Biomedical subjects
Publications and source records attributed to M H Cummings.
Erectile dysfunction, which is common among men with diabetes, leads to significant reduction in quality of life, and as with other complications of diabetes deserves to be treated on the NHS. This article explores the problem of erectile dysfunction and diabetes and the role of sildenafil, which is likely to be the first choice treatment of patients presenting with erectile dysfunction.
Dyslipidaemia is often associated with adult growth hormone (GH) deficiency. Reduced removal of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apo B-100) can, in part, explain the "unfavourable" lipid profile of these patients. By modifying VLDL composition and through its action on low-density lipoprotein (LDL) receptors, GH may improve the lipid profile by increasing direct hepatic uptake of VLDL apo B-100, thereby decreasing conversion to LDL. Although GH stimulates VLDL apo B-100 secretion, this is exceeded by its effects in upregulating LDL receptors and modifying VLDL composition. We hypothesize that the improved lipid profile, in particular the decrease in cholesterol-rich VLDL particles, may contribute to a possible antiatherogenic action of GH. GH appears to have an important role in hepatic apo B-100 metabolism. However, we are just at the beginning of understanding the underlying mechanism. Further studies are required to investigate the effect of GH on other lipoprotein classes, in particular VLDL subfractions, intermediate-density lipoprotein, LDL and high-density lipoprotein. The key question, however, remains as to whether GH replacement therapy can reduce cardiovascular mortality. Long-term studies with sufficient numbers of patients are required to answer this question.
Using stable isotope techniques to establish turnover rates for very low density lipoprotein (VLDL), a group of eight adult patients with growth hormone deficiency (GHD) exhibited an increased VLDL apoprotein B (apo B) secretion and decreased VLDL apoB metabolic clearance rate compared to controls. Such increased secretion is seen in some dyslipidemic states, including GHD, which are associated with atherosclerosis. The study of VLDL metabolism may provide a clue to the lipid metabolism disorder associated with GHD.
Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P < 0.005 and P < 0.001), C peptide (P < 0.01 and P < 0.005), insulin-like growth factor I (P < 0.001), and glucose concentrations (P < 0.01 and P < 0.005) and a decrease in the leucine concentration (P < 0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P < 0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P < 0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.
Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.
Increased cardiovascular mortality in adult growth hormone deficiency (GHD) may be, in part, explained by the dyslipidaemia associated with this condition. It is possible that abnormalities of very low density lipoprotein apolipoprotein B-100 (VLDL apoB) metabolism contribute to this dyslipidaemia. To test this hypothesis, we measured VLDL apoB kinetics in adult GH deficient patients (4 females, 3 males; age 50.1 +/- 4.7 yr (mean +/- SEM); BMI 28.2 +/- 1.1 kg/m2; total cholesterol (TC) 6.6 +/- 0.3 mmol/l; triglyceride (TG) 2.8 +/- 0.6 mmol/l; HDL cholesterol 1.1 +/- 0.1 mmol/l) and in control subjects (4 females, 3 male; age 47.0 +/- 4.7 yr; BMI 27.0 +/- 2.6 kg/m2; TC 5.0 +/- 0.4 mmol/l; TG 0.9 +/- 0.2 mmol/l; HDL cholesterol 1.4 +/- 0.1 mmol/l). [1-(13)C] leucine was administered by a primed (1 mg/kg), constant intravenous infusion (1 mg/kg/hr) and VLDL apoB enrichment with 13C leucine was determined using gas-chromatography mass-spectrometry. The GHD patients had a significantly higher hepatic secretion rate of VLDL apoB (15.5 +/- 1.8 mg/kg/day vs 9.4 +/- 0.6 mg/kg/day p = 0.007) and reduced catabolism ofVLDL apoB (metabolic clearance rate; 12.3 +/- 1.7 ml/min vs 24.3 +/- 4.8 ml/min p < 0.05) compared with control subjects. These findings suggest that GH is integrally involved in the regulation of VLDL apoB metabolism.
To investigate the effect of insulin on cholesterol synthesis in vivo we measured plasma mevalonic acid (MVA) concentrations using gas chromatography-mass spectrometry in six non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM) [four men, two women; age 57.5 +/- 2.2 years (mean +/- SEM); glycated haemoglobin (HbA1) 8.5 +/- 0.5%; total cholesterol (TC) 5.7 +/- 0.5 mmol L-1, triglyceride (TG) 3.8 +/- 0.9 mmol L-1] and six non-diabetic, sex- and age-matched control subjects (age 55.7 +/- 2.8 years; HbA1 6.5 +/- 0.1%; TC 5.4 +/- 0.3 mmol L-1, TG 1.2 +/- 0.1 mmol L-1). Subjects were studied twice: during 13-h hyperinsulinaemic (1 mu kg-1 min-1), euglycaemic (5 mmol L-1) clamp and during a saline infusion. Baseline MVA concentration was significantly higher in diabetic patients than in control subjects (9.8 +/- 0.7 ng mL-1 vs. 5.6 +/- 0.9 ng mL-1, P = 0.004). At the end of each study, MVA concentration, expressed as a percentage of baseline, was significantly lower during the hyperinsulinaemic, euglycaemic clamp than during the saline study in both the diabetic (54.4 +/- 5.3% vs. 69.6 +/- 6.3%, P = 0.036) and control subjects (30.5 +/- 3.4% vs. 61.7 +/- 6.0%, P = 0.01). However, the decrease in MVA during the hyperinsulinaemic clamp study was more marked in the control subjects than in the diabetic subjects (P = 0.03). A significant positive correlation was found between percentage decrease of MVA and non-esterified fatty acids following the insulin clamp in NIDDM (r = 0.83, P = 0.04). We conclude that acute hyperinsulinaemia decreases cholesterol synthesis less in subjects with NIDDM than in non-diabetic subjects and that this phenomenon, together with increased basal cholesterol synthesis in NIDDM, may in part be due to insulin resistance.
