Diabetes mellitus

Diabetes affects most lipoprotein classes, including VLDL, LDL, HDL and Lp(a). As a rule, both in type 1 and type 2 diabetes, the total plasma C

and TG are usually within normal limits when the blood glucose is controlled, but elevation occurs with metabolic decompensation. In addition, qualitative alterations of lipoproteins (mainly LDL) do occur in diabetic patients, including glycation, oxidation and peroxidation as well as composition abnormalities consisting of smaller and more dense LDL. It has been reported that when TG are ?200 mg/dl, LDL particles are small and dense whereas when they are =90 mg/dl, the particles are of the large, light variety. These changes are potentially atherogenic, as the small, dense and peroxidized LDL are taken up in reduced amount by the specific LDL receptors, whereas they are susceptible to uptake by the macrophage scavenger receptors, thus leading to foam cell formation in the arterial wall. Thus, glycated/oxidized lipoproteins induce CE accumulation in human macrophages and may promote platelet and endothelial cell dysfunction. Furthermore, these modified lipoproteins have the ability to trigger an autoimmune response that leads to the formation of autoan- tibodies and subsequently to the formation of immune complexes containing LDL. These immune complexes, in turn, promote macrophage activation ac- companied by release of cytokines, thus initiating a sequence of events leading to endothelial cell damage.

Considering the dangerous effects of increased oxidative stress com- bined with oxidized lipoproteins, an antioxidant combination therapy of vita-

min E and vitamin C might be beneficial, but this needs to be further investi- gated.

Finally, it should be considered that long-term hyperlipidemia may exert direct inhibitory effects on b-cell function (lipotoxicity), which should form the basis of a more active approach to lipid screening and pharmacological treatment of hyperlipidemia in diabetes patients.

Type 1 Diabetes In insulin-treated type 1 diabetic patients in good metabolic control and

without micro- and macrovascular complications, the plasma levels of VLDL- TG, LDL-C and HDL-C are near normal. Indeed, a favorable pattern may without micro- and macrovascular complications, the plasma levels of VLDL- TG, LDL-C and HDL-C are near normal. Indeed, a favorable pattern may

Moreover, it has been shown that the development of microalbuminuria or overt diabetic nephropathy is associated with increased concentrations of

C, TG and of atherogenic lipoprotein species, including IDL as well as Lp(a), and low levels of HDL-C, and hence with increased cardiovascular risk. Notably, there are no differences between patients with microalbuminuria and those with overt albuminuria. Lp(a) has been found elevated also in diabetics with both nephropathy and retinopathy. It is uncertain whether the increase in Lp(a) is secondary to diabetic nephropathy or is a genetic marker of susceptibility to this diabetic complication. The relationship between glycemic control and the Lp(a) level has not been fully resolved. In addition, increase in HL activity has been found in microalbuminuric and albuminuric type 1 diabetics.

Concerning apoproteins, it is noteworthy that in type 1 diabetic patients with good metabolic control, although the level of LDL is often normal, the ratio LDL-C/ApoB is elevated, suggesting changes in the composition of the LDL particles. Depletion of the choline-containing phospholipids in the ApoB- containing lipoprotein particles has also been reported, suggesting an altera- tion of the surface components of atherogenic particles. With worsening of

the glycemic control, ApoB increases roughly correlated with HbA 1c . On the other hand, insulin treatment seems to suppress the production of VLDL- and LDL-ApoB. With regard to ApoA, it has been observed that the elevation of HDL, which may occur in insulin-treated type 1 diabetic patients, is mainly due to increase in ApoA-I (rather than ApoA-II), suggesting that the change

concerns mainly HDL 2 . This may result from increased activity of LPL and reduced activity of HL.

Type 2 Diabetes Lipid changes in type 2 diabetes include particularly elevated levels of

total and VLDL-TG and reduced levels of HDL-C, and may be minimal in compensated patients but become more pronounced when glycemic decompensation develops. Total and LDL-C levels also are usually normal if glycemic control is adequate, but show increase with worsening of glycemic control. These changes may be even stronger risk factors for CHD in type

2 diabetic patients than in nondiabetic individuals. Hypertriglyceridemia is often associated with the accumulation of IDL, abnormal postprandial lipid 2 diabetic patients than in nondiabetic individuals. Hypertriglyceridemia is often associated with the accumulation of IDL, abnormal postprandial lipid

Lipid abnormalities may be associated with coexisting visceral obesity and insulin resistance. Fasting TG and visceral obesity appear to independently predict mortality from CAD in glucose-intolerant and diabetic subjects. The predominance of small, dense LDL was found to be one of the interrelated risk factors that characterize the insulin resistance syndrome. The trend towards increased VLDL and reduced HDL has been found to be present already in first-degree relatives of type 2 diabetic patients with normal glucose tolerance. These lipid abnormalities therefore may represent early markers of insulin resistance.

