**5. Qualitative lipid abnormalities in type 1 diabetes**

Several qualitative abnormalities of lipoproteins are observed in patients with type 1 diabetes, even in those with good metabolic control, who do not have significant quantitative lipid changes. These qualitative lipid abnormalities are not totally reversed by optimal glycemic control and are likely to be atherogenic.

#### **5.1 VLDLs**

VLDLs from patients with type 1 diabetes are frequently enriched in esterified cholesterol at the expense of triglycerides leading to an increased VLDL cholesterol/triglyceride ratio (Rivellese et al., 1988; Bagdade et al., 1991a). It has been suggested that this compositional changes may be due to increased cholesteryl ester transfer between lipoproteins (Bagdade et al., 1991a). It has been shown that the VLDL cholesterol/triglyceride ratio was significantly reduced with intraperitoneal insulin therapy (Dunn, 1992). Furthermore, the free cholesterol /lecithin ratio within the peripheral layer of VLDL particles is increased (Dullaart, 1995; Bagdade et al., 1991a). Such increase in the free cholesterol /lecithin ratio within the peripheral layer of lipoproteins has been shown to raise the risk for cardiovascular events possibly by reducing fluidity and stability of lipoproteins (Kuksis, 1982). Moreover, VLDLs from patients with type 1 diabetes have been shown, in vitro, to induce abnormal response of cellular cholesterol metabolism in human macrophages (Klein et al., 1989).

#### **5.2 LDLs**

In patients with type 1 diabetes, LDLs are often enriched in triglycerides and increased number of small dense LDL particles is observed (Guy et al., 2009; Lahdenperä et al., 1994; James & Pometta, 1990; Skyrme-Jones et al., 2000). In a study performed in 2657 patients with type 1 diabetes, it has been shown that dense LDL increased with HbA1c with buoyant LDL shifting toward dense LDL for HbA1c values above 8% (Albers et al., 2008). It has been shown that the presence of small dense LDL particles is associated with increased cardiovascular risk (Austin et al., 1990). Many data indicate that small dense LDL particles have atherogenic properties. Indeed, small dense LDL particles have reduced affinity for the LDL B/E receptor and are preferentially taken up by macrophages, through the scavenger receptor, leading to the formation of foam cells. Small dense LDL particles have higher affinity for intimal proteoglycans than large LDL particles which may favor the penetration of LDL particles into the arterial wall (Chapman et al., 1998). It has been shown that subjects with small dense LDL particles show an impaired response to endothelium dependent vasodilator acetylcholine (Vakkilainen et al., 2000). Moreover, small dense LDL particles show an increased susceptibility to oxidation (Tribble et al., 1992). A reduction of the proportion of small dense LDL particles has been reported after optimization of glycemic control in patients with type 1 diabetes (Caixàs et al., 1997).

The free cholesterol /lecithin ratio within the peripheral layer of LDL particles is increased (Dullaart, 1995; Bagdade et al., 1991a). In patients with type 1 diabetes, glycation of ApoB

Moreover, serum lipids have been shown to be associated with the progression of nephropathy in type 1 diabetes. In a prospective study performed in 152 patients with type 1 diabetes followed for 8-9 years, LDL-cholesterol was an independent factor associated

Several qualitative abnormalities of lipoproteins are observed in patients with type 1 diabetes, even in those with good metabolic control, who do not have significant quantitative lipid changes. These qualitative lipid abnormalities are not totally reversed by

VLDLs from patients with type 1 diabetes are frequently enriched in esterified cholesterol at the expense of triglycerides leading to an increased VLDL cholesterol/triglyceride ratio (Rivellese et al., 1988; Bagdade et al., 1991a). It has been suggested that this compositional changes may be due to increased cholesteryl ester transfer between lipoproteins (Bagdade et al., 1991a). It has been shown that the VLDL cholesterol/triglyceride ratio was significantly reduced with intraperitoneal insulin therapy (Dunn, 1992). Furthermore, the free cholesterol /lecithin ratio within the peripheral layer of VLDL particles is increased (Dullaart, 1995; Bagdade et al., 1991a). Such increase in the free cholesterol /lecithin ratio within the peripheral layer of lipoproteins has been shown to raise the risk for cardiovascular events possibly by reducing fluidity and stability of lipoproteins (Kuksis, 1982). Moreover, VLDLs from patients with type 1 diabetes have been shown, in vitro, to induce abnormal response of cellular cholesterol metabolism in human macrophages (Klein

In patients with type 1 diabetes, LDLs are often enriched in triglycerides and increased number of small dense LDL particles is observed (Guy et al., 2009; Lahdenperä et al., 1994; James & Pometta, 1990; Skyrme-Jones et al., 2000). In a study performed in 2657 patients with type 1 diabetes, it has been shown that dense LDL increased with HbA1c with buoyant LDL shifting toward dense LDL for HbA1c values above 8% (Albers et al., 2008). It has been shown that the presence of small dense LDL particles is associated with increased cardiovascular risk (Austin et al., 1990). Many data indicate that small dense LDL particles have atherogenic properties. Indeed, small dense LDL particles have reduced affinity for the LDL B/E receptor and are preferentially taken up by macrophages, through the scavenger receptor, leading to the formation of foam cells. Small dense LDL particles have higher affinity for intimal proteoglycans than large LDL particles which may favor the penetration of LDL particles into the arterial wall (Chapman et al., 1998). It has been shown that subjects with small dense LDL particles show an impaired response to endothelium dependent vasodilator acetylcholine (Vakkilainen et al., 2000). Moreover, small dense LDL particles show an increased susceptibility to oxidation (Tribble et al., 1992). A reduction of the proportion of small dense LDL particles has been reported after optimization of glycemic

The free cholesterol /lecithin ratio within the peripheral layer of LDL particles is increased (Dullaart, 1995; Bagdade et al., 1991a). In patients with type 1 diabetes, glycation of ApoB

with progression of nephropathy (Thomas et al., 2006).

