Lipid Abnormalities and Lipid Lowering in Diabetes

E. Belfiore, S. Iannello

Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Pathophysiology

The metabolism and function of the various lipoproteins (VLDL, LDL and HDL) is quite complex. Here a brief summary will be given, referring to the various steps illustrated in figure 1.

Metabolism of Lipoproteins in the Normal State

VLDL are produced by the liver and secreted into circulation (step 1 in figure 1). In the liver they are formed by assembling TG, formed through the esterification of FFA (coming from adipose tissue, where they are released through lipolysis effected by the hormone-sensitive lipase), C, and the apoprotein B-100 (ApoB-100), besides other components such as phospholipids. The VLDL particles can be distinguished into two subclasses, VLDL1 and VLDL2, with Svedberg flotation (Sf) rates of 60-400 and 20-60, respectively. After secretion, VLDL reach 'peripheral tissues', i.e. adipose tissue and muscle (step

Abbreviations

Apo = Apoproteins; C = cholesterol; CAD = coronary artery disease; CE = cholesteryl esters; CETP = cholesteryl ester transfer protein; CHD = coronary heart disease; CVD = cardiovascular disease; FFA = free fatty acids, HDL-R = high-density lipoprotein receptor; HDL = high-density lipoproteins; HL = hepatic lipase; HMG-CoA = hydroxy-methyl-gluta-ryl-CoA; IDL = intermediate density lipoproteins; LCAT = lecithin:cholesterol acyltransfer-ase; LDL-R = LDL receptor (ApoB/ApoE receptor); LDL = low-density lipoproteins; Lp(a) =lipoprotein(a); LPL = lipoprotein lipase; LRP= LDL receptor-related protein; TG = triglycerides; UC = unesterified cholesterol; VLDL = very low-density lipoproteins.

Secretory Pathway Lipoprotein
Fig. 1. Simplified scheme of the metabolism of lipoproteins involved in plasma TG and C transport. In addition to the abbreviations used in the text (see p. 1), the following ones are also used: AI = ApoA-I; AII = ApoA-II; B-100 = ApoB-100; CII = ApoC-II; CIII = ApoC-III; E = ApoE.

2 in figure 1) where they are subjected to the action of LPL. While in the circulation, VLDL are enriched with ApoC-II, ApoC-III and ApoE, which are transferred to VLDL from the HDL. ApoC-II is the cofactor required for the activity of LPL (ApoC-III would inhibit LPL). This enzyme is produced by the cells of adipose tissue and muscle, and then transferred to the endothelial capillary surface, where it hydrolyzes the TG in VLDL, thus releasing FFA. The latter are taken up by cells and then re-esterified and stored as TG (in the adipose tissue) or mainly oxidized (in the muscle). The action of LPL profoundly alters the structure of the VLDL, with collapse of the TG-contain-ing core. The excess surface components, including UC and phospholipids, are transferred to HDL. ApoC and ApoE are also transferred back to HDL. Through this process, the original VLDL particle is first converted into IDL, containing ApoB-100 and ApoE (step 3 in figure 1), and then into LDL, which are mainly composed of C and ApoB-100 (step 4 in figure 1). LDL

particles are taken up and degraded by the liver (and other tissues) through the LDL receptors (fig. 1, step 5 for extrahepatic tissue, step 6 for the liver), which recognizes ApoB-100 and ApoE. When LDL-lipid peroxidation occurs (such as in diabetes), LDL are taken up by endothelial cells and macrophages through an alternative 'scavenger pathway' (not shown in figure 1). In the artery wall this may contribute to the genesis of the atherosclerotic lesions.

