Regulation of hepatic lipase expression in HepG2 cells.
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Carcinoma, Hepatocellular↗
Biomedical subjects
W Richmond
Publications and source records attributed to W Richmond.
Elevated leptin concentrations in growth hormone-deficient hypopituitary adults.
BACKGROUND: Hypopituitarism with growth hormone (GH) deficiency is associated with obesity characterized by central (abdominal) distribution of fat. Recent work has demonstrated that leptin, a product of obese gene, is raised in obesity. OBJECTIVE: To study circulating leptin levels in GH-deficient hypopituitary adults and to investigate its anthropometric, gender and metabolic relations. METHODS: After an overnight fast of 10-12 hours, anthropometric parameters and body composition were measured and blood was collected for the measurement of circulating leptin, glucose, intact insulin, proinsulin, IGF-I, total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. SUBJECTS: Fifteen (7 men) GH-deficient hypopituitary adults (maximum stimulated serum GH to provocative testing < 6 mU/l) and 21 (10 men) normal control subjects matched for age, gender and body mass index (BMI). RESULTS: Fasting serum leptin was significantly higher in hypopituitary patients than controls (12.0 +/- 1.8 vs 8.0 +/- 1.5 micrograms/l, P = 0.04). The increase was more marked in obese (BMI > 26.0 kg/m2) patients compared with obese controls (15.3 +/- 2.0 vs 8.8 +/- 2.3 micrograms/l, P = 0.03) than in lean patients and controls. Obese control women and men had higher leptin levels than non-obese (women, 16.6 +/- 2.7 vs 8.6 +/- 0.6 micrograms/l, P = 0.03; men, 4.9 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P = 0.035). Similar changes were observed for obese versus non-obese patients, although the changes did not reach statistical significance. Women in each group had significantly higher leptin concentrations than men (patients: 15.5 +/- 2.3 vs 7.3 +/- 1.4 micrograms/l, P = 0.009; controls: 12.6 +/- 2.4 vs 4.3 +/- 0.5 micrograms/l, P = 0.0001). These gender differences remained significant even when expressed in relation to BMI (patients: 0.57 +/- 0.09 vs 0.26 +/- 0.05 ng.m2/ml.kg, P = 0.009; controls: 0.43 +/- 0.05 vs 0.16 +/- 0.02 ng.m2/ml.kg, P = 0.0001). Serum leptin was positively associated with body mass index (P = 0.003), percentage body fat mass (P = 0.0001) and inversely related with age (P = 0.043). It demonstrated no relation with body weight, waist circumference, waist to hip ratio, fasting IGF-I, glucose, insulin, proinsulin, total cholesterol, triglycerides, HDL and LDL cholesterol in patients nor controls; 85% of variance in leptin was explained by a model including body mass index, gender, age and hypopituitarism. CONCLUSIONS: Leptin concentrations are raised in GH-deficient hypopituitary adults to a greater extent than would be expected from the degree of obesity.
Adult↗
ACP Broad Sheet no 151: September 1997. Investigation of dyslipidaemias.
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Apolipoproteins↗
Fasting and postprandial lipid abnormalities in hypopituitary women receiving conventional replacement therapy.
Hypopituitary patients, particularly women, have excess mortality, mostly due to vascular disease. We have studied circulating lipid and lipoprotein concentrations, fasting and over 24 h, in hypopituitary women and men and in matched controls. Firstly, 67 hypopituitary patients (36 women) and 87 normal controls (54 women) were studied after an overnight fast. Secondly, 12 patients (6 women) and 14 matched controls (7 women) were studied over 24 h of normal meals and activity. The patients were all GH deficient and were replaced with cortisol, T4, and sex hormones where appropriate, but not with GH. In the first study, circulating triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol were measured after an overnight fast. In the second study, fasting levels of apolipoprotein B, apolipoprotein A1, and lipoprotein(a) were also measured, and then circulating triglyceride and total cholesterol concentrations were measured over 24 h. Fasting concentrations of triglyceride (mean +/- SEM, 1.73 +/- 0.22 vs. 1.11 +/- 0.09 mmol/L; P = 0.0025), total cholesterol (6.45 +/- 0.25 vs. 5.59 +/- 0.21 mmol/L; P = 0.002), LDL cholesterol (4.58 +/- 0.24 vs. 3.80 +/- 0.19 mmol/L; P = 0.007), and apolipoprotein B (135 +/- 10 vs. 111 +/- 9 mg/dL; P = 0.048) were elevated in hypopituitary compared to control women. The lipid alterations were observed in older and younger women and occurred independently of sex hormone or glucocorticoid replacement. Fasting values were not significantly different in hypopituitary and control men. Patients and controls (women and men) had similar fasting HDL cholesterol, apolipoprotein A1, and lipoprotein(a) concentrations. Although the differences that existed in fasting lipid values were most marked in women, the men were also abnormal in this respect, in that a higher proportion of hypopituitary than control men had total and LDL cholesterol above recommended values (> or = 6.2 and > or = 4.1 mmol/L, respectively). In the postprandial period (0730-2030 h), the areas under the curve (AUC) for circulating triglyceride and total cholesterol were significantly higher in hypopituitary than control women (P = 0.0089 and P = 0.0016, respectively). The AUC for triglyceride and total cholesterol over 24 h were also significantly increased (P = 0.009 and P = 0.0004, respectively). No significant differences were observed for postprandial and 24-h AUC for triglyceride and total cholesterol concentrations in men. We conclude that hypopituitarism with conventional replacement therapy is associated with unfavorable fasting and postprandial lipid and lipoprotein concentrations, particularly in women. The changes may contribute to the observed increased vascular morbidity and mortality.
