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Atherosclerosis in diabetes mellitus
I 10
J Chran Dis Vol 34. pp 4 Perpmon Presr Lid 19X1 Prmted in Great Brttain
Editorial ATHEROSCLEROSIS
IN DIABETES
MELLITUS
JOHN A. COLWELL* V.A. Medical Center and Endocrinology-Metabolism-Nutrition Division, Department of Medicine, Medical University of South Carolina, Charleston. SC 29403, U.S.A. (Receioed 3 Februury
1980)
INSULIN-DEPENDENT diabetes mellitus is characterized by a progressive form of microvascular disease which typically affects the retina, kidneys, toes and small vessels in virtually every organ. This disorder proceeds as a function of the duration of diabetes in most cases, and appears to bear a clear relationship to metabolic control of the disorder. Similar findings in the microcirculation occur in non insulin-dependent diabetes of long duration. In addition to this typical problem of microvascular disease, both major types of diabetics are characterized by an accelerated form of atherosclerosis. Typically, this appears after many years of insulin-dependent diabetes and is usually recognized long after microvascular disease is apparent. In contrast, the non insulin-dependent patient frequently presents with atherosclerosis of the coronary or peripheral vessels relatively early in the course of known diabetes. In spite of these rather obvious clinical facts, relatively little work had been done on the pathogenesis of atherosclerosis in the diabetic state until recently. An increased understanding of some of the reasons for accelerated atherosclerosis in diabetes is now emerging. Ross and Glomset [l] have proposed that the process of atherosclerosis is initiated by endothelial injury, followed by platelet adhesion and aggregation at the site of the injury. Platelets release intracellular material(s) which stimulate smooth muscle cell migration into the area of injury. Lipids are deposited from circulating lipoproteins in the area, and a connective tissue matrix of collagen, elastic fiber proteins and glycosaminoglycans is formed. The process may be arrested at any stage, or it may proceed to plaque formation, intimal closure and thrombosis. It is now apparent that diabetes has abnormalities in many steps of this process. In particular, endothelial and platelet malfunction and lipoprotein disturbances are present. Endothelial injury is suggested by high plasma levels of von Willebrand factor [2,3], a glycoprotein found only in endothelial cells, platelets and megakaryocytes. Some evidence suggests that this platelet-active protein may be an important contributor to the atherosclerotic process [4]. An altered endothelial barrier to plasma proteins is indicated by studies showing leakage of fluorescein into the vitreous in the diabetic state [5]. The presence of the enzyme aldose reductase in the endothelium [6] suggests that accumulation of the sugar alcohol sorbitol may occur, just as it does in lens and in nervous tissue in the presence of hyperglycemia. It has been suggested that sorbitol accumulation may be involved in cataract formation and neuropathy. Thus, biochemical, functional and physiological abnormalities of the endothelium appear to be part of the diabetic state.
*Supported by V.A. Institutional Research Funds and NIGMS Grant 20387. Dr Colwell is Associate Chief of Staff for Research and Development at the Charleston V.A. Medical Center and Director, EndocrinologyMetabolism-Nutrition Division. Department of Medicine. Medical University of South Carolina. I71 Ashley Ave. Charleston, SC 29403 U.S.A. Reprint requests should be directed to him at that address. c-0341
A
1
2
JOHN A. COLWELI
Similarly, platelet function is altered in diabetes mellitus [7,8]. Older studies showing heightened platelet adhesiveness in diabetes have been extended by many studies showing increased sensitivity to aggregating agents in uirro. Reviews have been published [7,8]. The biochemical pathways responsible for this hypersensitivity have now been defined. Platelets from diabetics produce more prostaglandin E2 [9], Fz, [lo], malonyldialdehyde [l I] and thromboxane [12] than control platelets, when stimulated with arachidonic acid. Thromboxane is the most potent pro-aggregating prostaglandin metabolite known, and is the prostaglandin metabolite which is primarily responsible for hypersensitivity to platelet aggregating agents in diabetics. It is now recognized that the healthy endothelium will attempt to counter-regulate against local platelet deposition by manufacturing another prostaglandin, prostacyclin, a potent vasodilator and platelet de-aggregator [ 13,141. Several studies have shown that endothelial release of prostacyclin is impaired in the diabetic state [IS, 161. Thus, diabetes is characterized by endothelial damage, platelet hyperaggregability and a diminished capacity to counter-regulate against platelet deposition on damaged endothelium. An important consideration is whether these abnormalities precede vascular disease, are a result of established vascular disease or bear no relationship to vascular disease. Evidence is mounting which indicates that platelet hyperfunction precedes the development of vascular disease. In early studies, we suspected that this was the case, since we found platelet hypersensitivity and increased platelet prostaglandin Ez production in insulin-deficient patients without clinically apparent vascular disease [3,9,17]. More definitive evidence, however, is provided by studies showing increasing platelet prostaglandin release in juvenile-onset patients of short duration [lo] and platelet hyperfunction and heightened prostaglandin production in animal models of diabetes [18]. While vascular injury may be present in these short-term models, it is unlikely that any significant degree of atherosclerosis or thrombosis is present. These findings suggest that some metabolic or hormonal consequence of insulin deficiency may lead to altered platelet metabolism and function in diabetes mellitus. Established vascular disease has been shown to compromise platelet function[19,20]. As already noted, accelerated vascular disease is characteristic of diabetes. In the diabetic, therefore, platelet functional abnormalities could contribute to, as well as result from, vascular disease. There are no published studies of platelet mitogenic activity in diabetics, and smoothmuscle response to platelet factors has not been investigated in the diabetic state. However, an explosion of new information on plasma lipid and lipoprotein metabolism in diabetes is now helping to unravel other reasons for accelerated atherosclerosis in that disorder, While this exhaustive literature cannot be reviewed here, it should be noted that it has long been recognized that the poorly controlled diabetic may have elevated plasma triglyceride and cholesterol levels. In many of these patients with high plasma triglyceride levels, there is a predictable depression of the plasma level of HDL-cholesterol. In addition, some maturity-onset diabetic patients have low HDL-cholesterol levels with normal cholesterol and triglyceride concentrations [21]. The resulting high cholesterol to HDLcholesterol ratio favors the deposition of cholesterol in tissues. It is likely that this is a major cause of accelerated atherosclerosis in diabetes. It must be recognized that this scheme may represent only a fragment of the important influences in the atherosclerotic process. Thus, obesity, hypertension, cigarette smoking, personality traits, genetic influences, vascular-wall metabolism, the coagulation system, blood supply to the vessels and a variety of other influences may be operative in the diabetic as in the nondiabetic individual. Nevertheless, these observations have led to the idea that modification of platelet prostaglandin metabolism and circulating lipids and lipoproteins in diabetics may be useful in the prophylaxis of atherosclerosis in diabetes. Platelet synthesis of thromboxane can be blocked with low doses of aspirin t-22-241. This is the rationale for many trials with aspirin in the prevention of vascular disease. There are two ongoing studies in diabetics which are designed to explore the hypothesis that aspirin therapy will delay the rate of progression of atherosclerosis of the lower extremity or microvascular disease of the retinain that disorder. The discovery of prosta-
3
Atherosclerosis in Diabetes Mellitus
however, has suggested that a careful look must be directed at aspirin dosage to be used in such studies. Moderate daily doses of aspirin (8 mg/kg/day) have been shown to markedly suppress prostacyclin release in normal volunteers [25]. Lower doses (3.5 mg/kg/day) given every 3 days will block platelet thromboxane production, but have little or no effect on endothelial prostacyclin release [25]. This is only about threefourths of one standard aspirin tablet! Thus, studies which have chosen a typical dosage of aspirin such as one tablet three times daily may not be effective, if prostacyclin is a critical regulator of platelet deposition on endothelium. On the other hand, there are few
cyclin,
studies studies
which would
address
this
problem
in patients
with
established
vascular
disease.