IDL are in part converted into LDL (step 4 in figure 1) but in part are taken up and degraded by the liver (step 7 in figure 1) through another receptor (the remnant receptor) which is specific for ApoE, and is thought to be the LDL LRP. Thus, the VLDL-IDL-LDL pathway (steps 1-5 in figure 1) can be regarded as a pathway conveying C to peripheral tissues (including arteries), even if some amount of LDL-C is returned to liver (steps 1-4, 6 in figure 1). HDL, produced by liver (step 10 in figure 1) as well as by intestine (step not shown in figure 1) as native particles, are composed primarily of phospholipid, ApoA-I and ApoA-II, and other apoproteins. In the circulation, HDL can be distinguished into the larger and less dense HDL2 and the smaller and more dense HDL3. HDL serve important functions. They provide apoproteins (ApoC and ApoE) to VLDL (and chylomicrons) to allow the TG hydrolysis by LPL, and take up UC, phospholipid, and various apoproteins which form excess surface material in VLDL, after VLDL-TG hydrolysis by LPL. It seems probable that during the catabolism of VLDL effected by LPL, HDL3 is converted into HDL2. Moreover, HDL take up UC from tissues and esterify it through the action of the enzyme LCAT. Part of CE so formed is transferred to TG-rich lipoproteins (while these are being hydrolyzed), in exchange for TG, through the action of CETP, while the remaining is transported with the HDL to the liver, where the HDL particles may be taken up through a not yet well-defined HDL-R. Thus, the HDL-LCAT-CETP system or pathway (steps 8, 9, 12 in figure 1) can be regarded as a pathway for removing excess cellular C and for its transferring to the liver for excretion (reverse C transport). This may results in protection against CAD. Recently, antioxidant and antithrombotic properties have been attributed to HDL. In addition to LPL, a major role is also played by HP. This lipase, whose expression is regulated by hormones and nutritional state, is secreted by the hepatocytes and remains on the surface of hepatic endothelial cells and hepatocytes and (like LPL) acts on circulating lipoprotein particles. HL is thought to act on the uptake of CE from IDL and HDL (and also from chylomicron remnants), and may be involved in the conversion of HDL2 to HDL3. HL also participates in the VLDL to IDL and LDL cascade by contributing to the conversion of IDL into LDL (deficiency of HL is associated to accumulation of IDL).

Comment on Normal Lipoprotein Metabolism

Hepatic production of VLDL is regulated by insulin (and the anti-insulin hormones) at different sites. In fact, insulin, by inhibiting lipolysis at adipose tissue level, refrains the afflux of FFA to the liver, which is one of the factors stimulating VLDL production. Moreover, insulin (although favoring FFA esterification to TG in the liver) exerts a direct suppressive effect on the production of VLDL-ApoB in the liver and decreases the production of large TG-rich VLDL1 particles, independently of the availability of FFA. On the other hand, acute lowering of FFAs (acipimox administration, which inhibits lipolysis) does not change the overall production rate of VLDL particles, but shifts the production towards to smaller and denser VLDL2 particles, without changing the amount of total VLDL particles secreted.

ApoE is the ligand required for lipoprotein binding to ApoB/ApoE receptors in liver (as well as for the binding of chylomicron remnants). The gene for ApoE is polymorphic and includes three common alleles designated E2, E3 and E4. Type 3 hyperlipidemia may occur only in the subjects who are homozygous for the E2 allele, i.e. with the genotype E2/E2. It has also been suggested that the ApoE phenotype may modulate the response of LDL to diet or drug therapy. It has been suggested that ApoE4 is associated with elevation of TG and decrease in HDL-C both in nondiabetic and diabetic populations. On the other hand, the frequency of ApoE alleles was found not significantly different in type 1 or 2 diabetic patients compared to nondiabetic population.

ApoA-IV is considered to play a role in TG-rich lipoprotein metabolism, in reverse C transport, and in facilitation of CETP activity. Moreover, ApoA-IV is genetically polymorphic in humans, in whom two major isoproteins (ApoA-IV1 and ApoA-IV2) are known to occur. In the normal population, a potential protective lipid profile (characterized by increased HDL- and HDL2-C levels) is related to the Apo-A-IV1/ApoA-IV2 phenotype.

Lp(a) is a lipoprotein particle similar to LDL in which, however, the ApoB-100 is linked to a glycoprotein named Apo(a). Lp(a) shows size heterogeneity, which is genetically determined, and has been identified as an independent risk factor for atherosclerotic vascular disease in nondiabetic populations.

