SummaryTo answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric gg/min, median and range], in 46 microalbuminuric btg/min] and in 33 proteinuric [AER 422 (233-1756)btg/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger L DL particles than non-diabetic control subjects (260 A vs 254 A, p < 0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p < 0.05 for normoalbuminuric andp < 0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p < 0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p < 0.05 for both) was mainly due to the increment of light LDL (density 1.0212-1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles. The prevalence of atherogenic small dense LDL particles in IDDM patients with microalbuminuria and proteinuria is closely dependent on plasma triglyceride concentration. [Diabetologia (1994) 37: 681q588] Key words IDDM, diabetic nephropathy, microalbuminuria, proteinuria, lipid metabolism, small dense LDL Cardiovascular disease is the major cause of excess morbidity and mortality among IDDM patients [1][2][3][4]. In particular the patients with diabetic nephropathy are at high risk of cardiovascular disease and have a relative Abbreviations: AER, urinary album excretion rate; CETR cholesteryl ester transfer protein; IDDM, insulin-dependent diabetes mellitus; CHD, coronary heart disease; ApoB, apolipoprotein B. mortality 30-times higher than patients without nephropathy [5,6]. Recently, microalbuminuria per se has been recognized as a risk marker for CHD mortality in both NIDDM and non-diabetic populations [7][8]. In IDDM patients microalbuminuria predicts the development of clinical proteinuria but so far the impact of microalbuminuria on CHD mortality in IDDM has been evaluated only in small groups [9]. The link between dyslipidaemias and diabetic nephropathy is commonly recognized, and lipid abnormalities may contribute to the excess CHD risk although the quantitative and differential impact of the several risk factors present in these...

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

SummaryThe activities of hepatic and lipoprotein lipase and the levels of lipo-and apoproteins were compared in two groups of normoglycaemic men representing the highest (n = 18) and lowest (n = 15) fasting insulin quintiles of first degree male relatives of non-insulin-dependent diabetic patients. The high insulin group representing insulin-resistant individuals had significantly lower post-heparin plasma lipoprotein lipase activity than the low insulin group (14.2 + 4.0 vs 20 + 5.8 ~mol NEFA-m1-1 9 h -1, p < 0.001); hepatic lipase activity did not differ between the two groups (24.2 + 11 vs 18.0 _+ 5.3 ~mol NEFA-ml -~ . h -1, NS). The lipoprotein lipase/hepatic lipase ratio in the high insulin group was decreased by 66 % as compared to the low insulin group (0.75 + 0.57 vs 1.25 +_ 0.65, p < 0.01). In the high insulin group both total and VLDL triglycerides were higher than in the low insulin group (1.61 + 0.57 vs 0.86 + 0.26 mmol/1, p < 0.001 and 1.00 + 0.47 vs 0.36 + 0.16 mmol/1, p < 0.001, respectively) whereas HDL cholesterol and HDL 2 cholesterol were lower (1.20 + 0.30 vs 1.43 + 0.22 mmol/1, p<0.05 and 0.49+0.21 vs 0.71+0.17mmol/1, p < 0.05, respectively). Total cholesterol, LDL cholesterol or HDL 3 cholesterol did not differ between the two groups. The mean particle size of LDL was smaller in the high insulin group than in the low insulin group (258 + 7 vs 265 + 6 A, p < 0.05). We propose that the changes of lipoprotein lipase and lipoprotein lipase/hepatic lipase ratio cluster with insulin resistance and provide a possible mechanism to explain the lowering of HDL cholesterol and elevation of triglyceride concentrations observed in insulin-resistant subjects. [Diabetologia (1995) rides and lowering of HDL-cholesterol, is an inherent feature in this cluster of metabolic abnormalities which also include insulin resistance, hyperinsulinism, central obesity, impaired glucose tolerance or non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. Recently, the preponderance of small dense LDL has been linked with this constellation [4,5]. The lipoprotein pattern has been termed as the atherogenic lipoprotein phenotype and it is associated with excess risk of coronary heart disease [6, 7].A major challenge is to define the causal sequence between dyslipidaemia and insulin resistance. Several studies have demonstrated that fasting insulin is related to high trigtyceride levels [8][9][10][11]. Substantial evidence indicates that hypertriglyceridaemia is indeed