Adult↗
Relative fasting hypoinsulinaemia and ultrasonically measured early arterial disease in type 2 diabetes. The SENDCAP Study Group, St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study.
Macrovasular disease is the most important cause of morbidity and mortality in Type 2 (non-insulin-dependent) diabetes. Dyslipidaemia and hyperinsulinaemia have been proposed as aetiological factors. This paper describes the interrelationships between fasting serum insulin, serum lipids, and the extent of ultrasonically measured early arterial disease in Type 2 diabetic subjects screened for entry into a prospective study set up to ascertain whether improving serum lipids can alter the progress of arterial disease in Type 2 diabetes. Measurements were made of the initima media thickness (IMT) in the carotid artery, and an arterial ultrasound score (AUS) based on appearances of both carotid and femoral arteries was calculated for 192 established Type 2 diabetic subjects, males and females, mean age 51 (range 35-66) years, median duration of diabetes 3.5 years, with no known cardiovascular disease. Multiple regression analysis showed that carotid IMT increased with age and was inversely related to serum insulin (variance accounted for, R2, = 8.8%, p = 0.0002). AUS increased with age and was related inversely to serum insulin, or to C-peptide when this was substituted in the model. In addition to age and serum insulin, AUS was positively associated with non-HDL cholesterol and negatively with HDL 3 cholesterol (R2 = 26%, p = 0.0001). Early thickening and damage to the arterial wall in Type 2 diabetes may be related to relative fasting hypoinsulinaemia.
Adult↗
Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries.
OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN: A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS: We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS: Results are expressed as mean +/- SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 +/- 0.7 vs LP 35.2 +/- 1.2, P < 0.01; OC 34.7 +/- 1.8 vs OP 37.8 +/- 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 +/- 9 vs LP 179 +/- 9, NS; OC 168 +/- 12 vs OP 133 +/- 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL2-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38-0.62), LP 0.31 (0.26-0.44), P < 0.05; OC 0.34 (0.21-0.47), OP 0.21 (0.12-0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL2-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION: Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.
Adult↗
Post-heparin plasma lipase activity in hypopituitary adults.
Twenty-six hypopituitary patients on conventional replacement therapy were compared with 31 matched normal controls. Plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities were measured 15 min after a bolus of intravenous heparin (100 IU/kg body weight). Fasting plasma lipids, lipoproteins, glucose and insulin and triceps to subscapular skin fold ratio and waist to hip circumference ratio were also measured. Total and low density lipoprotein cholesterol were significantly higher in patients than in controls. Plasma activity of both LPL and HL was significantly higher in hypopituitary patients than in controls (p < 0.005 and p < 0.04 respectively). When men and women were analysed separately, significant differences between HP patients and controls remained for total cholesterol and LPL in women and for HL in men.
Adult↗
The effects of short and long-term growth hormone replacement therapy in hypopituitary adults on lipid metabolism and carbohydrate tolerance.
