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Does increased leukotriene B4 in type 1 diabetes result from elevated cholesteryl ester transfer protein activity?
Medical Hypotheses (2002) 59(5), 607–610 ª 2002 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-9877(02)00216-5, available online at http://www.idealibrary.com
Does increased leukotriene B4 in type 1 diabetes result from elevated cholesteryl ester transfer protein activity? C.-K. Chang,1 T. K. Tso,2,1 J. T. Snook,2 Y.-S. Huang3 1
Department of Nutrition and Health Science, Fooyin Institute of Technology, Kaohsiung, Taiwan; 2OSU Nutrition Program, Ohio State University, Columbus, Ohio, USA; 3Medical Nutritional R&D, Ross Products Division, Abbott Laboratories, Columbus, Ohio, USA
Summary Elevated cholesteryl ester transfer protein (CETP) activity has been reported in type 1 diabetic subjects and may be one cause of the high incidence of macrovascular complications in these patients. LDL delivers arachidonic acid (AA), in the form of cholesteryl ester (CE), to cells such as monocytes and fibroblasts, as precursor for eicosanoid synthesis. We discovered that AA content in LDL CE was significantly correlated with CETP activity, even after controlling for CETP concentration, in type 1 diabetic children. The production of LTB4 , a potent chemotactic and pro-inflammatory factor which plays a role in atherogenesis, has been shown to be increased in type 1 diabetic patients. We hypothesized that in these subjects, increased AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia, may lead to enhanced synthesis of LTB4 and subsequently the higher incidence of cardiovascular disease. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Plasma cholesteryl ester transfer protein (CETP) plays an important role in the continuous remodelling process of plasma lipoproteins. It facilitates the transfer of HDL cholesterol, mainly in the form of cholesteryl ester (CE) which is generated by the reaction of lecithin:cholesterol acyltransferase (LCAT), to apo B-containing lipoproteins (1). Through this reverse cholesterol transport process, peripheral tissue cholesterol can be redistributed for reutilization or to liver for excretion.
Received 5 March 2002 Accepted 8 May 2002 Correspondence to: Dr Jean T. Snook, OSU Nutrition Program, Ohio State University, 1787 Neil Ave, Columbus, OH 43210, USA. Phone: +1-614-2921680; Fax: +1-614-2928880; E-mail: [email protected] 1 Present address: Department of Food and Nutrition, Shih Chien University, Taipei, Taiwan.
It was reported that CETP activity was increased in type 1 diabetic subjects (2). The enhanced CETP activity has been suggested to be at least partially responsible for the high incidence of macrovascular complications in these patients (3), mainly because of its ability to decrease HDL cholesterol (4), which is generally believed to have a protective effect against atherosclerosis. Previously, we showed that increased CETP activity, combined with enhanced LCAT activity, resulted in the accumulation of LDL cholesterol in type 1 diabetic subjects (5). This may be partially responsible for atherogenesis in these subjects because high LDL cholesterol has long been recognized as a risk factor for coronary heart disease (6). However, the detailed mechanism as to how CETP increases the atherogenesis in type 1 diabetic patients remains to be elucidated. It has been shown that leukotriene (LT) B4 production was increased in both type 1 and 2 diabetic patients (7). LTB4 , synthesized through lipoxygenase pathway using arachidonic acid (AA) as the precursor (8), is one of the most potent naturally occurring leukocyte chemoattr-