In the clinical setting, determination of plasma total-C, LDL-C, HDL-C and TG has an established diagnostic value. Recently, measurement of apopro-teins has become feasible and may result in additional useful information. Considering that each lipoprotein particle has only one apoprotein molecule, measurement of ApoB and ApoA-I allows the assessment of the number of LDL and HDL particles, respectively. Moreover, simultaneous determination of lipid concentration (C and TG) allows detection of changes in lipoprotein composition. However, the use of apoprotein determination in the clinical setting is limited by the lack of standardized procedures. As a whole, it is still uncertain whether the determination of ApoB and ApoA-I has diagnostic advantage over the measurement of LDL-C and HDL-C.

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 endo-thelial 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 accompanied by release of cytokines, thus initiating a sequence of events leading to endothelial cell damage.

Considering the dangerous effects of increased oxidative stress combined with oxidized lipoproteins, an antioxidant combination therapy of vitamin E and vitamin C might be beneficial, but this needs to be further investigated.

Finally, it should be considered that long-term hyperlipidemia may exert direct inhibitory effects on (3-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 often occur, as tight control in IDDM usually reduces LDL and VLDL to normal (or even subnormal) levels and may raise HDL above the normal range, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. However, with the loss of glycemic control, marked elevation in TG and C can develop and is often due to superimposed genetic abnormalities in lipoprotein metabolism.

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 alteration of the surface components of atherogenic particles. With worsening of the glycemic control, ApoB increases roughly correlated with HbA1c. 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 HDL2. 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 gly-cemic 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 metabolism and small, dense LDL and HDL (which are also enriched with TG as compared with C). Both low HDL-C and mild to moderate elevations of VLDL-TG are more frequent in type 2 diabetics when proteinuria is also present.

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 hypertri-glyceridemia in type 2 diabetes may be the inability of insulin to inhibit the release of VLDL1 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 involved 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 hyper-lipidemia 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-^po5 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 mechanism of these changes is not fully understood, but insulin resistance together with the enhanced afflux of FFA to liver may play a significant role.

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 HDL2 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 distribution is not changed.

It has been reported that the potential protective lipid profile (characterized by increased HDL- and HDL2-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 macrovas-cular 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 ApoE2 allele may be more susceptible to develop hypertri-glyceridemia in some populations but not in others, which suggests that the effect of ApoE2 is population-specific. It has also been reported that CHD shows higher prevalence among type 2 diabetic patients with phenotype E4/E4 compared to those with different ApoE phenotypes. In addition, ApoE2 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.

Lipid-Lowering Intervention in Diabetes

It is now well established that hyperlipidemia is a risk factor for CVD in the diabetic population. In type 2 diabetes, lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. On the other hand, it has been demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. However, it should be stressed that the rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in nondiabetic populations. Indeed, no trials of lipid-lowering therapy in the primary or secondary prevention of CVD have been targeted specifically to the diabetic population, and available data have been obtained through post-hoc subgroup analyses. However, four important multicenter studies are currently in progress.

American Diabetes Association guidelines call for aggressive treatment of high TG and LDL-C. TG should be <200 mg/dl, are considered borderline high between 200 and 400 mg/dl, and high when >400 mg/dl. Low HDL is defined as <35 mg/dl. Control of obesity with diet and exercise and reduced intake of saturated fat and C are important first steps. If needed, drug therapy is appropriate to lower TG and, specifically, to reduce LDL-C to levels

< 130 mg/dl in all adult diabetics and < 100 mg/dl in those with CVD. The lipid profile should be monitored at beginning and during treatment, including TG and total and LDL-C.

The therapeutic interventions to reduce body weight, increase physical activity and control the glycemic condition are described in chapters II-VI. Here we recall that the National Cholesterol Education Program guidelines suggested a dietary two-step approach. Step 1 consists of reduction of % calorie assumption to <10% from saturated fat, <10% from polyunsaturated fats and 10-15% from monounsaturated fats, while C assumption should be

< 300 mg/day. If the therapeutical goals are not reached, then step 2 should be adopted, which consists in further reduction of saturated fat to < 5% of total calories and C intake to < 200 mg/day.

