16
The complete diabetic metabolic syndrome may thus be a consequence of deranged function of both the a and /3 cells. Perhaps therapy directed at correcting the a-cell abnormality through control of glucagon secretion will improve present methods of
therapeutic glucoregulation. Requests for reprints should be addressed
to R.
PLASMA-HIGH-DENSITY-LIPOPROTEIN CONCENTRATION AND DEVELOPMENT OF ISCHÆMIC HEART-DISEASE G. J. MILLER Medical Research Council Pneumoconiosis Unit,
Llandough Hospital, Penarth, South Wales
H. U., 4500
S. Lancaster Road, Dallas, Texas 75216, U.S.A.
N. E. MILLER
Department of Cardiology and Lipid Research Laboratory, REFERENCES 1.
2. 3. 4.
5. 6. 7. 8. 9. 10.
11.
12. 13.
von
Royal Infirmary, Edinburgh, Scotland
Mering, J., Minkowski, O. Arch. exp. Path. Pharmak. 1889,
26, 371. Banting, F. G., Best, C. H. J. Lab. clin. Med. 1922, 7, 251. Aguilar-Parada, E., Eisentraut, A. M., Unger, R. H. Am. J. med. Sci. 1969, 257, 415. Unger, R. H., Aguilar-Parada, E., Muller, W. A., Eisentraut, A. M. J. clin. Invest. 1970, 49, 837. Muller, W. A., Faloona, G. R., Aguilar-Parada, E., Unger, R. H. New Engl. J. Med. 1970, 283, 109. Unger, R. H., Madison, L. L., Muller, W. A. Diabetes, 1972, 21, 301. Buchanan, K. D., McCarroll, A. M. Lancet, 1972, ii, 1394. Frankel, B. J., Gerich, J. E., Ryoko, H., Fanska, R. E., Gerritsen, G. C., Grodsky, G. M. J. clin. Invest. 1974, 53, 1637. Muller, W. A., Faloona, G. R., Unger, R. H. ibid. 1971, 50, 1992. Meier, J. M., McGarry, J. D., Faloona, G. R., Unger, R. H., Foster, D. J. Lipid Res. 1972, 13, 228. Katsilambros, N. Y., Abdel, R., Minz, M., Fussganger, K. E., Schroder, K. E., Straub, K., Pfeiffer, E. F. Horm. metab. Res. 1970, 2, 268. Amherdt, M., Harris, V., Renold, A. E., Orci, L., Unger, R. H. J. clin. Invest. 1974, 54, 188. Samols, E., Tyler, J. M., Kajinuma, H. in Proceedings of the Seventh
Congress
of the
International Diabetes
Federation
(edited by R. R. Rodriguez and J. Vallance-Owen); p. 636. Amsterdam, 1971. 14. Lindsey, C. A., Santeusanio, F., Braaten, J., Faloona, G. R., Unger, R. H. J. Am. med. Ass. 1974, 227, 757. 15. Wilmore, D. W., Lindsey, C. A., Moylan, J. A., Faloona, G. R., Pruitt, B., Unger, R. H. Lancet, 1974, i, 73. 16. Willerson, J. T., Hutcheson, D., Leshin, S. J., Faloona, G. R., Unger, R. H. Am. J. Med. 1974, 57, 747. 17. Lindsey, C. A., Faloona, G. R., Unger, R. H. Diabetes (in the press). 18. Pek, S., Vranic, M., Kawamori, R. Program of the Fifth Annual Meeting of the Endocrine Society, 1974 (abst. 176). 19. Matsuyama, T., Foa, P. P. Diabetes, 1974, 23 (suppl. 1), 344. 20. Mashiter, G. D., Harding, P. E., Chou, M., Stout, J., Diamond, D., Field, J. B. Endocrinology (in the press). 21. Dobbs, R. E., Sakurai, H., Sasaki, H., Faloona, G. R., Valverde, I., Baetens, D., Orci, L., Unger, R. H. Science (in the press). 22. Sasaki, H., Rubalcava, B., Baetens, D., Srikant, C. B., Orci, L., Unger, R. H. Unpublished. 23. Sasaki, H., Rubalcava, B., Srikant, C. B., Blazquez, E., Faloona, G. R., Unger, R. H. Unpublished. 24. Brazeau, P., Vale, W., Burgus, R., Ling, N., Butcher, M., Rivier, J., Guillemin, R. Science, 1973, 179, 77. 25. Mortimer, C. H., Tunbridge, W. M. G., Carr, D., Yeomans, L., Lind, T., Doy, D. H., Bloom, S. R., Kastin, A., Mallinson, C. N., Besser, G. M., Schally, A. V., Hall, R. Lancet, 1974, i, 697. 26. Koerker, D. J., Ruch, W., Chideckel, E., Palmer, J., Goodner, C. J., Ensinck, J., Gale, C. C. Science, 1974, 184, 482. 27. Alberti, K. G. M. M., Christensen, N. J., Christensen, S. E., Hansen, Aa. P., Iversen, J., Lunbæk, K., Seyer-Hansen, K., Ørskov, H. Lancet, 1973, ii, 1299. 28. Goodner, C. J., Ensinck, J. W., Chideckel, E., Palmer, J., Koerker, D. J., Ruch, W., Gale, C. C. J. clin. Invest. 1974, 53, 28 (abst.). 29. Sakurai, H., Dobbs, R. E., Unger, R. H. ibid. 1974, 54, 1395. 30. Alford, F. P., Bloom, S. R., Nabarro, J. D. N., Hall, R., Besser, G. M., Cay, D. H., Kastin, A. J., Schally, A. V. Lancet, 1974, ii, 974. 