**5. Qualitative lipid abnormalities in type 1 diabetes** 

optimal glycemic control and are likely to be atherogenic.

control in patients with type 1 diabetes (Caixàs et al., 1997).

**5.1 VLDLs** 

et al., 1989).

**5.2 LDLs** 

occurs within LDL in parallel with plasma hyperglycemia. It has been shown that apoB glycation reduces significantly LDL binding to the B/E receptor even when apoB glycation is moderate (Witztum et al., 1982; Steinbrecher et al, 1984). Furthermore, glycated LDLs are preferentialy taken up by macrophages through the scavenger receptor, leading to the formation of foam cells in the arterial wall. In patients with type 1 diabetes, advanced glycation end products-modified LDL have been shown to be positively associated with increased intima media thickness (IMT) (Lopes-Virella et al., 2011).

Moreover, patients with type 1 diabetes may show an increased oxidation of LDL which is promoted by glycemic excursions (de Castro et al., 2005). Increased urinary excretion of malondialdehyde, reflecting enhanced lipid peroxidation, has been reported in patients with type 1 diabetes (Hoeldtke et al., 2009). Oxidative modification of LDL results in rapid uptake by macrophages, leading to foam cell formation. Oxidized LDLs produce chemotactic effects on monocytes by increasing the synthesis of adhesion molecules, such as ICAM-1 (intercellular adhesion Molecule 1) by endothelial cells. Oxidized LDLs stimulate the formation by macrophages of cytokines, such as TNF or IL1, which amplify the inflammatory atherosclerotic process. It has recently been shown that oxidized LDL particles were significantly associated with progression and increased levels of IMT in type 1 diabetes (de Castro et al., 2005).

#### **5.3 HDLs**

HDL particles from patients with type 1 diabetes are often enriched in triglycerides (Dullaart, 1995; Bagdade et al., 1991a). This modification has been attributed to increased cholesteryl ester transfer between lipoproteins (Bagdade et al., 1991a). In HDL particles from patients with type 1 diabetes, sphingomyelin/lecithin ratio within the peripheral layer is augmented, which may increase HDL rigidity (Bagdade & Subbaiah, 1989). These alterations are not totally reversed after achievement of optimal glycemic control (Bagdade et al., 1991b). ApoA-I within HDL is glycated in patients with type 1 diabetes, which may impair the HDL-mediated reverse cholesterol pathway. Indeed, it has been shown that HDL particles containing glycated apoA-I were less effective to promote cholesterol efflux from the cells (Fievet et al., 1992).

In addition to their role in the reverse cholesterol pathway, HDLs have anti-oxidative, antiinflammatory, anti-thrombotic and vasorelaxant properties, potentially anti-atherogenic (Link et al., 2007). Some of these properties have been shown to be reduced in patients with type 1 diabetes. Indeed, a significant reduction of the activity of paraoxonase, an antioxidative enzyme associated with HDLs, is observed in patients with type 1 diabetes (Boemi et al., 2001; Ferretti et al., 2004). As a consequence, HDLs from patients with type 1 diabetes protect less efficiently erythrocyte membranes and LDL particles against oxidative damage than HDLs from normal individuals (Boemi et al., 2001; Ferretti et al., 2004). Furthermore, using rabbit aorta rings, it has been shown that HDL from patients with type 1 diabetes are no more able to prevent the endothelium dependent vasoconstriction induced by oxidized LDL, whereas HDL from normal individuals can prevent it (Perségol et al., 2007).

#### **5.4 Lipid transfer proteins**

In some studies, an increased cholesteryl ester transfer between lipoproteins (Bagdade et al., 1991a; Bagdade et al., 1994) or an augmented activity of CETP (Colhoun et al., 2001) have been found in normolipidemic patients with type 1 diabetes. In some other studies, increased CETP activity has been reported only in type 1 diabetic patients that smoke or

Lipid Disorders in Type 1 Diabetes 55

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those having microalbuminuria (Dullaart et al., 1989b; Dullaart et al., 1991). This augmented CETP activity may explain the increase in free cholesterol/ triglycerides ratio within VLDL and its decrease within HDL. Some studies have shown a positive correlation between CETP activity and hyperglycemia (Ritter & Bagdade, 1994; Chang et al., 2001). However, the main factor which is likely to be responsible for increased CETP activity, in type 1 diabetes, could be peripheral hyperinsulinemia secondary to the subcutaneous route of insulin administration. Indeed, peripheral hyperinsulinemia has been shown to be responsible for increased lipoprotein lipase activity in patients with type 1 diabetes (Nikkilä et al., 1977) and it has been reported that lipoprotein lipase, in presence of VLDL, enhances CETP activity (Sammett & Tall,1985; Pruneta et al., 1999). Moreover, it has been shown, in patients with type 1 diabetes, that the increase in both lipoprotein lipase and CETP activities was abolished when insulin was administrated intraperitoneously with implantable insulin pumps, mimicking the physiologic portal route or after pancreatic graft (Bagdade et al., 1994; Bagdade et al., 1996).

Increased PLTP activity has been reported in patients with type 1 diabetes (Colhoun et al., 2001). In this study, PLTP activity was positively correlated with CETP activity, LDLcholesterol and HDL-cholesterol (Colhoun et al., 2001). The reasons and consequences of this increased PLTP activity are not clear.
