Non-insulin-dependent diabetes mellitus and atherosclerosis: a lipoprotein perspective.
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Coronary Artery Disease↗
Biomedical subjects
G Steiner
Publications and source records attributed to G Steiner.
Hyperinsulinaemia and hypertriglyceridaemia.
Hyperinsulinaemia and hypertriglyceridaemia are frequently associated. This may be as a part of the syndrome of insulin resistance or in diabetes, particularly non-insulin-dependent diabetes (NIDDM). The importance of this association lies in the facts that atherosclerosis is the most frequent complication of diabetes, that hypertriglyceridaemia is a risk factor for coronary artery disease in diabetic populations and that hyperinsulinaemia also appears to be a risk factor for atherosclerosis. Hypertriglyceridaemia, even without obesity, is associated with resistance to insulin. This can result in compensatory hyperinsulinaemia. Chronic hyperinsulinaemia has been shown to increase the production of triglyceride (TG)-rich lipoproteins. The vast majority of particles in the TG-rich lipoprotein spectrum are in the intermediate-density-lipoprotein (IDL) range. Furthermore, increased levels of TG result primarily from increased numbers of these particles, rather than from increased particle size. This is important because, at least in nondiabetic individuals, increased levels of IDL are associated with increased atherosclerosis. Thus, there may be a vicious cycle of insulin resistance, hyperinsulinaemia, hypertriglyceridaemia and atherosclerosis. We have found that by reducing plasma TG levels alone, one can increase sensitivity to insulin and break this cycle.
Coronary Disease↗
Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein.
A preponderance of small, dense low density lipoprotein (LDL) particles has been linked to increased risk of myocardial infarction, and a dense and protein-rich LDL has proved to be a characteristic of patients with manifest coronary heart disease (CHD). The present study focused on metabolic determinants of the LDL subfraction distribution with the emphasis placed on alimentary lipaemia. The relations of plasma levels and composition of light (1.019 < d < 1.040 kg/l) and dense (1.040 < d < 1.063 kg/l) LDL subfractions to postprandial triglyceride-rich lipoproteins (TGRL), postheparin plasma lipase activities and the activity of cholesteryl ester transfer protein (CETP) were studied in 32 men with angiographically ascertained premature coronary atherosclerosis (age 48.8 +/- 3.2 years) and in 10 age matched healthy control men. LDL subfractions were separated by equilibrium density gradient ultracentrifugation of fasting plasma drawn before participants were subjected to an oral fat tolerance test of a mixed meal type. The response of TGRL to the oral fat load was determined by measuring plasma triglycerides, and the apolipoprotein (apo) B-48 and apo B-100 content of Sf 60-400 and Sf 20-60 lipoprotein fractions. At a second visit plasma samples were taken for determination of postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and for measurement of CETP activity. Hypertriglyceridaemic patients had a preponderance of dense LDL particles compared with normotriglyceridaemic patients and controls. The magnitude of the response of TGRL to the oral fat load showed a positive association with the dense LDL apo B concentration (r = 0.32-0.52, P < 0.05), whereas the LPL activity correlated positively with the free (r = 0.50, P < 0.001) and esterified cholesterol (r = 0.45, P < 0.01) and apo B (r = 0.42, P < 0.01) content of the light LDL fraction. The HL activity was found to be inversely associated with the plasma level of light LDL triglycerides (r = -0.38, P < 0.05). In contrast, no relations were noted between CETP activity and plasma concentrations of LDL constituents. Multiple stepwise linear regression analysis with the proportion of total LDL apo B contained in the dense LDL subfraction (% dense LDL apo B) used as the dependent variable indicated that the combined effect of LPL activity and postprandial plasma levels of TGRL (areas under the curve for plasma triglycerides or Sf 60-400 apo B-48) accounted for around 50% of the variability in the distribution of LDL particles between light and dense subfractions.(ABSTRACT TRUNCATED AT 400 WORDS)
Carrier Proteins↗
Hyperinsulinemia and VLDL kinetics.
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Animals↗
[Methodological studies of the estimation of loss of sodium, potassium,calcium and magnesium through the skin during a 10 km run].
An estimation of the electrolytic losses through the skin was evaluated in a run over a distance of 10 km on a 400 m Tartan-trac. Na, K, Ca, and Mg excreted by the skin were collected in standardised clothing and thereafter washed out. The remaining electrolytes on the skin were collected by washing the body with deionized water. In addition, the concentrations of hormones and metabolites in blood before and after the race were ascertained. Mean ambiant temperature and relative humidity amounted to 21 degrees C and 35%, respectively. The mean performance was 40.5 min. and the average body weight loss was 1.45 kg. The only significant changes in the serum concentrations were the increases of free fatty acids and glycerol. This can be explained, together with a slight increase of glucose and a decrease of insulin, by a higher sympathoadrenergic activity. In the mean 20 mg calcium, 5 mg magnesium, 200 mg potassium, and 800 mg sodium were lost by the skin per kg body weight loss. Those amounts compared well with corresponding data found in literature. The described method can be proposed for further experiments.