607
608 Chang et al.
actants (9). Because of its pro-inflammatory effect and ability to promote adherence of neutrophils to endothelium, LTB4 has been suggested to be involved in atherogenesis (9–11). We hypothesized that higher AA content in LDL CE, resulting from elevated CETP activity, leads to increased LTB4 production in type 1 diabetic patients. Subsequently, it may promote atherogenesis in these subjects. ROLE OF LDL IN EICOSANOID PRODUCTION In a group of 35 type 1 diabetic children 12 males and 23 females, ages 5–12, we discovered that plasma CETP activity was positively correlated with AA in LDL CE (Fig. 1, Pearson’s correlation coefficient r ¼ 0:59, P < 0:01Þ. CETP activity was also positively correlated with plasma CETP concentration ðr ¼ 0:51, P < 0:01Þ (12). However, the correlation between AA in LDL CE and CETP activity remained significant even after adjusting statistically for CETP concentration. LDL is known to deliver AA, in the form of CE, to various cell types, including fibroblasts (13) and monocytes (14), as substrate for eicosanoid synthesis. This transportation is mediated by a LDL receptor-dependent mechanism (14). Migration of monocytes into the arterial wall is an important step of early development of atherosclerosis, as monocytes have been found in the very early stage of atherosclerotic lesions (15). After stimulating fibroblasts and monocytes with calcium ionophore A23187 or formyl-Met-Leu-Phe, LTB4 , a potent chemotactic and pro-inflammatory factor, was one of the dominant products of exogenous AA in the form of LDL CE (13, 14). Furthermore, LDL has been shown to stimulate LTB4 production by human leukocytes in vitro (16) and chemotactic response of monocytes (17). On the other hand, after inhibition of endosomal LDL degradation by chloroquine, or prostanoid synthesis by indomethacin or acetylsalicylic acid,
the stimulation effect of LDL was significantly reduced (17). In addition, production of LTB4 by calcium ionophore-stimulated neutrophils (18) and TXB2 by whole blood and platelet-rich plasma were lower in abetalipoproteinemic subjects (18,19). These data indicated that LDL plays an essential role in eicosanoid synthesis. CETP AND LTB4 PRODUCTION IN TYPE 1 DIABETES It has been demonstrated that CETP activity is higher in type 1 diabetic patients than normal subjects (2, 3). It was also reported that polymorphonuclear cells secreted more LTB4 with and without calcium ionophore stimulation in type 1 and 2 diabetic subjects compared to controls (7). In our type 1 diabetic subjects, the AA content in LDL CE was considerably higher than values published for nondiabetic adults in another study (20) (Table 1), although there were significant age differences between them. Furthermore, the increased AA content in LDL CE was significantly correlated with CETP activity in this group of diabetic children. Therefore, the increased LTB4 production in type 1 diabetic patients may at least partly result from higher AA content in LDL CE, induced by elevated CETP activity. ROLE OF INSULIN AND GLYCEMIC CONTROL IN LTB4 PRODUCTION Previously, we showed that in the same group of type 1 diabetic children, CETP activity was significantly higher in patients with high fasting plasma glucose (>6.39 mmol/L, 115 mg/dL) than in the ones with normal plasma glucose, suggesting the possible role of glycemic control in CETP activity and possibly LTB4 production
Table 1 Fatty acid composition of LDL CE in type 1 diabetic children (age 9:0 2:2 years, n ¼ 35) and nondiabetic adults (adapted from (20), age 58:4 1:6 years, n ¼ 34), presented as the percentage of total major identified fatty acids
Fig. 1 The correlation between plasma CETP activity and AA content in LDL CE in type 1 diabetic children. CETP activity was measured according to Chang et al. (12).
Medical Hypotheses (2002) 59(5), 607–610
Fatty acid
Diabetic children
Nondiabetic adults
C10:0 C12:0 C14:0 C16:0 C16:1x7 C18:0 C18:1x9 C18:2x6 C20:4x6
<0.1 0:85 0:57 1:52 0:74 25:03 5:36 3:84 1:36 2:57 0:85 28:96 9:37 18:52 10:98 14:42 3:88
– – 0:5 0:1 11:5 0:5 2:6 0:3 1:5 0:1 19:6 0:6 47:3 1:5 5:5 0:5
The data are expressed as means SD. CE was purified by thinlayer chromatography and transmethylated with BF3 –methanol (28) after total lipids were extracted from LDL according to the method of Folch et al. (29). The fatty acid methyl esters were analyzed by gas chromatography using a Hewlett Packard 5890 Series II with Omegawax320 column (Supelco, Bellefonte, PA, USA).
ª 2002 Elsevier Science Ltd. All rights reserved.