Such
be more relevant to the problem than studies in normal volunteers. It is not yet clear whether careful metabolic control with insulin will improve platelet function in man. Encouraging early results in animal models with insulin therapy [18] or pancreatic islet transplantation [26] suggest, however, that both platelet hyperaggregation and platelet and endothelial prostaglandin metabolism may be improved towards normal by tight metabolic control. Carefully designed prospective studies on this important area are needed in man. The story is promising in regard to therapy directed at the lipid disorders characteristic of the diabetic state. Longitudinal studies have now shown that precise control of the insulin-dependent diabetic will return elevated plasma levels of cholesterol, LDLcholesterol and VLDL-cholesterol to normal [27]. Simultaneously, the low HDL-cholesterol levels will rise and the cholesterol to HDL-cholesterol ratio will become normal. Cross-sectional studies in insulin-dependent patients suggest that reasonably good control is all that is needed to normalize or elevate HDL-cholesterol levels [28]. The situation may be more complicated in non insulin-dependent diabetes, but the same trends are apparent. Co-existence of a primary lipoprotein disorder in either group may require dietary control and lipid-lowering agents. It is thus apparent that great strides have been made in our understanding of atherosclerosis in diabetes mellitus. It is intriguing to speculate that careful metabolic control may be an important factor in preventing atherosclerosis in diabetes, at least as it may relate to altered lipid and lipoprotein metabolism. Previous studies have strongly suggested that careful metabolic control may delay or prevent the progression of microvascular disease in diabetes. Thus, continued attempts to mimic the normal endogenous insulin secretory pattern of the pancreas, as suggested a decade ago in this journal [29]. are indicated. Such studies now have high priority in a number of major medical centers lI301.
10
REFERENCES Ross R. Glomset JA: The pathogenesis of artherosclerosis. New Eng J Med 295: 42W25, 1975 Pandolfi M. Elmer L. Holmbere L: Increased von Willebrand antihemoohilic factor A in diabetic retinopathy. Acta Ophthal 52: 823-828, 1974 Colwell JA, Halushka PV, Sarji K et al.: Altered platelet function in diabetes mellitus. Diabetes 25 (Suppl 2): 826831, 1976 Fuster V, Bowie EJW, Lewis JC er a/.: Resistance to arteriosclerosis in pigs with von Willebrand’s disease. J CIin Invest 61: 722-730, 1978 Cunha-Vaz JG, Faria de Abreau JR, Campos AJ et ul.: Early breakdown of the blood&etinal barrier m diabetes. Br J Ophthal 59: 649-656, 1975 Ludvigson MA, Sorenson RL: Immunohistochemical localization of aldose reductase in the rat. Diabetes (Suppl. 2) 27: 463, 1978 Colwell JA. Halushka PV. Sarji KE, Sage1 J: Platelet function and diabetes mellitus. Med Clin N Am 62: 753-756, 1978 Colwell JA, Halushka PV, Sarji KE er al.: Vascular disease in diabetes. Arch Int Med 139: 225.-230. 1979 Halushka PV, Lurie D, Colwell JA: Increased synthesis of prostaglandin E-like material by platelets from patients with diabetes mellitus. New Eng J Med 297: 1306-1310. 1977 Chase HP, Williams RL. DuPont J: Increased prostaglandin synthesis in childhood diabetes mellitus. J
11
Pediat 94: 185-189, 1979 Stuart MJ, Elrod H, Graeber JL, Hakanson
I 2 3. 4. 5. 6 7. 8 9
12
DO, Barvinchak MK: Increased synthesis of prostaglandin endoperoxides and platelet hyperfunction in infants of mothers with diabetes mellitus. J Lab Clin Med 94: 12-17, 1979 Halushka PV. Colwell JA, Rogers C et al.: Increased thromboxane synthesis by platelets from patients with diabetes mellitus: studies with a thromboxane synthetase inhibitor and a thomboxane antagonist. Clin Res 27: 296A. 1979
JOHN A. COLWELL.
4
Moncada S. Cryglewski R. Bunting S cr ol.: An enzyme isolated from arteries transforms prostaglandin endoperoxides lo an unstable substance that inhibits platelet aggregation. Nature 263: 663-665. 1976 14. Moncada S. Higgs EA. Vane JR: Human arterial and venous tissues generate prostacyclin (prostaglandin X). a potent inhibitor of platelet aggregation. Lance1 I : 18-21. 1977 15. Silberbauer K. Schernthaner G, Sinzinger H et al.: Decreased vascular prostacyclin in juvenile-onset diabetes. New Eng J Med 300: 366-367. 1979 16. Harrison H. Reece AH, Johnson M: Decreased vascular prostacyclin in experimental diabetes. Life Sci 23: 13.
