Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls (P < 0.05) and had raised concentrations of proinsulin (P < 0.05), although insulin content did not differ significantly. 32-33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients (P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls (P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls (P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects (P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics (P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state (R2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants (R2 = 61%) of LDL-III.
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PMID:Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance. 760 66

To determine whether nonhuman primates demonstrate the same alterations in transport of cholesteryl ester (CE) in plasma observed in diabetic humans, cholesteryl ester transfer (CET) was measured in cynomolgus monkeys with chronic spontaneous diabetes mellitus (glycated hemoglobin: diabetics 10.7 +/- 4.1%; controls 3.8 +/- 0.8%, P < 0.005). Among the plasma lipids, only triglycerides were significantly increased in diabetic monkeys (diabetics 303 +/- 294 mg/dl; controls 85 +/- 34 mg/dl; P < 0.05); total plasma, LDL, HDL2, and HDL3 cholesterol concentrations did not differ significantly from those of control animals. Similar to human beings with insulin-dependent and non-insulin-dependent diabetes mellitus, CET estimated both as the mass of cholesteryl ester transferred from HDL to the apoB-containing lipoproteins (VLDL + LDL) and as the loss of radiolabeled cholesteryl ester from HDL was significantly greater (P < 0.001) in diabetic compared to control monkeys. Glycated hemoglobin levels in the combined control and diabetic groups correlated directly with both the mass of cholesteryl ester transferred at 2 h (r = 0.75; P < 0.001) and the isotopic transfer (k) (r = 0.64; P < 0.005). The mass of cholesteryl ester transfer protein (CETP) tended to be higher in the diabetic animals (diabetic 4.06 +/- 0.73 microgram/ml versus control 3.05 +/- 0.93; P < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Accelerated cholesteryl ester transfer and altered lipoprotein composition in diabetic cynomolgus monkeys. 761 22

High density lipoprotein (HDL) subfractions (2b, 2a, 3a, 3b, and 3c) separated by gradient gel electrophoresis (GGE) and defined by Gaussian summation analysis, and the compositions of HDL2 and HDL3, separated by preparative ultracentrifugation, were studied in four groups of men with or without non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD): group 1 (DM+CAD+, n = 50); group 2 (DM-CAD+, n = 50); group 3 (DM+CAD-, n = 50); and group 4 (DM-CAD-, n = 31). HDL GGE subfraction distributions, available in 125 subjects, were not significantly different among the groups. In contrast, dividing the whole study population into quartiles of serum triglyceride (TG) concentration showed that high TG levels were significantly associated with low HDL2b and high HDL3b concentrations. In a multivariate linear regression model, postheparin plasma hepatic lipase (HL) activity, and fasting serum insulin and TG concentrations were all associated independently and inversely with low HDL2b, but lipoprotein lipase or cholesteryl ester transfer protein activities were not correlated with HDL2b concentrations. Group 1 tended to have the smallest mean particle sizes in the HDL subfractions, significantly (P < 0.03, CAD vs. non-CAD) for HDL2b and for HDL2a. These differences were independent of TG, insulin and HL, but lost their significance when adjusted for beta-blocker therapy. Both HDL2 and HDL3 particles in group 1 were significantly depleted of unesterified cholesterol, and their HDL2 was TG-enriched (P = 0.053). A high HL activity, hyperinsulinemia and hypertriglyceridemia are independently associated with low levels of HDL2b and generally small HDL particle size. HDL particles in subjects with NIDDM and CAD are small-sized and have a low free cholesterol content. Both these characteristics may be markers of impaired reverse cholesterol transport.
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PMID:High density lipoprotein subfractions in non-insulin-dependent diabetes mellitus and coronary artery disease. 777 69

The effect of variation at the cholesteryl ester transfer protein (CETP) gene locus and in the apolipoprotein (apo) AI-CIII-AIV gene cluster on the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 136 male and 122 female patients with NIDDM. The prevalence of myocardial infarction was high (38%) in patients with the EcoNI genotype 2-2 of the CETP gene locus (= 2-2; subjects homozygous for the absence of the restriction site) compared with patients with the genotype 1-1 (= 1-1; subjects homozygous for the presence of the restriction site) (18%, p < 0.02). The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was high in 2-2 (73%) compared with the genotype 1-2 (= 1-2; heterozygous for the presence of the restriction site) (52%, p < 0.02) and genotype 1-1 (p = 0.06). CHD was more prevalent in men with 2-2 (70%) than in those with 1-1 (42%, p < 0.05), but in women no significant differences were found in the prevalences of CHD between the EcoNI genotypes. Neuropathy was more often present in the patients with 2-2 (31%) than in those with 1-1 (12%, p < 0.02) or 1-2 (14%, p < 0.01). Plasma total cholesterol and total- and VLDL-triglycerides were higher in women with the EcoNI genotype 1-1 than in those with the genotype 1-2. In men no significant differences in plasma lipids were found. In addition, the prevalence of cerebrovascular disease was high (21%) in the patients with the genotype 1-1 of the TaqIB polymorphism compared with the genotype 2-2 (6%, p < 0.02). None of the alleles defined by four polymorphisms in the apo AI-CIII-AIV gene region were associated with an increased risk for macroangiopathy. The PstI polymorphism had an effect on plasma triglyceride levels. At the CETP locus one pair of loci (TaqIB and EcoNI) and three pairs of loci at the apo AI-CIII-AIV gene cluster (SacI and MspI, SacI and PvuII and MspI and PvuII) showed significant allelic association. In conclusion, the variation of CETP locus modulates the risk for diabetic complications in patients with NIDDM and the effect seems to be different between men and women. In contrast, the AI-CIII-AIV gene cluster polymorphisms seem not to be related to the risk of CHD in NIDDM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:DNA polymorphisms at the locus for human cholesteryl ester transfer protein (CETP) are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus. 782 Sep 35

Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (CET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA1c IDDM, 6.9 +/- 1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P < .001) and both systemic insulin levels and LPL specific activity were increased (P < .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22 +/- 6.5 versus IP, 2.77 +/- 2.4 microU/mL; mean +/- SD; P < .025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL2) cholesterol, HDL3 cholesterol, cholesteryl ester transfer protein mass, and glycemic control (HbA1c, 6.3 +/- 0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus. 798 Nov 82

The present study was designed to evaluate the potential role of plasma cholesteryl ester transfer protein (CETP) activity in the regulation of high-density lipoprotein (HDL) subclasses in non-insulin-dependent diabetes mellitus (NIDDM). We studied 45 men with NIDDM and angiographically defined coronary artery disease ([CAD] DM+CAD+, aged 54.4 +/- 6.1 years, mean +/- SD); 47 nondiabetic men with similarly proven CAD (DM-CAD+, aged 54.9 +/- 6.6 years; 43 men with NIDDM but no CAD (DM+CAD-, aged 55.2 +/- 7.3 years); and 29 nondiabetic men without CAD (DM-CAD-, aged 53.2 +/- 5.3 years). The groups were matched for age and body mass index (BMI). Plasma CETP activity was determined by measuring the ability of the plasma sample to transfer esterified cholesterol from exogenous 14C-cholesteryl ester-labeled low-density lipoprotein (LDL) to exogenous HDL. Plasma lipoproteins were separated by ultracentrifugation. The concentration of HDL cholesterol was reduced in the DM+CAD+ group as compared with the DM-CAD- group (P < .01). This change was due to a decrease of both HDL2 cholesterol (P < .05) and HDL3 cholesterol (P < .001). There was a clear-cut decrease in HDL3 cholesterol in the DM-CAD+ (P < .01) and DM+CAD- (P < .05) groups as compared with the DM-CAD- group. Plasma CETP activity was lower in the DM+CAD- group (1.06 +/- 0.24 arbitrary units [AU]) than in the DM-CAD- group (1.19 +/- 0.26 AU, P < .05). In the DM+CAD+ group, the mean of CETP activities was 1.09 AU.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma cholesteryl ester transfer protein activity in non-insulin-dependent diabetic patients with and without coronary artery disease. 799 Jul 2

In IDDM patients, serum high-density lipoprotein cholesterol concentrations have been reported to be normal or elevated. The spectrum of high-density lipoprotein particles is highly heterogeneous, but no data are available on the subpopulations of high-density lipoprotein in IDDM. We, therefore, studied the spectrum of high-density lipoprotein particles in 86 IDDM patients (51 men and 35 women) 37 +/- 10 yr of age and in 74 sex-, age-, and body mass index-matched healthy nondiabetic subjects. The concentrations of high-density lipoprotein and HDL2 cholesterol were higher in the IDDM group than in the control subjects (P < 0.01). The apoA-I-to-apoA-II ratio was higher in the IDDM patients than in the nondiabetic subjects (P < 0.001) because of an increased concentration of LpA-I particles (61 +/- 17 vs. 53 +/- 15, P < 0.01). LpA-I particles correlated positively with high-density lipoprotein and HDL2 cholesterol in the two groups. Postheparin plasma lipoprotein lipase activity was significantly higher in the IDDM group than in the control group (P < 0.001), whereas postheparin plasma hepatic lipase activities were similar in both groups. Plasma cholesteryl ester transfer protein activity was estimated in an in vitro isotopic assay using exogenous labeled donor (low-density) and acceptor (high-density) lipoproteins in the absence of native lipoproteins. We observed no difference in cholesteryl ester transfer protein activity between the groups, and no significant correlations existed between cholesteryl ester transfer protein activity and high-density lipoprotein subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Sep
PMID:Regulation of apolipoprotein A-I-containing lipoproteins in IDDM. 834 39