Increased leukotriene B4 in type 1 diabetes 609
(5). In agreement with our hypothesis, Parlapiano et al. (7) reported that LTB4 levels were positively correlated with HbA1c in diabetic subjects. It has been shown that insulin enhanced biosynthesis of AA through stimulation of D5- and D6-desaturase activities (21). In addition, insulin may directly increase CETP activity through positive regulation of lipoprotein lipase (22, 23). The accumulation of fatty acids on the surface of VLDL remnants after lipolysis increases the CETP activity by facilitating the binding of CETP to its substrate (24). Therefore, hyperinsulinemia caused by insulin injections may result in elevated CETP activity and AA availability, which then in combination may lead to higher AA content in LDL CE and greater delivery of AA for LTB4 synthesis. Thus, the transient hyperinsulinemia resulting from insulin injection may promote atherogenesis. This could be one of the reasons why intensive treatment in controlling blood glucose reduced the incidence of microvascular complications (25), but had little impact on macrovascular disease in type 1 diabetic patients (26, 27). Recently, intraperitoneal injection of insulin has been shown to reduce the exposure of peripheral tissues to hyperinsulinemia, while offering sufficient insulin level for glycemic control (23). As compared to traditional subcutaneous injection, the intraperitoneal route normalizes the accelerated LPL activity and CETP activity in type 1 diabetic patients (23), and may lead to lower AA availability and LTB4 production. Therefore, we hypothesized that elevated AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia in type 1 diabetic patients, may lead to enhanced synthesis of LTB4 . This may be one of the mechanisms that causes higher cardiovascular disease incidence in type 1 diabetic patients. Further investigations on eicosanoid synthesis by various cell types in diabetic subjects, as well as dietary interventions and intraperitoneal insulin injection modifying LDL CE lipid compositions and eicosanoid production, are warranted.
5.
6.
7.
8.
9. 10.
11. 12.
13.
14.
15. 16.
17.
18.
REFERENCES 1. Tall A. R. Plasma lipid transfer proteins. J Lipid Res 1986; 27: 361–367. 2. Bagdade J. D., Ritter M. C., Subbaiah P. V. Accelerated cholesteryl ester transfer in patients with insulin-dependent diabetes mellitus. Eur J Clin Invest 1991; 21: 161–167. 3. Dullaart R. P., Groener J. E., Dikkeschei L. D., Erkelens D. W., Doorenbos H. Increased cholesteryl ester transfer activity in complicated type 1 (insulin-dependent) diabetes mellitus – its relationship with serum lipids. Diabetologia 1989; 32: 14–19. 4. Agellon L. B., Walsh A., Hayek T. et al. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer
ª 2002 Elsevier Science Ltd. All rights reserved.
19.
20.
21.
protein transgenic mice. J Biol Chem 1991; 266: 10796–10801. Chang C.-K., Tso T. K., Snook J. T., Huang Y.-S., Lorazo R. A., Zipf W. B. Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose. Acta Diabetol 2001; 38: 37–42. Frick M. H., Elo O., Haapa K. et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Eng J Med 1987; 317: 1237–1245. Parlapiano C., Danese C., Marangi M. et al. The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus. Diabetes Res Clin Pract 1999; 46: 43–45. Borgeat P., Naccache P. H. Biosynthesis and biological activity of leukotriene B4. Clin Biochem 1990; 23: 459– 468. Crooks S. W., Stockley R. A. Leukotriene B4. Int J Biochem Cell Biol 1998; 30: 173–178. Hoover R. L., Karnovsky M. J., Austen K. F., Corey E. J., Lewis R. A. Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion. Proc Natl Acad Sci USA 1984; 81: 2191–2193. Makheja A. N. Atherosclerosis: the eicosanoid connection. Mol Cell Biochem 1992; 111: 137–142. Chang C. K., Tso T. K., Snook J. T., Zipf W. B., Lozano R. A. Sandwich enzyme-linked immunosorbent assay for plasma cholesteryl ester transfer protein concentration. Clin Biochem 1999; 32: 257–262. Habenicht A. J., Salbach P., Goerig M. et al. The LDL receptor pathway delivers arachidonic acid for eicosanoid formation in cells stimulated by platelet-derived growth factor. Nature 1990; 345: 634–636. Salbach P. B., Specht E., von Hodenberg E. et al. Differential low density lipoprotein receptor-dependent formation of eicosanoids in human blood-derived monocytes. Proc Natl Acad Sci USA 1992; 89: 2439–2443. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–809. Croft K. D., Proudfoot J., Moulton C., Beilin L. J. The effect of lipoproteins on the release of some eicosanoids by stimulated human leukocytes. A possible role in atherogenesis. Eicosanoids 1991; 4: 75–81. Kreuzer J., Denger S., Jahn L. et al. LDL stimulates chemotaxis of human monocytes through a cyclooxygenase-dependent pathway. Arterioscler Thromb Vasc Biol 1996; 16: 1481–1487. Croft K. D., Beilin L. J. Platelet and neutrophil function and eicosanoid release in a subject with abetalipoproteinaemia. Thromb Res 1993; 69: 333–342. Surya I. I., Mommersteeg M., Gorter G., Erkelens D. W., Akkerman J. W. Abnormal platelet functions in a patient with abetalipoproteinemia. Thromb Haemost 1991; 65: 306–311. Mironova M. A., Klein R. L., Virella G. T., Lopes-Virella M. F. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with type 2 diabetes. Diabetes 2000; 49: 1033–1041. Brenner R. R. Nutritional and hormonal factors influencing desaturation of essential fatty acids. Prog Lipid Res 1981; 20: 41–47.