35lm-356. 1978
17. Sage1 J. Colwell JA, Crook L rr ul.: Increased platelet aggregation in early diabetes mellitus. Ann Int Med 82:733-738,
1975
18. Johnson M, Harrison HE: Platelet abnormalities
in experimental diabetes. Thromb
Haemostss
42: 333.
1979 Salky M. Dugdale M: Platelet abnormalities
19. in ischemic heart disease. Am J Cardiol 32: 612-617. 1973 20. Green LH, Seroppian E. Handin RI: Platelet activation during exercise-induced myocardial ischemia New Eng J Med 302: 193-197, 1980 21. Lopes-Virella MFL, Stone PG. Colwell JA: Serum high density lipoprotein in diabetic patients. Diabetologia 13: 285-291. 1977 Smith JB, Willis AL: Aspirin selectively inhibits prostaglandin
production in human platelets. Nature 231 : 235-237, 197I 23. Roth GJ, Stanford N. Majerus PW: Acetylation of prostaglandin synthetase by aspirin. Proc Natn Acad
22.
!%i 72: 3073-3076.
24.
624-632,
25. 26. 27. 28.
29. 30.
1975
Roth GJ, Majerus PW: The mechanism of the effect of aspirin in human platelets. J Clin Invest 56: 1975
Masotti G. Eoggesi L. Galanti G er rrl.: Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet 2: 143-146, 1979 Gerrard JM. Stuart MH. Gundy HR et trl.: Alteration in the balance of prostaglandin and thromboxane synthesis in diabetes. Clin Res 27: 7OOA,1979 Lopes-Virella MF. Wohltmann H: Plasma high density lipoprotein cholesterol (HDL-CHOL) increases with control in insulin-dependent young male diabetics. Diabetes 28: 348. 1979 Nikkila EA. Hormila P: Serum lipids and lipoproteins in insulin treated diabetics. Demonstration of increased high density lipoprotein concentrations. Diabetes 27: 1078-1086. 1978 Colwell JA: Do we need a new way lo treat diabetes mellitus? J Cbron Dis 23: 209-212. 1970 Santiago JV, Clemens AH, Clarke WL, Kipnis DM: Closed-loop and open-loop devices for blood glucose control in normal and diabetic subjects. Diabetes 28: 71-84, 1980
J Chran Dis Vol 34. pp 4 Perpmon Presr Lid 19X1 Prmted in Great Brttain
Editorial ATHEROSCLEROSIS
IN DIABETES
MELLITUS
JOHN A. COLWELL* V.A. Medical Center and Endocrinology-Metabolism-Nutrition Division, Department of Medicine, Medical University of South Carolina, Charleston. SC 29403, U.S.A. (Receioed 3 Februury
1980)
INSULIN-DEPENDENT diabetes mellitus is characterized by a progressive form of microvascular disease which typically affects the retina, kidneys, toes and small vessels in virtually every organ. This disorder proceeds as a function of the duration of diabetes in most cases, and appears to bear a clear relationship to metabolic control of the disorder. Similar findings in the microcirculation occur in non insulin-dependent diabetes of long duration. In addition to this typical problem of microvascular disease, both major types of diabetics are characterized by an accelerated form of atherosclerosis. Typically, this appears after many years of insulin-dependent diabetes and is usually recognized long after microvascular disease is apparent. In contrast, the non insulin-dependent patient frequently presents with atherosclerosis of the coronary or peripheral vessels relatively early in the course of known diabetes. In spite of these rather obvious clinical facts, relatively little work had been done on the pathogenesis of atherosclerosis in the diabetic state until recently. An increased understanding of some of the reasons for accelerated atherosclerosis in diabetes is now emerging. Ross and Glomset [l] have proposed that the process of atherosclerosis is initiated by endothelial injury, followed by platelet adhesion and aggregation at the site of the injury. Platelets release intracellular material(s) which stimulate smooth muscle cell migration into the area of injury. Lipids are deposited from circulating lipoproteins in the area, and a connective tissue matrix of collagen, elastic fiber proteins and glycosaminoglycans is formed. The process may be arrested at any stage, or it may proceed to plaque formation, intimal closure and thrombosis. It is now apparent that diabetes has abnormalities in many steps of this process. In particular, endothelial and platelet malfunction and lipoprotein disturbances are present. Endothelial injury is suggested by high plasma levels of von Willebrand factor [2,3], a glycoprotein found only in endothelial cells, platelets and megakaryocytes. Some evidence suggests that this platelet-active protein may be an important contributor to the atherosclerotic process [4]. An altered endothelial barrier to plasma proteins is indicated by studies showing leakage of fluorescein into the vitreous in the diabetic state [5]. The presence of the enzyme aldose reductase in the endothelium [6] suggests that accumulation of the sugar alcohol sorbitol may occur, just as it does in lens and in nervous tissue in the presence of hyperglycemia. It has been suggested that sorbitol accumulation may be involved in cataract formation and neuropathy. Thus, biochemical, functional and physiological abnormalities of the endothelium appear to be part of the diabetic state.