Adult↗
A randomized comparative open study of the effects of two oral contraceptives, Triphasil and Ortho 7/7/7, on lipid metabolism.
This study assessed serum lipid, lipoprotein and apolipoprotein changes during one year in 3 groups of nonsmoking women: 1) Triphasil(R); 2) Ortho(R) 7/7/7; 3) Controls. Both oral contraceptives contain the estrogen, ethinyl estradiol(EE), in combination with a progestin in three different ratios during each cycle. The progestin in Triphasil is d-norgestrel, as the dl-racemate norgestrel (NG), whereas that in Ortho 7/7/7 is norethindrone(NE). Total plasma triglycerides were elevated significantly from baseline (p < 0.001) with Ortho 7/7/7 at 3, 6 and 12 months, but only at 3 months with Triphasil, p = 0.047. Triglycerides were elevated in the LDL fraction with Ortho 7/7/7 at 3 months (p = 0.001), 6 months (p = 0.018) and 12 months (p = 0.010). In contrast, LDL triglycerides were not significantly elevated with Triphasil. Similarly, IDL triglycerides were elevated only in the Ortho 7/7/7 group at 6 months (p = 0.002) and 12 months (p = 0.001). Plasma cholesterol was elevated only in the Ortho 7/7/7 group at 3, 6 and 12 months with p values of 0.009, 0.005 and 0.010, respectively. Cholesterol in the LDL fraction was elevated with Ortho 7/7/7 at 12 months (p = 0.002). Plasma apolipoprotein B (apo B) increased at least 24% from baseline for both the Triphasil and Ortho 7/7/7 groups at 3 and 12 months (p < 0.001). However, at 6 months, apolipoprotein B increased only 17.7% (p = 0.008) with Triphasil compared to 29.7% (p < 0.001) with Ortho 7/7/7 at 6 months. Apo B was increased (p < 0.001) in LDL with Triphasil at 3 months only, whereas LDL apo B was increased at 3, 6 and 12 months with Ortho 7/7/7 (p < 0.001, p = 0.020 and p = 0.012, respectively). Apo B increased dramatically in the IDL fraction of both oral contraceptive user populations, with the range of increases being between 48% and 87% during the year (p < 0.001 at all times). Significant elevations in VLDL apo B ranged from 71% to 106% (p < 0.001) with Triphasil and from 42.4% (p < 0.005) to 72.6% (p < 0.001) with Ortho 7/7/7. In conclusion, norethindrone- and dl-norgestrel-formulations have divergent effects on several components of plasma lipoprotein and lipid metabolism, but both products increase plasma and IDL apo B.
Administration, Oral↗
Autoantibody to the nuclear antigen RA33: a marker for early rheumatoid arthritis.
Sera from 47 patients with early (< 3 months) arthritis of any type were investigated for anti-RA33, a new anti-nuclear autoantibody characteristic of RA, and the diagnoses determined within the following 8-14 months. In addition, seven patients with unclassified arthritis of > 4 months duration, who were all anti-RA33 positive, were followed for up to 2 years to establish their final rheumatologic diagnoses. Four of 47 early arthritis patients' sera were anti-RA33 positive at the initial evaluation; 14 of these 47 patients (30%) could be classified as RA (according to established criteria) at the final evaluation. All four anti-RA33 positive patients belonged to the RA group (27% of RA patients); of the 33 non-RA patients none had anti-RA33 (P = 0.005). Rheumatoid factor was found in four RA (none of whom had anti-RA33), but also in two non-RA patients (P = 0.05). Finally, the study involved seven additional patients with longer standing, initially unclassified, anti-RA33 positive arthritis: in all of them a diagnosis of RA could be established within 3 years of disease onset. These results suggest that anti-RA33 helps to discriminate early RA from other forms of early arthritis and, in the absence of an established diagnoses, it is predictive of RA. Its discriminative capacity appears to be better than and complementary to that of RF.
Adolescent↗
Similar frequency of autoantibodies against 70-kD class heat-shock proteins in healthy subjects and systemic lupus erythematosus patients.