Medical Hypotheses (2002) 59(5), 607–610
610 Chang et al.
22. Schnatz J. D., Williams R. H. The effect of acute insulin deficiency in the rat on adipose tissue lipolytic activity and plasma lipids. Diabetes 1963; 12: 174–178. 23. Bagdade J. D., Dunn F. L., Eckel R. H., Ritter M. C. Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus. Arterioscler Thromb 1994; 14: 1933–1939. 24. Sammett D., Tall A. R. Mechanisms of enhancement of cholesteryl ester transfer protein activity by lipolysis. J Biol Chem 1985; 260: 6687–6697. 25. Reichard P., Nilsson B. Y., Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Eng J Med 1993; 329: 304–309.
Medical Hypotheses (2002) 59(5), 607–610
26. Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complication of insulin-dependent diabetes mellitus. N Eng J Med 1993;329:977–986. 27. Mann J. I. The role of nutritional modifications in the prevention of macrovascular complications of diabetes. Diabetes 1997; 46: S125–S130. 28. Morrison W. R., Smith L. M. Preparation of fatty acid methyl esters and dimethyl acetals from lipids with boron fluoride–methanol. J Lipid Res 1964; 5: 600– 608. 29. Folch J., Lee M., Sloane-Stanley G. H. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–509.
ª 2002 Elsevier Science Ltd. All rights reserved.
Does increased leukotriene B4 in type 1 diabetes result from elevated cholesteryl ester transfer protein activity? C.-K. Chang,1 T. K. Tso,2,1 J. T. Snook,2 Y.-S. Huang3 1
Department of Nutrition and Health Science, Fooyin Institute of Technology, Kaohsiung, Taiwan; 2OSU Nutrition Program, Ohio State University, Columbus, Ohio, USA; 3Medical Nutritional R&D, Ross Products Division, Abbott Laboratories, Columbus, Ohio, USA
Summary Elevated cholesteryl ester transfer protein (CETP) activity has been reported in type 1 diabetic subjects and may be one cause of the high incidence of macrovascular complications in these patients. LDL delivers arachidonic acid (AA), in the form of cholesteryl ester (CE), to cells such as monocytes and fibroblasts, as precursor for eicosanoid synthesis. We discovered that AA content in LDL CE was significantly correlated with CETP activity, even after controlling for CETP concentration, in type 1 diabetic children. The production of LTB4 , a potent chemotactic and pro-inflammatory factor which plays a role in atherogenesis, has been shown to be increased in type 1 diabetic patients. We hypothesized that in these subjects, increased AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia, may lead to enhanced synthesis of LTB4 and subsequently the higher incidence of cardiovascular disease. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION Plasma cholesteryl ester transfer protein (CETP) plays an important role in the continuous remodelling process of plasma lipoproteins. It facilitates the transfer of HDL cholesterol, mainly in the form of cholesteryl ester (CE) which is generated by the reaction of lecithin:cholesterol acyltransferase (LCAT), to apo B-containing lipoproteins (1). Through this reverse cholesterol transport process, peripheral tissue cholesterol can be redistributed for reutilization or to liver for excretion.
Received 5 March 2002 Accepted 8 May 2002 Correspondence to: Dr Jean T. Snook, OSU Nutrition Program, Ohio State University, 1787 Neil Ave, Columbus, OH 43210, USA. Phone: +1-614-2921680; Fax: +1-614-2928880; E-mail: [email protected] 1 Present address: Department of Food and Nutrition, Shih Chien University, Taipei, Taiwan.