31. Vranic, M. in Insulin Action (edited by I. B. Fritz); p. 529. New York, 1972. 32. Liljenquist, J. E., Bomboy, J. D., Lewis, S. B., Sinclair-Smith, B. C., Felts, P. W., Lacy, W. W., Crofford, O. B., Liddle, W. J. clin. Invest. 1974, 53, 190. 33. Glinsman, W. H., Mortimore, G. E. Am. J. Physiol. 1968, 215, 553. 34. Mackrell, D. J., Sokal, J. E. Diabetes, 1969, 18, 724. 35. Gerich, J. E., Lorenzi, M., Schneider, V., Karam, J. H., Rivier, J., Guillemin, R., Forsham, P. H. New Engl. J. Med. 1974, 291, 544. 36. Dobbs, R., Sakurai, H., Unger, R. H. Clin. Res. 1974, 22, 648A. 37. Madison, L. L., Combes, B., Adams, R., Strickland, W. J. clin. Invest. 1960, 39, 507. 38. Ohneda, A., Aguilar-Parada, E., Eisentraut, A. M., Unger, R. H. Diabetes, 1969, 18, 1. 39. Alberti, K. G. M. M., Iversen, J., Christensen, N. J. Diabetologia, 1974, 10, 357. 40. McGarry, J. D., Foster, D. W. Personal communication.
body cholesterol pool increases decreasing plasma-high-densitylipoprotein (H.D.L.), but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. This finding supports existing evidence that H.D.L. facilitates the uptake of cholesterol from peripheral Summary
The with
tissues and its transport to the liver for catabolism and excretion. Plasma-H.D.L. is reduced in several conditions associated with an increased risk of future ischæmic heart-disease (I.H.D.), namely hypercholesterolæmia, hypertriglyceridæmia, male sex, obesity, and diabetes mellitus, while subjects with existing clinical I.H.D. have lower levels of H.D.L. than healthy subjects within the same community. It is proposed that a reduction of plasma-H.D.L. concentration may accelerate the development of atherosclerosis, and hence I.H.D., by impairing the clearance of cholesterol from the arterial wall. INTRODUCTION
CORONARY atherosclerosis, the major cause of ischaemic heart-disease (I.H.D.), is characterised histologically by the accumulation of lipid, predominantly cholesterol, in the arterial wall together with a local connective-tissue reaction 1 However, the origin of the cholesterol and the cause of its accumulation remain uncertain. Although there is evidence that this may be due, at least in part, to the filtration into the arterial intima of cholesterol-rich low-density lipoprotein (L.D.L.) from plasma,2 the possible contributions of local synthesis and of impaired clearance of cholesterol from the arterial wall have not been resolved. It has been suggested that the transport of cholesterol from peripheral tissues to the liver, for subsequent catabolism and excretion, may be a function of plasmahigh-density-lipoprotein (H.D.L.).3 We present new evidence for the regulation of tissue-cholesterol pools by H.D.L., and draw attention to the association of low plasma-H.D.L. concentrations with clinical I.H.D. and with several coronary risk factors. It is suggested that a reduction in plasma-H.D.L. may impair the normal clearance of cholesterol from the arterial wall and thereby accelerate the development of atherosclerosis. H.]Y.L.
AND
TISSUE
CHOLESTEROL
Tissue cholesterol pools, measured indirectly by isotope dilution 9 or directly by chemical analysis,lo,n have been reported to be unrelated or only weakly related to the plasma concentration of total cholesterol in man. However, the possibility that tissue cholesterol might be correlated with the concentration of individual plasmalipoproteins has not been explored. The opportunity to examine this question was recently presented by the
17
parallel study
of
plasma-lipoprotein
concentrations and
Males, r=-0·70 p < 0’001,52 groups 0--- Females,I’=-0’33 p
The complete diabetic metabolic syndrome may thus be a consequence of deranged function of both the a and /3 cells. Perhaps therapy directed at correcting the a-cell abnormality through control of glucagon secretion will improve present methods of
therapeutic glucoregulation. Requests for reprints should be addressed
to R.