The effects of replacement with biosynthetic human GH on carbohydrate tolerance and lipid metabolism were studied in 40 hypopituitary adults during a randomized double blind, placebo-controlled trial for 6 months, followed by a 12-month open trial. The daily GH dose was 0.04 +/- 0.01 IU/kg. Fasting plasma glucose, serum fructosamine, plasmid lipids, lipoproteins, and plasma C-peptide concentrations were measured, and an oral glucose tolerance test was performed every 6 months. There was no change in fasting triglyceride levels at any stage of the study. There was no significant change in fasting total or LDL cholesterol, total HDL cholesterol, high density lipoprotein2 (HDL2) cholesterol, HDL3 cholesterol, apoprotein-A1, or apoprotein-B during GH or placebo treatment in the placebo-controlled 6-months study. In the open phase of the trial, total and low density lipoprotein cholesterol showed a sustained downward trend during GH therapy. Compared to the pretreatment level, the HDL cholesterol concentration was significantly higher at 18 months. Cholesterol subfractions HDL2 and HDL3 and apoprotein-A1 and -B were not different from the pretreatment levels. The total/HDL cholesterol ratio decreased significantly at 12 and 18 months. During the controlled phase, fasting plasma glucose was similar during GH and placebo administration, but fasting insulin and C-peptide increased during GH therapy, but not during placebo treatment. The mean area under the curve (AUC) for glucose increased by a small, but significant, extent over the 6 months of GH treatment and was higher at 6 months than during placebo treatment. The AUC for insulin also increased during GH treatment. During the open trial, the fasting plasma glucose level increased at 6 and 12 months, and the fasting plasma insulin level increased at 6, 12, and 18 months of GH treatment. The plasma glucose AUC during the oral glucose tolerance test was significantly higher at 6 months, and the plasma insulin AUC was significantly higher at 6, 12, and 18 months of GH therapy. In conclusion, GH therapy has some metabolic effects that are considered beneficial and others that are less desirable.
Adult↗
Serum lipids and apolipoproteins and their relationship with macrovascular disease in type 1 diabetes.
In order to examine the relationship between serum lipids and apolipoproteins and macrovascular disease in patients with Type 1 diabetes mellitus, 50 patients with Type 1 diabetes mellitus attending the diabetic clinics at St Mary's and St Charles' Hospitals, London were recruited into a cross-sectional study. B-mode ultrasound was used to measure intima-media thickness and define an arterial ultrasound score for each patient as a non-invasive indicator of atherosclerotic change. Intima-medial (i-m) thickness was significantly higher in those subjects with clinical evidence of macrovascular disease compared to those without macrovascular disease (0.865 +/- 0.191 vs 0.695 +/- 0.162 mm, p = 0.0038). In the study group there were significant correlations between i-m thickness and age (r = 0.65, p < 0.01), total serum cholesterol (r = 0.32, p < 0.01), and serum fibrinogen (r = 0.43, p < 0.01) but no other lipid or apolipoprotein variable. When i-m thickness was corrected for age there were significant correlations with total cholesterol (r = 0.43, p < 0.01) and LDL-cholesterol (r = 0.42, p < 0.01). Whereas total and LDL-cholesterol and serum fibrinogen concentrations were related to the extent of atherosclerotic disease by ultrasound techniques, there was no relationship with high density lipoprotein (HDL) or subfraction cholesterol concentrations. HDL-cholesterol may not be a useful marker for cardiovascular disease in Type 1 diabetes.
Adult↗
Serum lipoprotein levels and plasma concentrations of insulin, intact and 32, 33 split proinsulin in normoglycaemic relatives of patients with type 2 diabetes.
Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean +/- S.E. 33 +/- 2 vs 34 +/- 2 years), body mass index (23.7 +/- 0.5 vs 23.7 +/- 0.6 kg m-2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 +/- 0.1 vs 4.9 +/- 0.1 mmol l-1), total cholesterol (4.51 +/- 0.13 vs 4.54 +/- 0.17 mmol l-1), HDL-cholesterol (1.21 +/- 0.06 vs 1.10 +/- 0.05 mmol l-1), LDL-cholesterol (2.84 +/- 0.14 vs 2.96 +/- 0.14 mmol l-1) and triglyceride (median (range) 0.78 (0.44-2.45) vs 0.83 (0.41-4.03) mmol l-1). Fasting levels of insulin (50.4 (18.9-174.0) vs 51.6 (10.0-118.0) pmol l-1, intact proinsulin (2.8 (0.1-15.0) vs 2.1 (0.6-6.4) pmol l-1 and 32, 33 split proinsulin (2.0(0-23.7) vs 1.6 (0.3-6.0) pmol l-1) were not significantly different between relatives and controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Local anesthesia and inguinal hernia repair; a cautionary tale.
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Anesthesia, Local↗
Evidence for a regulatory link between hepatic lipase secretion and intra-hepatocyte cholesterol.
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Cells, Cultured↗
The effects of glibenclamide on glucose homeostasis and lipoprotein metabolism in poorly controlled type 2 diabetes.
Six patients with type 2 diabetes underwent detailed metabolic studies before and after a minimum of 3 months' glibenclamide therapy. Treatment was associated with a small but significant increase in body weight. Despite improvements in almost all the measured parameters of glucose homeostasis (plasma glucose, glycosylated haemoglobin (HbA1), hepatic glucose production and insulin-mediated glucose disposal) neither fasting serum triglycerides nor HDL cholesterol changed and apoprotein A1 concentrations actually decreased significantly. NEFA and glycerol in fasting plasma and during the clamp studies did not change significantly with treatment. Post-heparin lipoprotein lipase and hepatic lipase activity did not change significantly. Thus, despite substantial improvements in glycaemic control and insulin sensitivity with sulphonylurea therapy, several aspects of lipid and lipoprotein metabolism remain largely unaffected. This small study suggests either that lipoprotein concentrations in type 2 diabetes are not influenced by insulin sensitivity or that the improvement is offset by another change that occurs during this form of therapy. It also suggests that other forms of therapy will be required to improve these cardiovascular risk factors in type 2 diabetes.