It was reported that CETP activity was increased in type 1 diabetic subjects (2). The enhanced CETP activity has been suggested to be at least partially responsible for the high incidence of macrovascular complications in these patients (3), mainly because of its ability to decrease HDL cholesterol (4), which is generally believed to have a protective effect against atherosclerosis. Previously, we showed that increased CETP activity, combined with enhanced LCAT activity, resulted in the accumulation of LDL cholesterol in type 1 diabetic subjects (5). This may be partially responsible for atherogenesis in these subjects because high LDL cholesterol has long been recognized as a risk factor for coronary heart disease (6). However, the detailed mechanism as to how CETP increases the atherogenesis in type 1 diabetic patients remains to be elucidated. It has been shown that leukotriene (LT) B4 production was increased in both type 1 and 2 diabetic patients (7). LTB4 , synthesized through lipoxygenase pathway using arachidonic acid (AA) as the precursor (8), is one of the most potent naturally occurring leukocyte chemoattr-
607
608 Chang et al.
actants (9). Because of its pro-inflammatory effect and ability to promote adherence of neutrophils to endothelium, LTB4 has been suggested to be involved in atherogenesis (9–11). We hypothesized that higher AA content in LDL CE, resulting from elevated CETP activity, leads to increased LTB4 production in type 1 diabetic patients. Subsequently, it may promote atherogenesis in these subjects. ROLE OF LDL IN EICOSANOID PRODUCTION In a group of 35 type 1 diabetic children 12 males and 23 females, ages 5–12, we discovered that plasma CETP activity was positively correlated with AA in LDL CE (Fig. 1, Pearson’s correlation coefficient r ¼ 0:59, P < 0:01Þ. CETP activity was also positively correlated with plasma CETP concentration ðr ¼ 0:51, P < 0:01Þ (12). However, the correlation between AA in LDL CE and CETP activity remained significant even after adjusting statistically for CETP concentration. LDL is known to deliver AA, in the form of CE, to various cell types, including fibroblasts (13) and monocytes (14), as substrate for eicosanoid synthesis. This transportation is mediated by a LDL receptor-dependent mechanism (14). Migration of monocytes into the arterial wall is an important step of early development of atherosclerosis, as monocytes have been found in the very early stage of atherosclerotic lesions (15). After stimulating fibroblasts and monocytes with calcium ionophore A23187 or formyl-Met-Leu-Phe, LTB4 , a potent chemotactic and pro-inflammatory factor, was one of the dominant products of exogenous AA in the form of LDL CE (13, 14). Furthermore, LDL has been shown to stimulate LTB4 production by human leukocytes in vitro (16) and chemotactic response of monocytes (17). On the other hand, after inhibition of endosomal LDL degradation by chloroquine, or prostanoid synthesis by indomethacin or acetylsalicylic acid,
the stimulation effect of LDL was significantly reduced (17). In addition, production of LTB4 by calcium ionophore-stimulated neutrophils (18) and TXB2 by whole blood and platelet-rich plasma were lower in abetalipoproteinemic subjects (18,19). These data indicated that LDL plays an essential role in eicosanoid synthesis. CETP AND LTB4 PRODUCTION IN TYPE 1 DIABETES It has been demonstrated that CETP activity is higher in type 1 diabetic patients than normal subjects (2, 3). It was also reported that polymorphonuclear cells secreted more LTB4 with and without calcium ionophore stimulation in type 1 and 2 diabetic subjects compared to controls (7). In our type 1 diabetic subjects, the AA content in LDL CE was considerably higher than values published for nondiabetic adults in another study (20) (Table 1), although there were significant age differences between them. Furthermore, the increased AA content in LDL CE was significantly correlated with CETP activity in this group of diabetic children. Therefore, the increased LTB4 production in type 1 diabetic patients may at least partly result from higher AA content in LDL CE, induced by elevated CETP activity. ROLE OF INSULIN AND GLYCEMIC CONTROL IN LTB4 PRODUCTION Previously, we showed that in the same group of type 1 diabetic children, CETP activity was significantly higher in patients with high fasting plasma glucose (>6.39 mmol/L, 115 mg/dL) than in the ones with normal plasma glucose, suggesting the possible role of glycemic control in CETP activity and possibly LTB4 production
Table 1 Fatty acid composition of LDL CE in type 1 diabetic children (age 9:0 2:2 years, n ¼ 35) and nondiabetic adults (adapted from (20), age 58:4 1:6 years, n ¼ 34), presented as the percentage of total major identified fatty acids
Fig. 1 The correlation between plasma CETP activity and AA content in LDL CE in type 1 diabetic children. CETP activity was measured according to Chang et al. (12).