PLASMA-HIGH-DENSITY-LIPOPROTEIN CONCENTRATION AND DEVELOPMENT OF ISCHÆMIC HEART-DISEASE G. J. MILLER Medical Research Council Pneumoconiosis Unit,
Llandough Hospital, Penarth, South Wales
H. U., 4500
S. Lancaster Road, Dallas, Texas 75216, U.S.A.
N. E. MILLER
Department of Cardiology and Lipid Research Laboratory, REFERENCES 1.
2. 3. 4.
5. 6. 7. 8. 9. 10.
11.
12. 13.
von
Royal Infirmary, Edinburgh, Scotland
Mering, J., Minkowski, O. Arch. exp. Path. Pharmak. 1889,
26, 371. Banting, F. G., Best, C. H. J. Lab. clin. Med. 1922, 7, 251. Aguilar-Parada, E., Eisentraut, A. M., Unger, R. H. Am. J. med. Sci. 1969, 257, 415. Unger, R. H., Aguilar-Parada, E., Muller, W. A., Eisentraut, A. M. J. clin. Invest. 1970, 49, 837. Muller, W. A., Faloona, G. R., Aguilar-Parada, E., Unger, R. H. New Engl. J. Med. 1970, 283, 109. Unger, R. H., Madison, L. L., Muller, W. A. Diabetes, 1972, 21, 301. Buchanan, K. D., McCarroll, A. M. Lancet, 1972, ii, 1394. Frankel, B. J., Gerich, J. E., Ryoko, H., Fanska, R. E., Gerritsen, G. C., Grodsky, G. M. J. clin. Invest. 1974, 53, 1637. Muller, W. A., Faloona, G. R., Unger, R. H. ibid. 1971, 50, 1992. Meier, J. M., McGarry, J. D., Faloona, G. R., Unger, R. H., Foster, D. J. Lipid Res. 1972, 13, 228. Katsilambros, N. Y., Abdel, R., Minz, M., Fussganger, K. E., Schroder, K. E., Straub, K., Pfeiffer, E. F. Horm. metab. Res. 1970, 2, 268. Amherdt, M., Harris, V., Renold, A. E., Orci, L., Unger, R. H. J. clin. Invest. 1974, 54, 188. Samols, E., Tyler, J. M., Kajinuma, H. in Proceedings of the Seventh
Congress
of the
International Diabetes
Federation
(edited by R. R. Rodriguez and J. Vallance-Owen); p. 636. Amsterdam, 1971. 14. Lindsey, C. A., Santeusanio, F., Braaten, J., Faloona, G. R., Unger, R. H. J. Am. med. Ass. 1974, 227, 757. 15. Wilmore, D. W., Lindsey, C. A., Moylan, J. A., Faloona, G. R., Pruitt, B., Unger, R. H. Lancet, 1974, i, 73. 16. Willerson, J. T., Hutcheson, D., Leshin, S. J., Faloona, G. R., Unger, R. H. Am. J. Med. 1974, 57, 747. 17. Lindsey, C. A., Faloona, G. R., Unger, R. H. Diabetes (in the press). 18. Pek, S., Vranic, M., Kawamori, R. Program of the Fifth Annual Meeting of the Endocrine Society, 1974 (abst. 176). 19. Matsuyama, T., Foa, P. P. Diabetes, 1974, 23 (suppl. 1), 344. 20. Mashiter, G. D., Harding, P. E., Chou, M., Stout, J., Diamond, D., Field, J. B. Endocrinology (in the press). 21. Dobbs, R. E., Sakurai, H., Sasaki, H., Faloona, G. R., Valverde, I., Baetens, D., Orci, L., Unger, R. H. Science (in the press). 22. Sasaki, H., Rubalcava, B., Baetens, D., Srikant, C. B., Orci, L., Unger, R. H. Unpublished. 23. Sasaki, H., Rubalcava, B., Srikant, C. B., Blazquez, E., Faloona, G. R., Unger, R. H. Unpublished. 24. Brazeau, P., Vale, W., Burgus, R., Ling, N., Butcher, M., Rivier, J., Guillemin, R. Science, 1973, 179, 77. 25. Mortimer, C. H., Tunbridge, W. M. G., Carr, D., Yeomans, L., Lind, T., Doy, D. H., Bloom, S. R., Kastin, A., Mallinson, C. N., Besser, G. M., Schally, A. V., Hall, R. Lancet, 1974, i, 697. 26. Koerker, D. J., Ruch, W., Chideckel, E., Palmer, J., Goodner, C. J., Ensinck, J., Gale, C. C. Science, 1974, 184, 482. 27. Alberti, K. G. M. M., Christensen, N. J., Christensen, S. E., Hansen, Aa. P., Iversen, J., Lunbæk, K., Seyer-Hansen, K., Ørskov, H. Lancet, 1973, ii, 1299. 28. Goodner, C. J., Ensinck, J. W., Chideckel, E., Palmer, J., Koerker, D. J., Ruch, W., Gale, C. C. J. clin. Invest. 1974, 53, 28 (abst.). 29. Sakurai, H., Dobbs, R. E., Unger, R. H. ibid. 1974, 54, 1395. 30. Alford, F. P., Bloom, S. R., Nabarro, J. D. N., Hall, R., Besser, G. M., Cay, D. H., Kastin, A. J., Schally, A. V. Lancet, 1974, ii, 974. 