated for each patient over a 2-hour time course, and the ratio of peak insulin value over the basal fasting level was called the insulin rise. The
man
woman
Results
The insulin response to a glucose load in twentythree patients with peripheral vascular disease due to atheromatous occlusion of large arteries fell into three distinct patterns (fig. 1):
(1) Nine patients (40%) curves
had normal glucose-tolerance and normal insulin responses throughout the test.
(2) Eight patients (35%) had prediabetic glucose-tolerance
Fig. 2-Insulin rise in patients with large-vessel atheroma, arteritis, or Raynaud’s phenomenon, and controls. > 120 mg. per 100 ml. 2 hours after The absolute insulin output at peak response was in many cases high, and on average higher than the group with a normal response, but the fasting levels were also raised. These patients had an abnormal insulin response to the glucose stimulus, the insulin rise being only 3,2. (3) Six patients (25%) had the flat insulin unresponsiveness to a glucose stimulus that we had come to recognise as characteristic in the small-vessel disease patients. Their glucose-tolerance curves were normal. Circulating insulin was normal in the fasting basal state and remained at the same level throughout the glucose-tolerance test, failing to rise to a peak on the stimulus of hyperglycsmia.
(blood-sugar glucose load).
curves
the
Individual
insulin ratios for all fortyshown in fig. 2. The patients with atheromatous blocks in large vessels have already been discussed. Of the four patients with arteritis, three had normal glucose-tolerance curves and one, the 53-year-old woman with collagen disease, had a prediabetic curve. The basal fasting insulin level was a normal low value, and they all produced high insulin peaks after a glucose load-at the upper limit of normal in three patients and well above normal in the patient with true Takayasu disease. The twenty patients with Raynaud’s phenomenon had normal glucose-tolerance curves and normal basal circulating insulin levels. After glucose six patients produced insulin peaks higher than any value in the normal range; five of these patients were under 40, though the sixth patient was aged 60. seven
patients
peak/basal are
Discussion
Of the twenty-three patients with peripheral vascular disease due to large-vessel atheromatous block, none had the high insulin response to glucose which other workers have
Fig. I-Insulin rise in twenty-three patients with peripheral vascular disease and normal controls.
reported. Among our patients with atherosclerotic occlusive large-vessel peripheral vascular disease 35% had glucose intolerance-a finding that accords with Kingsbury’s39% for atherosclerotic peripheral vascular disease 8-a figure of 48% for patients with ischaemic
1231
heart-disease,4and 29% after myocardial infarction.a Our patients had raised fasting insulin levels, but the peak/basal insulin response was not high. Although
the term hyperinsulinism is sometimes applied because of the large amount of circulating insulin, in fact impaired insulin secretion is often seen in these patients. As with obesity 9,10 or maturity-onset diabetes mellitus,"," the basal fasting insulin may be high but there is no increased secretion in response to a
glucose load.
In all but one3 of six papers 1-6 the high insulin response to glucose reported in patients with atheroma referred, not to an increase in insulin output over the basal level after a glucose load, but to raised absolute values for circulating insulin both in the basal and stimulated state. The data show that the insulin response to glucose, as measured by peak/basal ratio, was, in fact, within the normal range or lower than normal. Tzagournis et al.did show a true high insulin peak response to glucose in patients 1 month after myocardial infarction. However, their basal fasting insulin level seems to be obtained from the combined data for patients and controls, so we cannot calculate the separate insulin rises for patients and controls; the mean basal level might be higher for the patients, thus giving similar peak/basal ratios in each
their metabolism is impaired by lack of glucose and insulin. In this respect it is of interest that the patients with the completely flat curves of insulin unresponsiveness are those whose occlusive lesions are in small arteries, vessels whose intimal cells are dependent for nutrients on diffusion from the circulating bloodstream and which are not nourished as well from the vasa vasorum.
We thank the British Heart Foundation for supporting this work and Prof. W. T. Irvine, Mr. H. H. G. Eastcott, and Mr. E. J. Williams for referring patients for study and to Dr. Claude Andre for useful discussion.
