Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL₂-CE (r= −0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL₂-CE remained unchanged. Postprandial HDL₃ of controls were enriched with phospholipid (PL) (30.3 ± 2.6% at 6 h) with respect to fasting (25.6 ± 2.5%, P < 0.01) and to NIDDM-HDL₃ (25.8 ± 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL₂-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL₃ with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL₃ enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.     

Determinants of lipid and lipoprotein level in elderly men

In an effort to better understand the relationship existing between lipoprotein pattern and longevity, we studied the lipid and lipoprotein distribution of 94 men over age 80 who lived in a nursing home, and assessed the role of selective mortality, body mass and sex hormone secretion in determining these distributions. High density lipoprotein subfraction and serum testosterone measurements were obtained on subsamples. The main findings were: (a) Presence of a lipoprotein pattern characterized by low LDL (total serum cholesterol: 179.6 ± 36.0 mg/dl; LDL cholesterol: 106.3 ± 31.2 mg/dl) and high HDL₂ cholesterol (18.5 ± 10.2 mg/dl) levels. (b) Occurrence of a positive association between LDL and HDL₃ (r = 0.51, P < 0.01), resulting in an overall high HDL₂/HDL₃ ratio. Mortality over a 6-month period was directly related to LDL level and possibly inversely related to HDL₂ level, suggesting that selective mortality played a major role in determining the pattern observed. Body mass and serum testosterone concentration, which tended to be low, were independently correlated with lipoprotein level, a particularly strong correlation (positive) existed between free testosterone and triglyceride (r = 0.68, P < 0.01). The latter results suggest that changes related to senescence also influenced lipid and lipoprotein levels.     

Different effects of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity

Two progestins with different androgenic activity were compared for their effects on plasma high density lipoproteins and postheparin plasma lipase activities in premenopausal women. Levonorgestrel, a nortestosterone-derived steroid with androgenic activity reduced plasma HDL cholesterol by 17% (P < 0.05) and HDL₂ cholesterol by 30% (P < 0.05), without changing the HDL₃ cholesterol concentration. At the same time the postheparin plasma hepatic lipase activity was increased by 56% (P < 0.01) whereas the lipoprotein lipase was not changed. None of these effects was reproduced during administration of medroxyprogesterone acetate, a progestin with low androgenic activity. The results suggest, first, that the decrease of HDL cholesterol observed during treatment with progestins is related to the androgenic activity of the steroid used, and, second, that the change in HDL (HDL₂) is caused by androgen-induced increase of hepatic lipase activity.     

Reduced platelet serotonin content and release in familial hypercholesterolaemia

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (−37%, P<0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH patients were combined (r=−0.48, P=0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r=−0.59, P=0.03; normal and FH data, r=−0.49, P=0.004) but positively with high-density lipoprotein (HDL) (FH, r=0.79, P=0.001; normal and FH, r=0.37, P=0.03). Collagen (5–160 μg/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 μg/ml collagen, −40%, P<0.05) and accompanied by increased collagen EC₅₀ values (P<0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.     

Glucose and insulin responses to intravenous glucose challenge in relatives of Nigerian patients with non-insulin-dependent diabetes mellitus