Medical Hypotheses (2002) 59(5), 607–610
Fatty acid
Diabetic children
Nondiabetic adults
C10:0 C12:0 C14:0 C16:0 C16:1x7 C18:0 C18:1x9 C18:2x6 C20:4x6
<0.1 0:85 0:57 1:52 0:74 25:03 5:36 3:84 1:36 2:57 0:85 28:96 9:37 18:52 10:98 14:42 3:88
– – 0:5 0:1 11:5 0:5 2:6 0:3 1:5 0:1 19:6 0:6 47:3 1:5 5:5 0:5
The data are expressed as means SD. CE was purified by thinlayer chromatography and transmethylated with BF3 –methanol (28) after total lipids were extracted from LDL according to the method of Folch et al. (29). The fatty acid methyl esters were analyzed by gas chromatography using a Hewlett Packard 5890 Series II with Omegawax320 column (Supelco, Bellefonte, PA, USA).
ª 2002 Elsevier Science Ltd. All rights reserved.
Increased leukotriene B4 in type 1 diabetes 609
(5). In agreement with our hypothesis, Parlapiano et al. (7) reported that LTB4 levels were positively correlated with HbA1c in diabetic subjects. It has been shown that insulin enhanced biosynthesis of AA through stimulation of D5- and D6-desaturase activities (21). In addition, insulin may directly increase CETP activity through positive regulation of lipoprotein lipase (22, 23). The accumulation of fatty acids on the surface of VLDL remnants after lipolysis increases the CETP activity by facilitating the binding of CETP to its substrate (24). Therefore, hyperinsulinemia caused by insulin injections may result in elevated CETP activity and AA availability, which then in combination may lead to higher AA content in LDL CE and greater delivery of AA for LTB4 synthesis. Thus, the transient hyperinsulinemia resulting from insulin injection may promote atherogenesis. This could be one of the reasons why intensive treatment in controlling blood glucose reduced the incidence of microvascular complications (25), but had little impact on macrovascular disease in type 1 diabetic patients (26, 27). Recently, intraperitoneal injection of insulin has been shown to reduce the exposure of peripheral tissues to hyperinsulinemia, while offering sufficient insulin level for glycemic control (23). As compared to traditional subcutaneous injection, the intraperitoneal route normalizes the accelerated LPL activity and CETP activity in type 1 diabetic patients (23), and may lead to lower AA availability and LTB4 production. Therefore, we hypothesized that elevated AA content in LDL CE, resulting from increased CETP activity and transient hyperinsulinemia in type 1 diabetic patients, may lead to enhanced synthesis of LTB4 . This may be one of the mechanisms that causes higher cardiovascular disease incidence in type 1 diabetic patients. Further investigations on eicosanoid synthesis by various cell types in diabetic subjects, as well as dietary interventions and intraperitoneal insulin injection modifying LDL CE lipid compositions and eicosanoid production, are warranted.
5.
6.
7.
8.
9. 10.
11. 12.
13.
14.
15. 16.
17.
18.
REFERENCES 1. Tall A. R. Plasma lipid transfer proteins. J Lipid Res 1986; 27: 361–367. 2. Bagdade J. D., Ritter M. C., Subbaiah P. V. Accelerated cholesteryl ester transfer in patients with insulin-dependent diabetes mellitus. Eur J Clin Invest 1991; 21: 161–167. 3. Dullaart R. P., Groener J. E., Dikkeschei L. D., Erkelens D. W., Doorenbos H. Increased cholesteryl ester transfer activity in complicated type 1 (insulin-dependent) diabetes mellitus – its relationship with serum lipids. Diabetologia 1989; 32: 14–19. 4. Agellon L. B., Walsh A., Hayek T. et al. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer
ª 2002 Elsevier Science Ltd. All rights reserved.
19.