Stress or heat-shock proteins may be involved in the initiation and perpetuation of autoimmune diseases. In order to investigate a possible role of autoantibodies against the 70-kD family of heat-shock proteins in systemic lupus erythematosus (SLE), sera of SLE patients and healthy subjects were tested for the presence of IgG and IgM antibodies to 70-kD class proteins. These proteins were purified by affinity chromatography on ATP-agarose and used in Western blotting studies. The data obtained revealed that antibodies to the 72-kD and the 73-kD heat-shock proteins occurred with similar frequencies both in healthy subjects and SLE patients. Thus, approximately 20% of the sera in each group contained IgG antibodies, and IgM antibodies were detected in about 30% of the sera tested. Moreover, in SLE patients no association between the occurrence and titre of these antibodies and disease activity was found. These data suggest that antibodies to the 70-kD class heat-shock proteins are naturally occurring and argue therefore against an involvement of these antibodies in the pathogenesis of SLE.
Antibodies, Antinuclear↗
HDLs and alimentary lipemia. Studies in men with previous myocardial infarction at a young age.
The plasma concentration, particle size, and chemical composition of high density lipoproteins (HDLs) are associated with the metabolism of triglyceride-rich lipoproteins (TGRLs). During alimentary lipemia there is active exchange of lipids and apolipoproteins between HDL and apolipoprotein B-containing lipoproteins. Whereas HDL has been assigned a protective role against the development of atherosclerosis, alimentary lipemia has been proposed to represent a potentially atherogenic state. We examined plasma HDL concentration, particle size, and composition and their relations to postprandial TGRLs in 32 postinfarction patients and 10 healthy control subjects after intake of a standardized oral fat load of a mixed-meal type. All patients had undergone coronary angiographies in connection with the myocardial infarction and around 5 years thereafter. The plasma HDL cholesterol concentration decreased significantly in response to the oral fat load, particularly in hypertriglyceridemic patients, with a concomitant increase of HDL triglycerides. A limited and reversible yet consistent increase of HDL particle size (1-2%) was seen 6 hours after intake of the oral fat load on nondenaturing gradient gel electrophoresis (GGE) in both patients and control subjects. Virtually no changes in the plasma concentration of HDL GGE subclasses, lipoproteins containing apolipoprotein A-I but no apolipoprotein A-II (LpA-I), or lipoproteins containing both apolipoproteins A-I and A-II (LpA-I:A-II) were induced in the postprandial state despite massive increases of large very low density lipoprotein (VLDL) and large chylomicron remnant levels (determined as apolipoproteins B-100 and B-48 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Strong inverse correlations with fasting plasma HDL cholesterol and the larger HDL GGE subspecies were found for large postprandial VLDL and large chylomicron remnants, whereas the corresponding relations for small VLDL and small chylomicron remnants were weaker. The relations of both large and small VLDL and chylomicron remnants to HDL cholesterol were confined to subjects in the lower fasting plasma HDL cholesterol range (< 1.2 mmol/l). None of the HDL parameters measured, either in the fasting or in the postprandial state (HDL cholesterol, HDL triglycerides, HDL GGE subclasses, LpA-I, and LpA-I:A-II), were related to the development of coronary atherosclerosis, whereas the postprandial plasma levels of small chylomicron remnants, which showed weak negative correlations with HDL, related positively to the progression of coronary atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Metabolism of triglyceride-rich lipoproteins during alimentary lipemia.
The metabolism of chylomicron remnants and VLDL was studied in healthy controls and normo- (NTG) and hypertriglyceridemic (HTG) patients with coronary artery disease after intake of an oral fat load. Specific determination of apo B-48 and B-100 enabled separation of the respective contribution of the two lipoprotein species. The postprandial plasma levels of small (Sf 20-60) and large (Sf 60-400) chylomicron remnants increased in controls and NTG patients. In contrast, only large chylomicron remnants increased in the HTG patients. An increase of large VLDL was seen in response to the oral fat load in all groups, whereas small VLDL were either unchanged in the controls and the NTG patients, or decreased in the HTG patient group. The whole plasma concentration of C apolipoproteins was essentially uninfluenced by the oral fat load, whereas the content in large triglyceride-rich lipoproteins paralleled the apo B elevations in controls and NTG patients. An even more prominent increase of apo B in large triglyceride-rich lipoproteins in the HTG group was not accompanied by an increase of C apolipoproteins. These findings indicate that chylomicrons compete with VLDL for removal of triglycerides by lipoprotein lipase and that the postprandial metabolism of triglyceride-rich lipoproteins is severely defective in hypertriglyceridemia.
Apolipoproteins B↗
Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals.
The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.
Acute Disease↗
Triglyceride-rich lipoproteins and atherosclerosis, from fast to feast.