We analysed blood insulin and glucose concentrations before and during frequently sampled intravenous glucose tolerance tests (FSIGT) in 2 groups of Nigerian subjects: (A) Control group (n = 18), without a positive family history of diabetes mellitus, and (B) Experimental group (n = 16), comprising age-, sex- and body mass-matched first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM). In comparison with Group A subjects, those in Group B had: (i) higher fasting plasma glucose level (mean ± S.E.M., 4.1 ± 0.1 vs. 3.8 ± 0.11 mmol/l, P < 0.05); (ii) similar fasting serum insulin levels (6.7 ± 5.0 vs. 5.8 ± 5.6 mU/l, P = NS); (iii) lower mean incremental area under the first-phase (t = 0–10 min) post-glucose challenge insulin curve (376.9 ± 8.8 vs. 435.6 ± 5.6 mU/min l⁻¹, P < 0.05); (iv) increased incremental area under the second-phase (t = 10–182 min) post-glucose challenge insulin curve (432.9 ± 11.5 vs. 161.3 ± 8.7 mU/min l⁻¹, P < 0.05); (v) reduced K_G rate constant of glucose elimination (0.97 ± 0.12 vs. 1.41 ± 0.12%/min, P < 0.05). These results suggest that the subjects with a positive family history of NIDDM have a reduced beta-cell insulin secretory reserve (from reduced first-phase insulin response), tendency to rebound hyperinsulinemia during the latter phase of the insulin secretory response, a degree of tissue insulin insensitivity (as evident from high fasting plasma glucose despite similar insulin levels) and a diminished glucose disposal rate, in comparison with subjects without a family history of NIDDM. These features predict subsequent development of diabetes and suggest that as in Caucasians, first-degree relatives of Nigerian patients with NIDDM are at greater risk for future development of the disease.     

Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency

Six homozygous, 10 heterozygous and 8 unaffected subjects in a CETP deficient family confirmed by CETP gene analysis were studied to characterize serum lipoproteins separated by ultracentrifugation, and to examine the relations between CETP levels and lipoprotein lipid concentration and composition. The serum CETP levels were measured by radioimmunoassay using ¹²⁵I-labeled monoclonal antibodies (TP2). The serum CETP levels in the homozygotes were undetectable and those in the heterozygotes were significantly lower than those in the unaffected subjects (1.5 ± 0.1 vs. 2.2 ± 0.5 μg/ml, P < 0.01). In the HDL fraction, esterified cholesterol (EC) levels in the homozygotes were significantly increased (P < 0.01), and those in the heterozygotes were slightly increased (n.s.), in comparison with those in the unaffected and the normolipidemic controls. The EC levels in the IDL fractions were lower in the homozygotes than in the normolipidemic controls. The EC/triglyceride (TG) molar ratios in IDL, the fraction obtained from the homo- and heterozygotes, were lower than those from the unaffected subjects (P < 0.01 and < 0.01, respectively), and the EC/TG ratios in the HDL fraction obtained from the homo- and heterozygotes were higher than those from the unaffected subjects (P < 0.01 and n.s., respectively). Linear regression analysis showed that positive correlates of the serum CETP levels in all subjects were: IDL-EC (r = 0.463), HDL-TG (r = 0.603) and VLDL- and IDL-EC/TG ratio (r = 0.698 and and 0.843). When the homozygotes were excluded from the analysis, the EC/TG ratios in VLDL IDL were still positively correlated with the serum CETP levels (r = 0.677 and 0.676). Inverse correlates of the serum CETP levels in all subjects were: HDL-EC (r = −0.783) and HDL-EC/TG ratio (r = −0.739). These results suggested that the decreased CETP concentration decreased IDL-cholesterol and increased HDL-cholesterol levels through reducing transport of EC from HDL to IDL, and produced an anti-atherogenic plasma lipoprotein pattern.     

Study of the rate of early glucose disappearance following insulin injection: insulin sensitivity index

The euglycaemic hyperinsulinaemic glucose clamp is usually considered as the reference technique to evaluate insulin sensitivity. As it is an-expensive and time-consuming tool, we therefore tried to validate a simple insulin tolerance test (ITT) (IV bolus of 0.1 IU/kg of regular insulin, with glucose sampling at −5, 0, 3, 5, 7, 10 and 15 min) and to demonstrate its usefulness. Insulin sensitivity was measured by DG/G0 ratio (G0 = initial glycaemia, DG is the variation between G0 and the glycaemia obtained at 15 min by the calculation of the regression plot). We confirmed the existence of a correlation between the glucose uptake (mg/kg per min) evaluated by glucose clamp and the DG/G0 index (r = 0.9, P < 0.01). There was no stimulation of hormonal counter regulation during the test. The ITT was significantly correlated both with fasting insulin (r = −0.43, P < 0.01), and post-glucose load insulin concentration (r = −0.67, P < 0.01); each measurement expressing insulin sensitivity. Four groups of patients with different insulin sensitivity; controls, NIDDM, gynoid and android obese subjects, were clearly separated by ITT. We showed that fasting glycaemia and DG/G0 were correlated (y = 2.63/x − 0.093; r = 0.82, P < 0.01). These results suggest that ITT could be an easy, quick and low cost method to evaluate insulin resistance in clinical practice and epidemiological studies.     