*Supported by V.A. Institutional Research Funds and NIGMS Grant 20387. Dr Colwell is Associate Chief of Staff for Research and Development at the Charleston V.A. Medical Center and Director, EndocrinologyMetabolism-Nutrition Division. Department of Medicine. Medical University of South Carolina. I71 Ashley Ave. Charleston, SC 29403 U.S.A. Reprint requests should be directed to him at that address. c-0341
A
1
2
JOHN A. COLWELI
Similarly, platelet function is altered in diabetes mellitus [7,8]. Older studies showing heightened platelet adhesiveness in diabetes have been extended by many studies showing increased sensitivity to aggregating agents in uirro. Reviews have been published [7,8]. The biochemical pathways responsible for this hypersensitivity have now been defined. Platelets from diabetics produce more prostaglandin E2 [9], Fz, [lo], malonyldialdehyde [l I] and thromboxane [12] than control platelets, when stimulated with arachidonic acid. Thromboxane is the most potent pro-aggregating prostaglandin metabolite known, and is the prostaglandin metabolite which is primarily responsible for hypersensitivity to platelet aggregating agents in diabetics. It is now recognized that the healthy endothelium will attempt to counter-regulate against local platelet deposition by manufacturing another prostaglandin, prostacyclin, a potent vasodilator and platelet de-aggregator [ 13,141. Several studies have shown that endothelial release of prostacyclin is impaired in the diabetic state [IS, 161. Thus, diabetes is characterized by endothelial damage, platelet hyperaggregability and a diminished capacity to counter-regulate against platelet deposition on damaged endothelium. An important consideration is whether these abnormalities precede vascular disease, are a result of established vascular disease or bear no relationship to vascular disease. Evidence is mounting which indicates that platelet hyperfunction precedes the development of vascular disease. In early studies, we suspected that this was the case, since we found platelet hypersensitivity and increased platelet prostaglandin Ez production in insulin-deficient patients without clinically apparent vascular disease [3,9,17]. More definitive evidence, however, is provided by studies showing increasing platelet prostaglandin release in juvenile-onset patients of short duration [lo] and platelet hyperfunction and heightened prostaglandin production in animal models of diabetes [18]. While vascular injury may be present in these short-term models, it is unlikely that any significant degree of atherosclerosis or thrombosis is present. These findings suggest that some metabolic or hormonal consequence of insulin deficiency may lead to altered platelet metabolism and function in diabetes mellitus. Established vascular disease has been shown to compromise platelet function[19,20]. As already noted, accelerated vascular disease is characteristic of diabetes. In the diabetic, therefore, platelet functional abnormalities could contribute to, as well as result from, vascular disease. There are no published studies of platelet mitogenic activity in diabetics, and smoothmuscle response to platelet factors has not been investigated in the diabetic state. However, an explosion of new information on plasma lipid and lipoprotein metabolism in diabetes is now helping to unravel other reasons for accelerated atherosclerosis in that disorder, While this exhaustive literature cannot be reviewed here, it should be noted that it has long been recognized that the poorly controlled diabetic may have elevated plasma triglyceride and cholesterol levels. In many of these patients with high plasma triglyceride levels, there is a predictable depression of the plasma level of HDL-cholesterol. In addition, some maturity-onset diabetic patients have low HDL-cholesterol levels with normal cholesterol and triglyceride concentrations [21]. The resulting high cholesterol to HDLcholesterol ratio favors the deposition of cholesterol in tissues. It is likely