There is increasing evidence that fasting hypertriglyceridaemia identifies individuals who are at increased risk for coronary artery disease. It is probable that this reflects the effects of the smaller triglyceride-bearing lipoproteins. It may also reflect increased levels of postprandial lipoproteins. There is considerable theoretical and experimental evidence to support an atherogenic role for the smaller, triglyceride-rich postprandial lipoproteins. Cross-sectional studies in humans also indicate that those with coronary disease have increased levels of postprandial lipids, probably in the remnants of chylomicrons. Recently we have completed a study examining the progression of coronary atherosclerosis angiographically. The study showed that the progression was linearly related to the numbers of chylomicron remnant particles, as reflected by the quantity of apoB48 in Sf20-60 lipoproteins, in the postprandial circulation. This paper reviews these studies, the physiology of postprandial lipoprotein metabolism and the therapeutic implications of this information.
Arteriosclerosis↗
[Methodological studies on estimating the loss of sodium, potassium, calcium and magnesium exemplified by a 10-km run].
An estimation of the electrolytic losses through the skin was evaluated in a run over a distance of 10 km on a 400 m track. Na, K, Ca and Mg excreted by the skin were collected in standardised clothes and thereafter washed out. The remaining electrolytes on the skin were collected by washing the body with deionized water. In addition the concentrations of hormones and metabolites in blood before and after the race were measured. Mean ambient temperature and relative humidity amounted to 21 degrees C and 35%, respectively. The mean performance was 40.5 min. and the average body weight loss was 1.45 kg (1.95% of body weight). The only significant changes in the serum concentrations were the increases of free fatty acids and glycerol. This can be explained, together with a slight increase of glucose and a decrease of insulin, by a higher sympathoadrenergic activity. In the mean 20 mg calcium, 5 mg magnesium, 200 mg potassium and 800 mg sodium were lost by the skin per kg body weight loss. These values compared well with corresponding data found in literature. The described method can therefore be proposed for further experiments.
Adult↗
Purification and partial sequencing of the nuclear autoantigen RA33 shows that it is indistinguishable from the A2 protein of the heterogeneous nuclear ribonucleoprotein complex.
RA33 is a nuclear autoantigen with an apparent molecular mass of 33 kD. Autoantibodies against RA33 are found in about 30% of sera from RA patients, but only occasionally in sera from patients with other connective tissue diseases. To characterize RA33, the antigen was purified from HeLa cell nuclear extracts to more than 90% homogeneity by affinity chromatography on heparin-Sepharose and by chromatofocusing. Sequence analysis of five tryptic peptides revealed that their sequences matched corresponding sequences of the A2 protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. Furthermore, RA33 was shown to be present in the 40S hnRNP complex and to behave indistinguishably from A2 in binding to single stranded DNA. In summary, these data strongly indicate that RA33 and A2 are the same protein, and thus identify on a molecular level a new autoantigen.
Amino Acid Sequence↗
Can treatment with the monoclonal antibody BMA031 induce cytokine release?
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Antibodies, Monoclonal↗
Acquired (secondary) forms of hypertriglyceridemia.
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Diabetes Complications↗
Management of hypertriglyceridemic patients. A. Treatment classifications and goals.
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Algorithms↗
Detection of silent myocardial ischemia in diabetes mellitus.
The prevalence of silent myocardial ischemia and its relation to autonomic dysfunction and pain threshold was studied in 58 men with diabetes mellitus and without cardiac symptoms. All patients underwent 48-hour ambulatory electrocardiographic monitoring and exercise testing after assessment of their autonomic function and pain threshold. Silent myocardial ischemia, defined as greater than or equal to 1 mm of ST-segment depression on either exercise testing or ambulatory electrocardiographic monitoring, was corroborated by exercise-induced reversible defect(s) on tomographic thallium scintigraphy. Autonomic function was assessed by heart rate response to: (1) Valsalva maneuver, (2) deep breathing, and (3) upright posture, as well as by diastolic blood pressure response to sustained handgrip and systolic blood pressure response to upright posture. Autonomic dysfunction was defined as greater than or equal to 2 abnormal responses. Pain threshold measurements were performed using electrical cutaneous stimulation of both forearms. Of the 58 diabetic patients, 21 were found to have autonomic dysfunction (36%). Silent myocardial ischemia was detected in 10 patients (17%), and was significantly more frequent in patients with than without autonomic dysfunction (38 vs 5%, p = 0.003). There was no difference in the electrical pain threshold or tolerance in subjects with and without silent myocardial ischemia. It is concluded that silent myocardial ischemia in asymptomatic diabetic men occurs frequently and in association with autonomic dysfunction, suggesting that diabetic neuropathy may be implicated in the mechanism of silent myocardial ischemia.
Adult↗