Homocysteine and endogenous markers of renal function in type 2 diabetic patients without coronary heart disease

The aim of this study was to assess parameters of renal function and other determinants of plasma homocysteine in type 2 diabetic patients without coronary heart disease (CHD). Fasting plasma homocysteine, serum cystatin C and serum creatinine were determined in 183 (75 men, 108 women) Type 2 diabetic patients without clinical evidence of CHD. Creatinine clearance was calculated and parameters such as blood pressure, body mass index (BMI), and glycated haemoglobin (HbA_1c) were assessed. The urine albumin:creatinine ratio was used to classify patients as normo-, micro- or macroalbuminuric. One hundred and ten patients were normoalbuminuric, 67 patients were microalbuminuric and six patients were macroalbuminuric. There was no statistically significant difference in plasma homocysteine concentration between patients with normoalbuminuria and microalbuminuria. There was a trend towards increasing plasma homocysteine with decreasing glomerular filtration rate (GFR) (r=−0.46; P<0.0001). There was statistically significant correlation between plasma homocysteine and age (r=0.37), serum cystatin C (r=0.47), and serum creatinine (r=0.56). Plasma homocysteine concentration was significantly higher in patients with BMI<30 kg/m² and showed significant inverse correlation with weight (r=−0.16; P=0.03) and body mass index (r=−0.24; P=0.001). Homocysteine and serum creatinine were significantly higher in males than females and higher in smokers than non smokers but was not associated with glycemic control and duration of diabetes. In conclusion, elevated homocysteine concentration in patients with type 2 DM without CHD is related to age, gender, smoking, BMI and GFR. Follow up studies will provide further information on the association between hyperhomocysteinemia and the development of cardiovascular disease.     

The role of obesity and cardiovascular fitness in the impaired glucose tolerance of aging

The prevalence of impaired glucose tolerance (IGT) increases with aging. Although some data suggest that age is independently associated with IGT, other studies suggest that age-associated changes in body composition and reduced cardiovascular fitness are responsible for the development of IGT. We, therefore, examined the relationship of age, total and regional adiposity, and level of fitness (VO₂max) to the presence of IGT in 155 healthy, nondiabetic, nonsmoking, older community dwelling men. Sixty-two of 155 men (40%) had IGT, while 93 men (60%) had normal glucose tolerance (WHO criteria). The subjects with IGT were of similar age (61.0 ± 1.0 vs. 59.0 ± 0.7 years, p = 0.49) and had the same maximal aerobic capacity, (VO₂max) (42 0 ± 1.0 vs. 44.0 ± 0.8 mL/kg ffm/min, p = 0.42), but had a higher waist to hip ratio (WHR) (0.98 ± 0.01) vs. 0.96 ± 0.01, p = 0.005) and percent body fat (30.0 ± 0.4 vs. 26.0 ± 0.6, p = 0.004) than the men with normal glucose tolerance. In univariate analysis, the 2-h glucose level correlated positively with percent body fat (r = 0.30, P = 0.0002), WHR (0.24, p = 0.002), and age (r = 0.17, P = 0.03) and negatively with VO₂max (r = −0.23, P = 0.005). In both multiple logistic and linear regression analyses, percent body fat was the only independent predictor of IGT (p = 0.002). These results suggest that the age-associated increase in total adiposity is a major contributor to the development of IGT in middle-aged and older men. Thus, lifestyle modifications that reduce body fat should reduce the risk for IGT and the development of noninsulin-dependent diabetes mellitus in the elderly.     