Aged↗
Hepatic and lipoprotein lipases selectively assayed in postheparin plasma.
Sensitive, reliable procedures are reported for the selective assay of lipoprotein lipase (LPL) and hepatic lipase (HL) in postheparin plasma samples. LPL is inhibited in the HL assay by inclusion of 0.76 mol/L sodium chloride in the substrate. In the LPL assay, specificity is attained by pretreating the sample with sodium dodecyl sulfate, which selectively denatures HL. This LPL method was validated by direct comparison with a procedure in which HL is inactivated by an antiserum to human HL. We used the described assays to quantify LPL and HL activity in 32 normal adults, demonstrating a clear sex difference for both enzymes. On average, the men displayed higher HL and lower LPL activities than did the women.
Adult↗
The response of hepatic lipase and serum lipoproteins to acute hyperinsulinaemia in type 2 diabetes.
Hepatic lipase has a putative role in the catabolism of HDL particles and, while its activity is dependent upon insulin in the rat, no such insulin responsiveness has been demonstrated in man. We studied 21 patients with type 2 diabetes to examine whether hepatic lipase activity was influenced by hyperinsulinaemia during a 2-4 h isoglycaemic clamp study. Acute changes in lipids, lipoproteins and apolipoproteins were also documented in pre- and post-clamp serum. Hepatic lipase activity during hyperinsulinaemia was compared with activity measured after an equivalent period without insulin. For comparison, nine non-diabetic subjects (matched for age and body mass index) underwent similar clamp studies. In the control experiment without insulin, hepatic lipase activity did not change significantly (mean 9.7 (range 2.3-22.3) in the morning and 9.9 (3.0-22.5) mmol h-1 l-1 in the afternoon, NS). In contrast, after the hyperinsulinaemic clamp, hepatic lipase activity fell significantly in diabetic subjects from 12.8 (4.4-30.6) to 10.4 (3.3-31.3) mmol h-1 l-1, P less than 0.0002 along with serum triglycerides and total and LDL cholesterol. The change in hepatic lipase activity was positively related to the fasting apoprotein B concentration (Spearman r = 0.54, P = 0.016). In the normal subjects, a similar decline in hepatic lipase activity was observed during hyperinsulinaemia (from 15.1 (9.8-32.7) to 12.6 (6.3-28.3) mmol h-1 l-1, P less than 0.01) along with decreases in total, HDL and LDL cholesterol, triglycerides and apoproteins A1 and B.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Analytical reviews in clinical biochemistry: the quantitative analysis of cholesterol.
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Cholesterol↗
Determinants of mild fasting hypertriglyceridaemia in non-insulin-dependent diabetes.
Factors contributing to fasting hypertriglyceridaemia were studied in 20 patients with non-insulin-dependent diabetes--nine with normal triglyceride concentrations [fasting triglyceride 0.94 (range 0.58-1.23) mmol l-1] and eleven with mild fasting hypertriglyceridaemia [fasting triglyceride 2.4 (1.82-4.0) mmol l-1]. The patients with hypertriglyceridaemia were more obese [body mass index 29.0 (24.6-33.8) vs. 25.7 (21.9-30.1) kg m-2, P less than 0.05] and demonstrated impaired glucose disposal in response to exogenous insulin at isoglycaemia [insulin sensitivity index, SIp 0.7 (0.27-2.5) vs. 2.4 (0.62-5.1) ml m-2 min per mU l-1, P less than 0.001]. Basal non-esterified fatty acid (NEFA) and glycerol concentrations were higher and were suppressed to a lesser extent during isoglycaemic hyperinsulinaemia. Fasting glucose and apolipoprotein B concentrations were higher in the hypertriglyceridaemic patients, but lipoprotein lipase activities were similar in the two groups. When the effect of obesity was removed (by weight-matching six normotriglyceridaemic with seven hypertriglyceridaemic patients) basal NEFA and glycerol concentrations and the suppression of NEFA in response to insulin remained significantly different between the two groups. We propose that defects in both the glucoregulatory and antilipolytic actions of insulin contribute to mild fasting hypertriglyceridaemia in NIDDM, and that these defects cannot be attributed solely to obesity. These disorders of insulin action may also have important implications for the postprandial metabolism of triglyceride-rich lipoproteins and hence atherogenesis.
Adult↗