31. Vranic, M. in Insulin Action (edited by I. B. Fritz); p. 529. New York, 1972. 32. Liljenquist, J. E., Bomboy, J. D., Lewis, S. B., Sinclair-Smith, B. C., Felts, P. W., Lacy, W. W., Crofford, O. B., Liddle, W. J. clin. Invest. 1974, 53, 190. 33. Glinsman, W. H., Mortimore, G. E. Am. J. Physiol. 1968, 215, 553. 34. Mackrell, D. J., Sokal, J. E. Diabetes, 1969, 18, 724. 35. Gerich, J. E., Lorenzi, M., Schneider, V., Karam, J. H., Rivier, J., Guillemin, R., Forsham, P. H. New Engl. J. Med. 1974, 291, 544. 36. Dobbs, R., Sakurai, H., Unger, R. H. Clin. Res. 1974, 22, 648A. 37. Madison, L. L., Combes, B., Adams, R., Strickland, W. J. clin. Invest. 1960, 39, 507. 38. Ohneda, A., Aguilar-Parada, E., Eisentraut, A. M., Unger, R. H. Diabetes, 1969, 18, 1. 39. Alberti, K. G. M. M., Iversen, J., Christensen, N. J. Diabetologia, 1974, 10, 357. 40. McGarry, J. D., Foster, D. W. Personal communication.
body cholesterol pool increases decreasing plasma-high-densitylipoprotein (H.D.L.), but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. This finding supports existing evidence that H.D.L. facilitates the uptake of cholesterol from peripheral Summary
The with
tissues and its transport to the liver for catabolism and excretion. Plasma-H.D.L. is reduced in several conditions associated with an increased risk of future ischæmic heart-disease (I.H.D.), namely hypercholesterolæmia, hypertriglyceridæmia, male sex, obesity, and diabetes mellitus, while subjects with existing clinical I.H.D. have lower levels of H.D.L. than healthy subjects within the same community. It is proposed that a reduction of plasma-H.D.L. concentration may accelerate the development of atherosclerosis, and hence I.H.D., by impairing the clearance of cholesterol from the arterial wall. INTRODUCTION
CORONARY atherosclerosis, the major cause of ischaemic heart-disease (I.H.D.), is characterised histologically by the accumulation of lipid, predominantly cholesterol, in the arterial wall together with a local connective-tissue reaction 1 However, the origin of the cholesterol and the cause of its accumulation remain uncertain. Although there is evidence that this may be due, at least in part, to the filtration into the arterial intima of cholesterol-rich low-density lipoprotein (L.D.L.) from plasma,2 the possible contributions of local synthesis and of impaired clearance of cholesterol from the arterial wall have not been resolved. It has been suggested that the transport of cholesterol from peripheral tissues to the liver, for subsequent catabolism and excretion, may be a function of plasmahigh-density-lipoprotein (H.D.L.).3 We present new evidence for the regulation of tissue-cholesterol pools by H.D.L., and draw attention to the association of low plasma-H.D.L. concentrations with clinical I.H.D. and with several coronary risk factors. It is suggested that a reduction in plasma-H.D.L. may impair the normal clearance of cholesterol from the arterial wall and thereby accelerate the development of atherosclerosis. H.]Y.L.
AND
TISSUE
CHOLESTEROL
Tissue cholesterol pools, measured indirectly by isotope dilution 9 or directly by chemical analysis,lo,n have been reported to be unrelated or only weakly related to the plasma concentration of total cholesterol in man. However, the possibility that tissue cholesterol might be correlated with the concentration of individual plasmalipoproteins has not been explored. The opportunity to examine this question was recently presented by the
17
parallel study
of
plasma-lipoprotein
concentrations and
Males, r=-0·70 p < 0’001,52 groups 0--- Females,I’=-0’33 p
