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      Lipoprotein Lipase Activity and Common Gene Variants in Severely Hypertriglyceridemic Patients with and without Diabetes

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          Objectives: In severe type IV hypertriglyceridemia (triglyceride levels >10 g/l), it is yet unknown whether lipoprotein lipase (LPL) differs according to the presence or not of diabetes. Methods: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus. Results: Maximum triglyceride, cholesterol levels and distribution of apolioprotein E phenotypes did not differ between the two subgroups. Mean post-heparin LPL activity was lower in non-diabetic compared to diabetic patients (9.74 vs. 12.98 µmol FFA/ml/h, p = 0.033). Four patients were carrying a mutation in exon 9 (1 non-diabetic), 6 patients in exon 2 (4 non-diabetic) and 1 patient in the non-diabetic subgroup in exon 5. All mutations were at the heterozygous state. Conclusion: We found that LPL activity was lower in type IV hyperlipidemia in the absence of diabetes. Genetic defects in the LPL gene that could lead to this lower LPL tended to be more frequently observed in patients without diabetes. These data suggest that the pathomechanisms which contribute to severe type IV hyperlipidemia are different according to the presence or not of diabetes.

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          Most cited references 11

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          Acute necrotizing pancreatitis.

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            Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.

            Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60-400) without affecting that of VLDL2 (Sf 20-60) sub-class. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 +/- 3 years, body mass index 27.0 +/- 1.0 kg/m2, plasma triglycerides 1.89 +/- 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin approximately 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper- and normoglycaemic conditions. [3-2H]-leucine was used as tracer and kinetic constants derived using a non-steady-state multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 +/- 8% after 8.5 h of hyperinsulinaemia (701 +/- 102 vs 672 +/- 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 +/- 21% under normoglycaemic conditions (603 +/- 145 mg/day). In contrast, in normal subjects insulin induced a 50 +/- 15% decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum nonesterfied fatty acids.
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              Diabetic dyslipidemia.

              Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                31 July 2003
                : 60
                : 2
                : 61-67
                aService d’Endocrinologie-métabolisme, Unités de prévention des maladies cardiovasculaires et Institut Fédératif de recherche Cœur Muscle et Vaisseaux, Assistance-Publique Hôpitaux de Paris (AP-HP); bLaboratoire de biochimie et cLaboratoire de biologie moléculaire, Hôpital Pitié-Salpêtrière, Paris, France
                71872 Horm Res 2003;60:61–67
                © 2003 S. Karger AG, Basel

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                Page count
                Tables: 4, References: 36, Pages: 7
                Original Paper


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