When dietary measures (plus exercise) and hypoglycemic agents have failed to achieve acceptable lipid levels, drug therapy should be prescribed. Drugs currently in clinical use for the treatment of hyperlipidemias are listed in table 1, in which the distinction is made between drugs mainly lowering C, represented by the HMG-CoA reductase inhibitors statins (besides bile acid-binding resins and niacin) and drugs primarly lowering TG, consisting of the group offibrate derivatives (besides niacin and fish oil). As a rule, the treatment in the diabetic patients should be based on the use of statins or fibrates (ciprofibrate and fenofibrate appearing more effective than bezafibrate), whereas other drugs are in general not recommended, unless severe hyperlypid-emia or intolerance to statins or fibrates is present.

Intensive treatment with lipid-regulating agents is often necessary to normalize diabetes-associated dyslipidemias. HMG-CoA reductase inhibitors are the only agents thus far shown in prospective multicenter trials to reduce the risk of coronary events in diabetic patients. Long-term statin treatment of coronary patients significantly lowers the recurrence of coronary events, in addition to improving the lipid disorder. However, no information is available concerning the preventive effect of long-term improvement of lipid disorders

Table 1. Lipid-lowering drugs

Drug

Mechanism

Effects

Hypercholesterolemia Bile acid (BA) binding resins1

(Cholestyramine, 8-12 g b.i.d. or t.i.d.) (Cholestipol, 10-15 g b.i.d. or t.i.d.)

jBA reabsorption; |BA synthesis; |LDL receptors

j LDL-C; THDL-C; jTG

Niacin2

(Niacin, starting; 100 mg t.i.d., then up to 1-2 g t.i.d.) (Niacin (extended release) 0.5-3 g/day)

jVLDL synthesis

jTG; jVLDL- & LDL-C; THDL

HMG-CoA reductase inhibitors3

(Lovastatin, 10-80 mg/day) (Pravastatin, 10-40 mg/day) (Simvastatin, 5-40 mg/day) (Fluvastatin, 20-40 mg/day) (Atorvastatin, 10-80 mg/day) (Cerivastatin, 0.1-0.3 mg/day)

^Cholesterol synthesis; |LDL receptors

j LDL-C; jVLDL secretion; jTG

Antioxidant

jLDL-C jAtherosclerosis

Fibric acid derivatives5

See below

See below

Hypertriglyceridemia Fibric acid derivatives5

(Gemfibrozil6,c 600 mg b.i.d.) (Fenofibrate, 100 t.i.d. or q.i.d.) (Fenofibrate, micronized 200-250 mg/day) (Bezafibrate6, 400 mg/day or 200 mg t.i.d.) (Ciprofibrate, 100 mg/day)

ÎLPL; ÎHPL; jVLDL production; jApoC-III synthesis; |LDL clearance

jTG; THDL; k|LDL-C3

Niacin2

See above

See above

Fish oil6 (4 g t.i.d. or q.i.d.)

jVLDL product

jTG

a Fenofibrate may be an exception, producing a decrease in LDL-C.

b Long-acting formulations of these fibrates are also available.

c This fibrate increases LDL particle size.

1 Resins may cause gastrointestinal symptoms (nausea, constipation, hemorrhoidal bleeding); contraindicated in biliary obstruction and in hypertriglyceridemia.

2 May cause various symptoms: cutaneous (flushing, dry skin), cardiac (tachycardia, arrhythmias), gastrointestinal (nausea, diarrhea, peptic ulcer, hepatic dysfunction), metabolic (insulin resistance, glucose intolerance, hyperuricemia); con-traindicated in peptic ulcer, cardiac arrhythmias, liver diseases, hyperuricemia, diabetes mellitus.

3 May cause abnormal liver function tests and myopathy; contraindicated in myopathies, renal failure, or in association with fibrates or niacin.

4 May reduce HDL-C.

5 May favor bile stone or cause nausea, abnormal liver function tests or myopathy; contraindicated in hepatobiliary disease.

