Severe hypertriglyceridaemia in Type II diabetes: involvement of apoC-III Sst-I polymorphism, LPL mutations and apo E3 deficiency

Abstract

Hypertriglyceridaemia and reduced HDL-cholesterol concentrations are the prominent features of the atherogenic dyslipaemia commonly observed in insulin-resistance states [1,2] and Type II (non-insulin-dependent) diabetes mellitus [3±6]. Severe hypertriglyceridaemia is not uncommon in Type II diabetes [7,8] but its prevalence and mechanism are not clearly established. Mild hypertriglyceridaemia in Type II diabetes is dependent upon glucose control and nutritional factors such as intake of carbohydrates and alcohol. Genetic factors might, however, determine individual susceptibility to major hypertriglyceridaemia. Although VLDL hepatic overproduction is well documented in Type II diabetes, genetic defect in the clearance of the triglyceride-rich Diabetologia (2000) Abstract Aims/hypothesis. Hypertriglyceridaemia is common in Type II (non-insulin-dependent) diabetes mellitus. Only subgroups of patient however have type V hyperlipidaemia. To investigate the coordination between genetic factors in the modulation of hypertriglyceridaemia in Type II diabetes, we studied three major modifier loci: apoC-III (both Sst-I and insulinresponsive element polymorphisms), apolipoprotein E genotypes and lipoprotein-lipase mutations. Methods. We studied apoCIII gene polymorphisms, apolipoprotein E genotypes and lipoprotein-lipase gene mutations in 176 patients with Type II (non-insulin-dependent) diabetes mellitus, either normolipaemic (group N, n = 116), mildly hypertriglyceridaemic (group T, n = 28) or with a history of severe hypertriglyceridaemia (triglyceride > 15 g/l) (group H, n = 32). Results. Mild hypertriglyceridaemia in Type II diabetes did not associate with any gene variants in this study. Severe hypertriglyceridaemia was, however, associated with the presence of the apoC-III S2 allele (50 % of the patients in group H compared with 15.5 % in group N, p < 0.0001). Additionally this particular phenotype was associated with a low prevalence of the apo E3 allele (35.9 % in group H vs 18.1 % in group N, p < 0.005) and a statistically significant over-representation of the E2E4 genotypes. Inactivating lipoprotein-lipase mutations were found in four patients (three heterozygotes, one homozygote), none was found in group N or T. Thus 68.7 % of group H patients (22/32) (vs 21.4 % in group T, p < 0.0005) were carriers of either S2 allele, lipoprotein-lipase mutants or E2E4 genotype with most lipoprotein-lipase mutants or E2E4 genotypes or both in the non-carriers for the S2 allele (6/7). Conclusion/interpretation. Our results strongly support the hypothesis that severe hyperlipaemia in Type II diabetes crucially depends on genetic factors which impair the clearance of triglyceride-rich lipoproteins.

Lipolysis, and Not Hepatic Lipogenesis, Is the Primary Modulator of Triglyceride Levels in Streptozotocin-Induced Diabetic Mice

“…Most humans with diabetes do not have marked hypertriglyceridemia. However humans, like mice, that have a defect in LpL regulation are most likely to develop severe hypertriglyceridemia with diabetes 60, 62,63. On the other hand, humans with robust LpL activity are likely to be protected from hypertriglyceridemia regardless of their degree of insulin deficiency or resistance.…”

Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment

“…Genomic DNA was extracted as described (5). Prior to direct sequencing of the APOA5 (nt -25 to +1820), genomic DNA (0.2 µg) was subjected to PCR with the 2 primers APOA5gF1 (5′-CAGGT-GGGCAGGGGAGAGGTGGTA-3′) and APOA5gR1 (5′-ATGGCAGCCCT-GGGGAGACAAGTG-3′) generating a 2526-bp product.…”

“…Severe hypertriglyceridemia (HTG) is a general condition with a few well-documented genetic contributors, including lipoprotein lipase (LPL), APOC2, and APOE, as well as environmental factors such as diet and/or conditions such as pregnancy and diabetes (2)(3)(4)(5). While genetic factors account for a large proportion of the rare type 1 hyperlipidemia, the complex interaction between genetics and environment is only partly understood in the more common type 5 hyperlipidemia.…”

Association of lipoprotein lipase (LPL) single nucleotide polymorphisms with type 2 diabetes mellitus

“…In T2DM, LPL activity is commonly deficient and contributes to the increased level of serum TGs and the decreased level of HDL (Taskinen, 1987;Klannemark et al, 2000;Kalmar et al, 2005). Several studies have shown an association between genetic variations in LPL and lipid metabolism in T2DM patients (Marcais et al, 2000;Ma et al, 2003;Socquard et al, 2006). For example, an association between higher plasma TGs and lower HDL cholesterol levels and the H+ allele of LPL HindIII polymorphism has been reported in Chinese patients with early-onset T2DM (Ma et al, 2003).…”