Antihypertensive drugs as predictors of type 2 diabetes among subjects with impaired glucose tolerance

Aims: to examine the incidence rate of progression to Type 2 diabetes and baseline prognostic risk factors, focusing on hypertension and antihypertensive medication, in a cohort (n=207) with impaired glucose tolerance (IGT). Methods: after 2 and 4.6 (1.9–6.4) years new cases of diabetes were diagnosed by the oral glucose tolerance test (OGTT). Hypertension (BP 160/95 or antihypertensive medication) was included in multiple regression analyses to assess the effect of risk factors on the development of diabetes. Results: diabetes developed in 32 subjects (19%), an incidence of 41/1000 (95% CI 28–57/1000) person-years. In univariate analyses, progression to diabetes was associated with a high (>9.0 mmol/l) 2-h OGTT value (P=0.008), a high fasting insulin (>12.0 mU/l) level (P=0.000), a high triglyceride (≥1.3 mmol/l) level (P=0.028), a high BMI (≥28.0 kg/m²) (P=0.013) and hypertension (P=0.003). The risk for the development of diabetes was not increased in hypertensive subjects without antihypertensive medication compared with normotensive subjects (OR 0.8, 95% CI 0.3–2.6). However, it was increased in subjects with on medication, especially diuretics alone or in combination with other drugs. Hypertensive subjects on diuretics had higher levels of fasting insulin and triglycerides and higher BMIs at baseline than normotensive subjects. After adjustment for 2-h OGTT, fasting insulin, triglycerides and BMI, the OR for diabetes was 7.7 (95% CI 2.1–28.2) in hypertensive subjects using diuretics alone or in combination with other drugs and 2.6 (95% CI 1.0–6.7) in those using other drugs compared with normotensive subjects. The OR of diabetes corresponding to a one-unit increase in the 2-h OGTT concentration was 2.5 (95% CI 1.6–4.0) in the whole cohort. Conclusions: the rate of progression from IGT to Type 2 diabetes in this population was similar to that seen in other studies among Caucasian populations. The use of antihypertensive medication, especially diuretics, and a high 2-h OGTT level were significant predictors of subsequent deterioration to diabetes.     

Association between hematological parameters and metabolic syndrome components in a Chinese population

Insulin resistance, an essential core contributing to the metabolic syndrome (MS), has been demonstrated in some studies to be associated with white blood cell (WBC) or red blood cell (RBC) counts. The present study was undertaken to assess systemically the relationship between WBC or RBC counts and various clinical features of MS in a large Chinese population at Taiwan. A total of 4938 subjects (2891 men and 2047 women with a mean age of 50.1±12.6 years), who had attended health examination at this hospital were enrolled. The Adult Treatment Panel III (ATP III) definition of MS components was adopted in this study with the exception of the definition of obesity. This was defined as body mass index (BMI) greater than 27 kg/m². Overall, 14% had high serum total triglyceride (TG), 8% had low high-density lipoprotein (HDL) cholesterol, and 18% were obese. WBC counts showed a statistically significant (P<.001) correlation with TG (r=.265), HDL(r=−.187), fasting glucose (r=.084), and BMI (r=.172) but not with blood pressure levels. In addition, RBC counts correlated significantly (P<.001) with TG (r=.250), HDL(r=−.269), fasting glucose (r=.098), and BMI (r=.228). WBC and RBC counts in subjects grouped according to the presence of 0, 1, 2, and ≥ 3 features of MS were 6268±1633, 6555±1782, 6995±1880, and 7185±1696 cells/mm³, and 4.63±0.56×10⁶, 4.73±0.54×10⁶, 4.84±0.60×10⁶, and 4.91±0.55×10⁶ cells/mm³, respectively (P for trend <.001). Subjects in the highest quartile of WBC or RBC counts demonstrated a three- or twofold increase, respectively, in the odds ratio for MS with 3 or more metabolic features compared to subjects in the lowest quartile of WBC or RBC counts. Increased WBC and RBC counts, albeit normal, were associated with a variety of MS features in a Taiwan Chinese population, suggesting that hematological parameters could potentially be used as indicators of this syndrome.     