that this is a major cause of accelerated atherosclerosis in diabetes. It must be recognized that this scheme may represent only a fragment of the important influences in the atherosclerotic process. Thus, obesity, hypertension, cigarette smoking, personality traits, genetic influences, vascular-wall metabolism, the coagulation system, blood supply to the vessels and a variety of other influences may be operative in the diabetic as in the nondiabetic individual. Nevertheless, these observations have led to the idea that modification of platelet prostaglandin metabolism and circulating lipids and lipoproteins in diabetics may be useful in the prophylaxis of atherosclerosis in diabetes. Platelet synthesis of thromboxane can be blocked with low doses of aspirin t-22-241. This is the rationale for many trials with aspirin in the prevention of vascular disease. There are two ongoing studies in diabetics which are designed to explore the hypothesis that aspirin therapy will delay the rate of progression of atherosclerosis of the lower extremity or microvascular disease of the retinain that disorder. The discovery of prosta-
3
Atherosclerosis in Diabetes Mellitus
however, has suggested that a careful look must be directed at aspirin dosage to be used in such studies. Moderate daily doses of aspirin (8 mg/kg/day) have been shown to markedly suppress prostacyclin release in normal volunteers [25]. Lower doses (3.5 mg/kg/day) given every 3 days will block platelet thromboxane production, but have little or no effect on endothelial prostacyclin release [25]. This is only about threefourths of one standard aspirin tablet! Thus, studies which have chosen a typical dosage of aspirin such as one tablet three times daily may not be effective, if prostacyclin is a critical regulator of platelet deposition on endothelium. On the other hand, there are few
cyclin,
studies studies
which would
address
this
problem
in patients
with
established
vascular
disease.
Such
be more relevant to the problem than studies in normal volunteers. It is not yet clear whether careful metabolic control with insulin will improve platelet function in man. Encouraging early results in animal models with insulin therapy [18] or pancreatic islet transplantation [26] suggest, however, that both platelet hyperaggregation and platelet and endothelial prostaglandin metabolism may be improved towards normal by tight metabolic control. Carefully designed prospective studies on this important area are needed in man. The story is promising in regard to therapy directed at the lipid disorders characteristic of the diabetic state. Longitudinal studies have now shown that precise control of the insulin-dependent diabetic will return elevated plasma levels of cholesterol, LDLcholesterol and VLDL-cholesterol to normal [27]. Simultaneously, the low HDL-cholesterol levels will rise and the cholesterol to HDL-cholesterol ratio will become normal. Cross-sectional studies in insulin-dependent patients suggest that reasonably good control is all that is needed to normalize or elevate HDL-cholesterol levels [28]. The situation may be more complicated in non insulin-dependent diabetes, but the same trends are apparent. Co-existence of a primary lipoprotein disorder in either group may require dietary control and lipid-lowering agents. It is thus apparent that great strides have been made in our understanding of atherosclerosis in diabetes mellitus. It is intriguing to speculate that careful metabolic control may be an important factor in preventing atherosclerosis in diabetes, at least as it may relate to altered lipid and lipoprotein metabolism. Previous studies have strongly suggested that careful metabolic control may delay or prevent the progression of microvascular disease in diabetes. Thus, continued attempts to mimic the normal endogenous insulin secretory pattern of the pancreas, as suggested a decade ago in this journal [29]. are indicated. Such studies now have high priority in a number of major medical centers lI301.