Elevated levels of plasma triglycerides (TG) and reduced concentrations of HDL cholesterol are very common in patients with diabetes, particularly NIDDM. Although regulation of the plasma concentrations of VLDL, the major TG-rich lipoprotein is extremely complex, it is clear from in vivo kinetic studies that increased rates of secretion of VLDL into plasma is almost uniformly present in patients with NIDDM and hypertriglyceridemia. Recent studies at the cellular level indicate that increased fatty acid flux to the liver, also common in NIDDM (and other insulin-resistant states associated with elevated plasma TG levels), will stimulate the assembly and secretion of apoprotein (apo) B-containing lipoproteins by targeting apoB for secretion rather than intracellular degradation. Increased rates of secretion of VLDL into plasma appears to drive the exchange of TG from these lipoproteins for HDL cholesteryl ester. This exchange, which occurs in plasma, is facilitated by cholesteryl ester transfer protein, and generates a TG-enriched HDL that is a substrate for either hepatic lipase or lipoprotein lipase. When the TG in HDL is hydrolyzed, the resultant particle is smaller, and this appears to affect the binding of the major HDL protein, apoA-I. ApoA-I dissociates from the smaller, lipid-poor HDL, and the free apoA-I (molecular weight 28,000) can be filtered by the glomerulus in the kidney and most likely is degraded in renal tubular cells after reabsorption. Thus, increased free fatty acid transport in plasma, a common abnormality in insulin-resistant states, may be the underlying driving force for the two common lipid abnormalities seen in diabetes.
Diabetes 1996 Jul
PMID:Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. 867 85

Patients with insulin-dependent diabetes mellitus (IDDM) have a pathological increase in cholesteryl ester transfer (CET) that enriches the apolipoprotein B-containing lipoproteins with cholesteryl ester and increases their atherogenicity. Since we have shown earlier that omega-3 (n-3) fatty acids present in marine lipids normalize both CET and lipoprotein composition in non-diabetic patients with hypercholesterolaemia, we sought to determine whether the same beneficial effects could be achieved in nine normolipidaemic (triglycerides 1.10; cholesterol 4.94, high density lipoprotein 1.10 mmol/l) IDDM patients (fructosamine 424 +/- 156; normal 174-286 mumol/l) treated for 2 months with n-3 fatty acids (4.6 g/day). Before treatment, CET measured by both mass and isotopic assays was abnormally accelerated (p < 0.001). While marine lipids modestly decreased triglyceride levels (-14%; p < 0.05 ), CET fell dramatically in all subjects (mass assay: -97% at 1 h; isotopic assay: -58%; p < 0.001) to below control levels with no change in glycaemic control (fructosamine 408 +/- 103 mumol/l). The mass of cholesteryl ester transfer protein paradoxically increased significantly (pre-treatment: 2.04 +/- 0.86 vs post-treatment 2.48 +/- 0.97 micrograms/ml; p < 0.05). Since it is believed that accelerated CET promotes the formation of atherogenic cholesteryl ester-enriched apo B-containing lipoproteins, the capacity of marine lipids to reverse this functional abnormality without altering glycaemic control suggests that these agents may have an adjunctive role to play in the nutritional therapy of IDDM.
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PMID:Marine lipids normalize cholesteryl ester transfer in IDDM. 877

Cholesteryl esters (CE) exchange between lipoproteins through the action of cholesteryl ester transfer protein (CETP). Situations at high risk for atherosclerosis are often accompanied by an accelerated net mass CE transfer (CET) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). However, the question as to whether the net mass CET is increased or decreased in non-insulin-dependent diabetes mellitus (NIDDM) has led to controversial data. To clarify this point, we have undertaken a detailed study of CET in 105 NIDDM patients by comparison with 17 control subjects. Net mass CET was approximately doubled in NIDDM. Plasma CETP activity and unidirectional CET from HDL to VLDL + LDL (CETHDL-->VLDL + LDL) or from VLDL + LDL to HDL (CETVLDL + LDL-->HDL) were measured under controlled lipoprotein concentrations using radioisotopic assays. No difference was observed in plasma CETP activity between NIDDM and controls. In NIDDM, CETHDL-->VLDL + LDL and CETVLDL + LDL-->HDL were decreased by 25% and 20%, respectively, as a consequence of alterations in lipoprotein compositions. Net mass CET was highly correlated with plasma triglyceride (TG) concentration (r = 0.66, P < 0.001) but not with that of LDL-cholesterol (r = 0.06, P > 0.6). When TG levels were decreased following dietetic recommendations or insulinotherapy, the net mass CET was lowered accordingly. We conclude that net mass CET is accelerated in NIDDM in spite of a decreased unidirectional CETHDL-->VLDL + LDL. This results from a lowered CETVLDL + LDL-->HDL and from elevated TG concentration, and the latter probably reflects a concentration effect of VLDL.
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PMID:Alterations in composition and concentration of lipoproteins and elevated cholesteryl ester transfer in non-insulin-dependent diabetes mellitus (NIDDM). 878 40


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