Hormonal control of glucose production and pyruvate kinase activity in isolated rat liver cells: influence of hypothyroidism

Hormonal control of glucose production and of -pyruvate kinase activity has been measured in isolated liver cells from fed control and thyroidectomized rats. In hypothyroid rats, sensitivity to isoproterenol as measured by these parameters was increased: the apparent K_0.5 for isoproterenol-induced stimulation of glucose production decreased from 8.0 ± 3 × 10⁻⁶ M in control rats to 2.0 ± 0.2 × 10⁻⁸ M in hypothyroid rats (P < 0.001) and the apparent K_0.5 for inhibition of -pyruvate kinase was 5 ± 2 X 10⁻⁷ M vs. 7 ± 2 × 10⁻⁹ M (P < 0.001) in control and thyroidectomized rats, respectively. Utilisation of specific adrenergic antagonists confirmed increased β-adrenergic responsiveness in hypothyroid rats. This phenomenon was not reversed by 3 days of T₃ treatment (10 μg/100 g body weight). Sensitivity to the -agonist was unchanged by thyroid status. Stimulation of glucose production and inhibition of -pyruvate kinase activity by glucagon and their reversal by insulin were not affected by hypothyroidism. The dose-response curve to vasopressin and its maximal effect measured on stimulation of glucose production were unchanged in thyroidectomized rats. Thus, hypothyroidism produces a specific enhancement of liver β-adrenergic responsiveness without affecting sensitivity to glucagon, insulin and vasopressin.     

Postprandial blood glucose and its relation to diabetic gastroparesis — a comparison of two methods

Delayed gastric emptying is known as an important organic cause for brittle diabetes. We proposed the interval from the start of a meal to the rise in blood glucose, defined as blood glucose latency (T BG) as an index for gastric emptying and a non-invasive test for diabetic gastropathy. In order to validate this test we compared it in 22 type 1 diabetic patients with an established scintigraphic method for the measurement of gastric half-emptying time (T_1/2) and found the following correlation: T BG = 4.4 + 0.162 × T_1/2; r 0.79, P < 0.001. We therefore suggest measuring the blood glucose latency as a simple non-invasive screening method.     

Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin

Objective: To compare glycaemic control and cardiovascular risk profile in patients with type 2 diabetes following 12 months’ treatment with either repaglinide or metformin. Study design and methods: This was an open uncontrolled randomised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents. Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period (to optimise dosage: repaglinide, 2–4 mg/day; metformin, 1500–2500 mg/day) followed by a 12-month treatment period. Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period. Results: Mean (S.D.) final drug doses were 3 (±1) mg/day in the repaglinide group and 2000 (±500) mg/day in the metformin group. Significant improvements in glycaemic control [glycated haemoglobin, fasting and 2-h postprandial plasma glucose (PPG)] were demonstrated in both treatment groups. The decrease in PPG was significantly greater in the repaglinide group (P<0.05). During the treatment period, fasting plasma insulin (FPI) decreased significantly in both groups, more so with metformin (P<0.05). Two-hour postprandial plasma insulin (PPI) levels decreased only in the metformin group (P<0.05). Significant improvements between baseline and final visit were demonstrated in one or both groups in the following cardiovascular risk factors: total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, plasminogen activator inhibitor, lipoprotein(a) and homocysteine. No changes were observed in high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein B, fibrinogen, body mass index (BMI) or blood pressure. Conclusions: The use of repaglinide or metformin in drug therapy-naïve patients with type 2 diabetes over a 12-month period is associated with improvements in both glycaemic control and cardiovascular risk profile. The latter cannot necessarily be attributed to the pharmacotherapy per se, but provides reassurance in the context of initiating oral hypoglycaemic drug therapy with these agents.     

Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (S_f 60–400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% ± 28% (P < 0.0005) and cholesterol ester mass by 176% ± 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% ± 61% (P < 0.005) and 202% ± 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% ± 18% (P < 0.01) and 177% ± 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% ± 20% (P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (−97% ± 13% (P < 0.0005) with anti-apo B 5E11 and − 68% ± 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (− 77% ± 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL + LPL-induced increases in cholesterol ester (+21%, + 15% and − 22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (− 86% ± 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (−79%) or lipolyzed re-isolated HTg-VLDL (−95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (− 95% ± 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.     

Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction

Elevated plasminogen activator inhibitor type 1 (PAI-1) activity has been shown to correlate with plasma insulin, proinsulin-like molecules, serum triglycerides and insulin sensitivity in both non-insulin dependent diabetic (NIDDM) subjects and subjects with coronary heart disease. We examined the relative roles of these variables in determining PAI-1 activity in four groups of male caucasian subjects: non-diabetic subjects with (n=38) and without (n=38) previous myocardial infarction (MI) and NIDDM subjects with (n=26) and without (n=30) previous MI. Insulin and proinsulin-like molecules were measured using specific two-site immunometric assays and insulin sensitivity estimated using the Homeostasis Model Assessment (HOMA) model. Subjects were comparable in age and body mass index. In univariate analysis, there were significant correlations of PAI-1 activity with intact and des-31,32-proinsulin and serum triglycerides in non-diabetic subjects with (r=0.52, P=0.001; r=0.58, P<0.001; r=0.41, P=0.010) and without (r=0.31, P=0.056; r=0.46, P=0.006; r=0.41, P=0.011) MI, but not with plasma insulin or insulin sensitivity. In NIDDM subjects, PAI-1 activity correlated significantly with intact and des-31,32-proinsulin and serum triglyceride (r=0.47, P=0.015; r=0.58, P=0.002; r=0.44, P=0.026) only in subjects with MI. In multiple regression analysis, MI was the most important determinant of PAI-1 activity levels (r²=0.31, F=55.6, P<0.001). In conclusion, concentrations of proinsulin-like molecules and serum triglycerides appear to be stronger determinants of PAI-1 activity than plasma insulin or insulin sensitivity in both NIDDM subjects and non-diabetic subjects with and without MI. However, the relationship of MI with PAI-1 activity is independent of these variables.     

Circulating erythropoietin in microalbuminuric type 2 diabetic patients with normal renal function: a pilot study

To verify the hypothesis of an early impairment of erythropoietin (Epo) production and to assess the adequacy of its circulating levels in diabetic nephropathy, we investigated Epo values in 18 microalbuminuric type 2 diabetic patients with normal renal function (7 anaemic and 11 nonanaemic), 24 subjects with uncomplicated iron-deficiency anaemia, and 15 healthy controls comparable for sex and age. Mean±S.D. plasma Epo level was 56.4±12.7 mU/mL in iron-deficient patients and 9.3±2.6 mU/mL in controls. In diabetic groups, mean±S.D. Epo level was 11.38±3.65 mU/mL in nonanaemic and 49.12±6.44 mU/mL in anaemic subjects. No significant difference (P>.05) in Epo values was found between controls and nonanaemic diabetic patients. Anaemic diabetics and iron-deficient subjects had significantly higher values than the nonanaemic groups (P>.001). An inverse significant relation between Epo levels and Hb concentration resulted in both anaemic diabetics (r=−.44, P>.05) and iron-deficient patients (r=−.61, P=.001). Analysis of covariance (P>.05) and comparison of the two regression lines (t=0.4, df=29, P>.05) did not show any significant difference between diabetic patients with anaemia and iron-deficient patients. These results suggest that normochromic anaemia observed in microalbuminuric diabetic patients with normal renal function is not due to Epo deficiency, and circulating levels of this hormone are suitably increased with regard to Hb concentration.     