10
REFERENCES Ross R. Glomset JA: The pathogenesis of artherosclerosis. New Eng J Med 295: 42W25, 1975 Pandolfi M. Elmer L. Holmbere L: Increased von Willebrand antihemoohilic factor A in diabetic retinopathy. Acta Ophthal 52: 823-828, 1974 Colwell JA, Halushka PV, Sarji K et al.: Altered platelet function in diabetes mellitus. Diabetes 25 (Suppl 2): 826831, 1976 Fuster V, Bowie EJW, Lewis JC er a/.: Resistance to arteriosclerosis in pigs with von Willebrand’s disease. J CIin Invest 61: 722-730, 1978 Cunha-Vaz JG, Faria de Abreau JR, Campos AJ et ul.: Early breakdown of the blood&etinal barrier m diabetes. Br J Ophthal 59: 649-656, 1975 Ludvigson MA, Sorenson RL: Immunohistochemical localization of aldose reductase in the rat. Diabetes (Suppl. 2) 27: 463, 1978 Colwell JA. Halushka PV. Sarji KE, Sage1 J: Platelet function and diabetes mellitus. Med Clin N Am 62: 753-756, 1978 Colwell JA, Halushka PV, Sarji KE er al.: Vascular disease in diabetes. Arch Int Med 139: 225.-230. 1979 Halushka PV, Lurie D, Colwell JA: Increased synthesis of prostaglandin E-like material by platelets from patients with diabetes mellitus. New Eng J Med 297: 1306-1310. 1977 Chase HP, Williams RL. DuPont J: Increased prostaglandin synthesis in childhood diabetes mellitus. J
11
Pediat 94: 185-189, 1979 Stuart MJ, Elrod H, Graeber JL, Hakanson
I 2 3. 4. 5. 6 7. 8 9
12
DO, Barvinchak MK: Increased synthesis of prostaglandin endoperoxides and platelet hyperfunction in infants of mothers with diabetes mellitus. J Lab Clin Med 94: 12-17, 1979 Halushka PV. Colwell JA, Rogers C et al.: Increased thromboxane synthesis by platelets from patients with diabetes mellitus: studies with a thromboxane synthetase inhibitor and a thomboxane antagonist. Clin Res 27: 296A. 1979
JOHN A. COLWELL.
4
Moncada S. Cryglewski R. Bunting S cr ol.: An enzyme isolated from arteries transforms prostaglandin endoperoxides lo an unstable substance that inhibits platelet aggregation. Nature 263: 663-665. 1976 14. Moncada S. Higgs EA. Vane JR: Human arterial and venous tissues generate prostacyclin (prostaglandin X). a potent inhibitor of platelet aggregation. Lance1 I : 18-21. 1977 15. Silberbauer K. Schernthaner G, Sinzinger H et al.: Decreased vascular prostacyclin in juvenile-onset diabetes. New Eng J Med 300: 366-367. 1979 16. Harrison H. Reece AH, Johnson M: Decreased vascular prostacyclin in experimental diabetes. Life Sci 23: 13.
35lm-356. 1978
17. Sage1 J. Colwell JA, Crook L rr ul.: Increased platelet aggregation in early diabetes mellitus. Ann Int Med 82:733-738,
1975
18. Johnson M, Harrison HE: Platelet abnormalities
in experimental diabetes. Thromb
Haemostss
42: 333.
1979 Salky M. Dugdale M: Platelet abnormalities
19. in ischemic heart disease. Am J Cardiol 32: 612-617. 1973 20. Green LH, Seroppian E. Handin RI: Platelet activation during exercise-induced myocardial ischemia New Eng J Med 302: 193-197, 1980 21. Lopes-Virella MFL, Stone PG. Colwell JA: Serum high density lipoprotein in diabetic patients. Diabetologia 13: 285-291. 1977 Smith JB, Willis AL: Aspirin selectively inhibits prostaglandin
production in human platelets. Nature 231 : 235-237, 197I 23. Roth GJ, Stanford N. Majerus PW: Acetylation of prostaglandin synthetase by aspirin. Proc Natn Acad
22.
!%i 72: 3073-3076.
24.
624-632,
25. 26. 27. 28.
29. 30.
1975
Roth GJ, Majerus PW: The mechanism of the effect of aspirin in human platelets. J Clin Invest 56: 1975
Masotti G. Eoggesi L. Galanti G er rrl.: Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet 2: 143-146, 1979 Gerrard JM. Stuart MH. Gundy HR et trl.: Alteration in the balance of prostaglandin and thromboxane synthesis in diabetes. Clin Res 27: 7OOA,1979 Lopes-Virella MF. Wohltmann H: Plasma high density lipoprotein cholesterol (HDL-CHOL) increases with control in insulin-dependent young male diabetics. Diabetes 28: 348. 1979 Nikkila EA. Hormila P: Serum lipids and lipoproteins in insulin treated diabetics. Demonstration of increased high density lipoprotein concentrations. Diabetes 27: 1078-1086. 1978 Colwell JA: Do we need a new way lo treat diabetes mellitus? J Cbron Dis 23: 209-212. 1970 Santiago JV, Clemens AH, Clarke WL, Kipnis DM: Closed-loop and open-loop devices for blood glucose control in normal and diabetic subjects. Diabetes 28: 71-84, 1980