Concerning the underlying mechanism, a contributory factor to hypertriglyceridemia in type 2 diabetes may be the inability of insulin to inhibit the release of VLDL 1 from the liver, despite efficient suppression of serum FFA. Indeed, in type 2 diabetes, secretion of VLDL in the postabsorptive state is higher than in normal, possibly because of impaired ability of insulin to inhibit lipolysis and to reduce hepatic VLDL secretion. Recent data suggest that TG- rich lipoproteins in the range Sf 12–60 may be associated with angiographic severity in both diabetic and nondiabetic individuals. A study in people with type 2 diabetes found that patients with moderate CAD had higher levels of both Sf 12–60 and 60–400 fractions. Multivariate analysis showed that this association was independent of both low LDL and HDL. Moreover, the risk correlated positively to the postprandial levels of ApoB-48 in the Sf 20–60 fraction. This suggests that elevated levels of chylomicron remnants are in- volved in progression of CAD.

Postprandial hyperlipidemia has been shown to be atherogenic. In type 2 diabetes patients, lipid intolerance (a greater increase of postprandial TG and

a slower return towards basal levels) was almost always present. An increased supply of glucose and FFA contributes to overproduction of VLDL, increasing the burden of TG-rich lipoproteins on the common lipolytic pathway at the level of LPL. In addition, the capacity of LPL to minimize postprandial hyperlipidemia may be reduced. The clearance of atherogenic remnants is also delayed in type 2 diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with VLDL remnants.

Concerning apoproteins, increased ApoB and ApoC-III concentration has been reported in type 2 diabetic patients. Moreover, enhanced production of VLDL-ApoB may be a main contributing factor of elevation in plasma VLDL in these patients, who also show increase in the ApoE content of VLDL. The Concerning apoproteins, increased ApoB and ApoC-III concentration has been reported in type 2 diabetic patients. Moreover, enhanced production of VLDL-ApoB may be a main contributing factor of elevation in plasma VLDL in these patients, who also show increase in the ApoE content of VLDL. The

On the other hand, the reduction in HDL level is associated with decrease of ApoA-I (while ApoA-II is often little changed) and therefore mainly concerns the HDL A-I particles (rather than the HDL A-III ones), i.e. the HDL 2 fraction. Considering that hypertriglyceridemia has been reported to be associated with increased clearance of HDL, these data might be secondary to enhanced VLDL-TG.

In type 2 diabetes, decreased ApoA-I has been reported, whereas ApoA-

IV levels are often increased, mainly related to hypertriglyceridemia and to a lesser extent to HDL-C level. On the other hand, ApoA-IV phenotype distribu- tion is not changed.

It has been reported that the potential protective lipid profile (character- ized by increased HDL- and HDL 2 -C levels) related to the ApoA-IV 1-2 phenotype, is no longer found in type 2 diabetic patients. In these patients, plasma ApoA-IV levels are associated with increased prevalence of macrovascular disease. Finally, in type 2 diabetes treated with insulin, ApoA-IV levels are increased and not related to hypertriglyceridemia.

Studies in different ethnic groups have suggested that type 2 diabetic patients carrying the ApoE 2 allele may be more susceptible to develop hypertri-

glyceridemia in some populations but not in others, which suggests that the effect of ApoE 2 is population-specific. It has also been reported that CHD

shows higher prevalence among type 2 diabetic patients with phenotype

E 4 /E 4 compared to those with different ApoE phenotypes. In addition, ApoE 2 may be overrepresented in diabetic populations. In type 2 diabetes, Lp(a) levels

are not significantly changed and not related to the degree of glycemic control. An association has been reported between elevated Lp(a) and macrovascular disease in type 2 diabetes (this link has not been found with type 1 diabetes). As a whole, the role of Lp(a) as a risk factor for CHD in diabetic patients remains uncertain.

Diabetes mellitus