Non-insulin-dependent diabetes, bone mineral density, and cardiovascular risk factors

People with Type 2 diabetes have bone mass alterations and may have a higher risk of hip fractures. Moreover, they have increased cardiovascular risk factors. The objective of this paper is to investigate the association among non-insulin-dependent diabetes, bone mineral density (BMD), and cardiovascular risk factors. Ninety-two patients (36 males and 56 females) were studied and cardiovascular risk factors were measured: total cholesterol, triglycerides, lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, HbA1c, and microalbuminuria. The densitometric studies were carried out in the calcaneal region using a DEXA densitometer. The diabetic women had a higher BMD than the control group (0.502±0.127 vs. 0.408±0.102, P=.027). The women showed a positive relationship between BMD and triglycerides (r=.478, P=.0001) and a negative relationship with HDL-C (r=−.322, P=.016). The men had a BMD similar to that of the control group, and there was no relationship with the cardiovascular risk factors. When a multivariate logistic regression analysis was performed with the presence of osteoporosis as a dependent variable and each lipid level, age, sex, and BMI as independent variables, only age and BMI were found to be associated with the presence of osteopososis. The diabetic women had a higher BMD than the controls, and there was no relationship between osteoporosis and cardiovascular risk factors in diabetics.     

Segmental blood flow and rheological determinants in diabetic patients with peripheral occlusive arterial disease

Vascular abnormalities are more prevalent in the lower extremities in diabetic patients and may cause diminished perfusion to surrounding tissues. We sought to identify blood flow abnormalities in the leg of diabetic patients with peripheral occlusive arterial disease (POAD) and to determine whether these were associated with abnormalities in rheological determinants, namely, plasma fibrinogen concentration (PFC), relative plasma viscosity (RPV), hematocrit (Hct), and whole blood viscosity (WBV). Seventeen diabetic patients with POAD were compared with 40 diabetic patients without POAD and 19 nondiabetic control subjects. Blood flow was measured by venous occlusion plethysmography, RPV was measured by capillary viscometry, WBV was measured by a Wells–Brooksfield viscometer [at high (230 s⁻¹) and low (23 s⁻¹) shear rates], and PFC was measured by the clot–weight method of Ingram [Ingram, G. I. C. (1961). A suggested schedule for the rapid investigation of acute haemostatic failure. Journal of Clinical Pathology, 14, 356–360]. Ankle blood flow (Q_ak) was significantly lower in diabetic patients with POAD than in diabetic patients without POAD (P<.05). PFC was higher and Hct was lower in diabetic patients with POAD than in diabetic patients without POAD (P<.05). RPV was 1.97±0.15 versus 1.92±0.15 in diabetic patients with POAD and diabetic patients without POAD, respectively (P>.05). There was no significant difference in WBV at low or high shear rates between the groups studied. There was a correlation between WBV at low shear rate and arterial flow in the calf (Q_c) (r=.94) and great toe (r=.95) in diabetic patients with POAD, and between Q_c and WBV at high (r=−.465) and low (r=−.472) shear rates in diabetic patients without POAD (P<.05). We conclude that vasodilatation occurring in diabetic patients without POAD is severely restricted or absent in diabetic patients with POAD. Increased plasma fibrinogen and plasma viscosity may contribute to this phenomenon.     

A short-term admission improved brachial-ankle pulse wave velocity in type 2 diabetic patients

Brachial–ankle pulse wave velocity (baPWV) is a non-invasive method for assessing arterial stiffness associated with atherosclerosis. We examined whether baPWV could improve during a 2-week hospital-based education program in patients with type 2 diabetes and whether improvement associates with changes in known atherogenic risk factors. Body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), insulin, lipid profiles and baPWV were measured in 32 type 2 diabetic patients before and after an educational program that included advice about nutrition and exercise. Relationship between the changes in baPWV and additional parameters, 24 h-urinary excretion of C-peptide, visceral and subcutaneous fat area by abdominal computer tomography and intima-medial thickness (IMT) of the carotid artery by ultrasonography, were also evaluated. Baseline values of baPWV significantly correlated with age, duration of diabetes, BP, IMT and FPG. BaPWV significantly decreased after the program (−120 ± 108.4 cm/s, P < 0.0001) and this change significantly correlated with that of systolic BP (r = 0.697, P < 0.0001) and FPG (r = 0.452, P < 0.05). These results indicate that short-term hospitalization with an educational program can improve arterial wall stiffness, perhaps due to improvements in BP and glycemic control.