20.
21.
protein transgenic mice. J Biol Chem 1991; 266: 10796–10801. Chang C.-K., Tso T. K., Snook J. T., Huang Y.-S., Lorazo R. A., Zipf W. B. Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose. Acta Diabetol 2001; 38: 37–42. Frick M. H., Elo O., Haapa K. et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Eng J Med 1987; 317: 1237–1245. Parlapiano C., Danese C., Marangi M. et al. The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus. Diabetes Res Clin Pract 1999; 46: 43–45. Borgeat P., Naccache P. H. Biosynthesis and biological activity of leukotriene B4. Clin Biochem 1990; 23: 459– 468. Crooks S. W., Stockley R. A. Leukotriene B4. Int J Biochem Cell Biol 1998; 30: 173–178. Hoover R. L., Karnovsky M. J., Austen K. F., Corey E. J., Lewis R. A. Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion. Proc Natl Acad Sci USA 1984; 81: 2191–2193. Makheja A. N. Atherosclerosis: the eicosanoid connection. Mol Cell Biochem 1992; 111: 137–142. Chang C. K., Tso T. K., Snook J. T., Zipf W. B., Lozano R. A. Sandwich enzyme-linked immunosorbent assay for plasma cholesteryl ester transfer protein concentration. Clin Biochem 1999; 32: 257–262. Habenicht A. J., Salbach P., Goerig M. et al. The LDL receptor pathway delivers arachidonic acid for eicosanoid formation in cells stimulated by platelet-derived growth factor. Nature 1990; 345: 634–636. Salbach P. B., Specht E., von Hodenberg E. et al. Differential low density lipoprotein receptor-dependent formation of eicosanoids in human blood-derived monocytes. Proc Natl Acad Sci USA 1992; 89: 2439–2443. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–809. Croft K. D., Proudfoot J., Moulton C., Beilin L. J. The effect of lipoproteins on the release of some eicosanoids by stimulated human leukocytes. A possible role in atherogenesis. Eicosanoids 1991; 4: 75–81. Kreuzer J., Denger S., Jahn L. et al. LDL stimulates chemotaxis of human monocytes through a cyclooxygenase-dependent pathway. Arterioscler Thromb Vasc Biol 1996; 16: 1481–1487. Croft K. D., Beilin L. J. Platelet and neutrophil function and eicosanoid release in a subject with abetalipoproteinaemia. Thromb Res 1993; 69: 333–342. Surya I. I., Mommersteeg M., Gorter G., Erkelens D. W., Akkerman J. W. Abnormal platelet functions in a patient with abetalipoproteinemia. Thromb Haemost 1991; 65: 306–311. Mironova M. A., Klein R. L., Virella G. T., Lopes-Virella M. F. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with type 2 diabetes. Diabetes 2000; 49: 1033–1041. Brenner R. R. Nutritional and hormonal factors influencing desaturation of essential fatty acids. Prog Lipid Res 1981; 20: 41–47.
Medical Hypotheses (2002) 59(5), 607–610
610 Chang et al.
22. Schnatz J. D., Williams R. H. The effect of acute insulin deficiency in the rat on adipose tissue lipolytic activity and plasma lipids. Diabetes 1963; 12: 174–178. 23. Bagdade J. D., Dunn F. L., Eckel R. H., Ritter M. C. Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus. Arterioscler Thromb 1994; 14: 1933–1939. 24. Sammett D., Tall A. R. Mechanisms of enhancement of cholesteryl ester transfer protein activity by lipolysis. J Biol Chem 1985; 260: 6687–6697. 25. Reichard P., Nilsson B. Y., Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Eng J Med 1993; 329: 304–309.
Medical Hypotheses (2002) 59(5), 607–610
26. Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complication of insulin-dependent diabetes mellitus. N Eng J Med 1993;329:977–986. 27. Mann J. I. The role of nutritional modifications in the prevention of macrovascular complications of diabetes. Diabetes 1997; 46: S125–S130. 28. Morrison W. R., Smith L. M. Preparation of fatty acid methyl esters and dimethyl acetals from lipids with boron fluoride–methanol. J Lipid Res 1964; 5: 600– 608. 29. Folch J., Lee M., Sloane-Stanley G. H. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–509.
ª 2002 Elsevier Science Ltd. All rights reserved.