6 Usually a mixture of eicosapentaenoic acid (~ 58-64%) and docosahexaenoic acid (~ 36-42%); may be associated with a slight increase in LDL-C.

in type 2 diabetic patients without CHD, or in patients with the 'classical' type of diabetic lipid disorder (hypertriglyceridemia with low HDL and normal LDL-C levels). In these latter patients, beneficial lipid effects can be obtained (although perhaps not normalization) with fibrates alone or, especially, in combination with current statins. Recent data showed that the risk reduction was 22-50% with statins and approximately 65% with fibrates (relative to placebo). Preliminary results indicate that fenofibrate treatment in type 2 diabetes under optimized metabolic control improves not only fasting lipid levels but also postprandial lipemia and associated abnormalites in lipoprotein levels and composition. However, it was pointed out that the statins should be regarded as the current lipid-lowering drugs of choice because the change in LDL-C to HDL-C ratio is better than with fibrates (gemfibrozil).

According to the IDF guidelines (1999) to type 2 diabetes, drugs for lowering lipids should be prescribed according to the following scheme. A statin should be used when LDL-C >115 mg/dl (>3.0 mmol/l) or, in subjects at low risk (including the thin elderly), when LDL-C >155 mg/dl (4.0 mmol/l). Afibrate should be used when TG are > 200 mg/dl (> 2.2 mmol/l) and LDL-C <115 mg/dl (< 3.0 mmol/l). Atorvastatin should be used when TG are 200-400 mg/dl (2.3-4.5 mmol/l) and LDL-C >115 mg/dl (>3.0 mmol/l). When TG are markedly elevated, i.e. > 600 mg/dl (> 6/8 mmol/l), a fibrate should be first used, and thyroid, renal, and liver function, and ApoE fenotype should be checked; if LDL-C levels remain elevated, combined fibrate-statin therapy should be advised. Combined therapy (beginning with a statin) is also suggested when both LDL-C and TG are markedly elevated.

Finally, it is noteworthy that antiproteinuric and lipid-lowering therapy can be expected to reduce vascular damage and the progression of diabetic nephropathy.

Suggested Reading

Austin MA, Edwards KL: Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-171.

Coppack SW: Postprandial lipoproteins in non-insulin-dependent diabetes mellitus. Diabet Med 1997; 14(suppl 3):67-74.

De Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de Bruin TW: Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: Post-prandial metabolism and relation to premature atherosclerosis. Eur J Clin Invest 1996;26:89-108.

Groop PH, Elliott T, Ekstrand A, Franssila-Kallunki A, Friedman R, Viberti GC, Taskinen MR: Multiple lipoprotein abnormalities in type I diabetic patients with renal disease. Diabetes 1996;45:974-979.

Gylling H, Miettinen TA: Treatment of lipid disorders in non-insulin-dependent diabetes mellitus. Curr Opin Lipidol 1997;8:342-347.

International Diabetes Federation (IDF), 1998-1999 European Diabetes Police Group: A Desktop Guide to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels 1999.

Jeakins AJ, Best JD: The role of lipoprotein(a) in the vascular complications of diabetes mellitus. J Intern Med 1995;237:359-365.

Kreisberg RA: Diabetic dyslipidemia. Am J Cardiol 1998;82:67U-73U, 85U-86U.

Laakso M: Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus. Lipoproteins and coronary heart disease in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:137-141.

Lopes-Virella MF, Virella G: Modified lipoproteins, cytokines and macrovascular disease in non-insulin-dependent diabetes mellitus. Ann Med 1996;28:347-354.

Malmstrom R, Packard CJ, Caslake M, Bedford D, Stewart P, Yki-Jarvinen H, Shepherd J, Taskinen MR: Effects of insulin and acipimox on VLDLj and VLDL2 apolipoprotein B production in normal subjects. Diabetes 1998;47:779-787.

Steiner G: Clinical trial assessment of lipid-acting drugs in diabetic patients. Am J Cardiol 1998;81: 58F-59F.

Taskinen MR: Lipoproteins and apoproteins in diabetes; in Belfiore F, Bergman RN, Molinatti GM (eds): Current Topies in Diabetes Research. Front Diabetes. Basel, Karger, 1993, vol 12, pp 122-134.

F. Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, I-95123 Catania (Italy)

Tel. +39 095 330981, Fax +39 095 310899, E-Mail [email protected]

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 186-198

Chapter XIII

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