Requests for reprints should be addressed
to
M. W. G.
REFERENCES 1. 2.
3.
4. 5. 6. 7. 8. 9.
Peters, N., Hales, C. N. Lancet 1965, i, 1144. Nikkilä, E. A., Miettinen, T. A., Vesenne, M-R., Pelkonen, R. ibid. 1965, ii, 508. Tzagournis, M., Seidensticker, J. F., Hamwi, G. J. Ann. intern. Med. 1967, 67, 42. Christiansen, I., Deckert, T., Kjerulf, K., Midtgaard, K., Worning, H. Acta med. scand. 1968, 184, 283. Devlin, J. G., Stephenson, N. Metabolism, 1968, 17, 999. Leetma, H. E., Gentler, M. M., Saluste, E., Whiter, H. Circulation, 1968, 37/38, suppl. VI, p. 124. Ghilchik, M. W., Morris, A. S. Lancet, 1971, ii, 1227. Kingsbury, K. J. ibid. 1966, ii, 1374. Bagdade, J. D., Bierman, E. L., Porte, D. J. clin. Invest. 1967, 46,
1549. 10. Phear, D. N. Lancet, 1962, ii, 955. 11. Berson, S. A., Yalow, R. S. Am. J. Med. 1961, 31, 874.
group.
40% of our patients handled glucose normally and had normal insulin release. There remains a small group (25%) who, as with patients with small-vessel disease,’ have normal glucose tolerance but a striking insulin unresponsiveness to a glucose load. These patients’ case-notes did not suggest that their disease had started with small-vessel lesions and progressed to large-vessel atheroma, and they were clinically indistinguishable from the other two groups of largevessel-disease patients. We have seen very high peak/basal ratios in patients with arteritis and in younger patients with Raynaud’s Neither disease process involves phenomenon. atheroma. In general, our findings indicate that patients with atherosclerosis do not have an excessive insulin secretion in response to a glucose load. The idea that individuals who respond to carbohydrate intake by pouring out insulin, shunt their glucose into fat under insulin overstimulation, and are at high risk of having fatty atheromatous plaques on their vessel walls, does not, therefore, accord with our findings: on the contrary, our patients with atheroma manifested as occlusive peripheral vascular disease often had a poor insulin response to glucose. Some are normal; some, like the obese or like patients with maturity-onset diabetes mellitus, have raised fasting insulin levels but respond inadequately in response to a glucose load; some, notably all the small-vessel-disease patients7 and a few of the large-vessel atheroma patients, have a flat insulin response to glucose. The explanation of the connection between inadequate insulin secretion and the development of atheroma may lie in the need for insulin to carry glucose into cells. Poor output of insulin in response to metabolic need may result in deprivation of the supply of glucose for cell metabolism. The cells constituting the intimal lining of arteries may be more vulnerable to fatty infiltration when
Preliminary Communications EXTERNAL METHOD FOR DETECTION OF FETAL BREATHING IN UTERO
K. BODDY
J. S. ROBINSON Nuffield Institute for Medical Research, University of Oxford for detecting has been developed using chronic fetal lamb preparations, and has been used successfully in pregnant women.
An ultrasonic
technique
Summary fetal breathing in
utero
INTRODUCTION
IN chronic
preparations of fetal lambs and rabbits episodic breathing occurs normally in utero, 1,2and work in sheep has indicated that such breathing is a good indicator of fetal health.33 Observations of fetal lambs delivered into a warm saline bath have shown that breathing movements are associated with alterations in the shape of the fetal chest 1; we describe here the detection of these changes using an ultrasonic A-scan. MATERIALS AND METHODS
diagnostic sounder (Hewlett Packard model 7214A) used on four chronic fetal lamb preparations and seven pregnant women. The ultrasonic source had a 2 mW per sq.cm. average power and a 500 Hz pulse repetition-rate delivered via a 2-5 MHz frequency transducer within. A water(12-5 mm.) lead-zirconate-titanate crystal. soluble transmission gel (’Aquasonic 100’) was used to form the coupling medium. Recording periods varied from 30 to 120 minutes. The techniques for the chronic sheep preparations A
was