AIMS: To assess the prevalence of microalbuminuria (MA) and elevated serum lipoprotein (a) (Lp (a)) concentration, and their association with coronary artery disease (CAD) and other conventional cardiovascular risk factors in non-diabetic patients attending a lipid clinic. METHODS: Clinical details were obtained from 96 consecutive non-diabetic patients from whom a fasting blood sample was taken to measure serum lipid, lipoprotein, apolipoprotein and plasma glucose, urea, and electrolyte concentrations. The urine albumin/creatinine ratio (Ua/Uc) was estimated from a random clinic sample. RESULTS: Of the patients, 26% had MA (defined as a Ua/Uc > 2.2 mg/mumol), 38% had an elevated Lp (a) concentration (defined as > 0.4 g/l), 36% were hypertensive (blood pressure > 160/95) or were taking antihypertensive medication, and 25% had established CAD defined on clinical criteria. In men the Ua/Uc ratio was highly associated with age, plasma low density lipoprotein cholesterol, and triglyceride concentrations. In women there was no association between the Ua/Uc ratio and variables examined. Lp (a) concentration was not associated with variables examined in either sex. In multiple logistic regression analysis adjusted for age and sex, serum Lp (a) concentration, diastolic blood pressure and treatment of hyperlipidaemia were highly associated with CAD. MA was not, however, associated with CAD. CONCLUSIONS: MA is common in a lipid clinic and is more likely to be found among older male patients with hyperlipidaemia. However, in contrast with Lp (a) concentrations, MA is not a risk factor for CAD in this high risk population. Lp (a) concentration may be a useful tool in the lipid clinic, but there does not seem to be a justification for measuring the Ua/Uc ratio, at least in non-diabetic subjects.
We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5 +/- 2.2 years (mean +/- SEM), weight 88.2 +/- 5.5 kg, glycated haemoglobin (HbA1) 8.5 +/- 0.5%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 3.8 +/- 0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0 +/- 0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7 +/- 2.8 years, weight 85.8 +/- 5.6 kg, HbA1 6.5 +/- 0.1%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 1.2 +/- 0.1 mmol/l, HDL cholesterol 1.4 +/- 0.1 mmol/l). HbA1, plasma triglyceride and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects (p = 0.006, p = 0.02 and p = 0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297 +/- 491 vs 921 +/- 115 mg/day, p < 0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide (r = 0.84, p = 0.04) and (ii) mevalonic acid concentration (r = 0.83, p < 0.05) in the diabetic patients but not in the non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
We have measured the hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B) in 6 patients with heterozygous familial hypercholesterolaemia (FH) (4 males, 2 females, age 47.0 +/- 2.7 years (mean +/- S.E.M.), weight 71.0 +/- 5.3 kg) and 6 normocholesterolaemic subjects matched for age, weight and sex (4 males, 2 females, age 47.5 +/- 3.1 years, weight 70.0 +/- 4.4 kg) using a stable isotope method. Each subject received a primed, constant infusion of [I-13C]leucine and isotopic enrichment of VLDL apo B was determined using gas-chromatography mass-spectrometry (GCMS). Mean plasma low-density-lipoprotein (LDL) cholesterol and apo B concentrations in the FH group were more than twice that in the control group (FH, 8.5 +/- 0.5 mmol/l vs. controls, 3.3 +/- 0.2 mmol/l, P < 0.001; and FH, 2.0 +/- 0.1 g/l vs. controls, 1.0 +/- 0.04 g/l, P < 0.0001, respectively). Plasma triglyceride (TG) and high-density-lipoprotein (HDL) cholesterol concentrations were not significantly different between the two groups. Although the fractional secretion rates of VLDL apo B were similar (FH, 14.3 +/- 3.6 pools/day vs. controls, 11.6 +/- 1.7 pools/day, P = 0.53), VLDL apo B pool size and VLDL apo B absolute secretion rates (ASR) were significantly higher in the FH group (FH, 234.2 +/- 27.8 mg vs. controls, 66.3 +/- 13.5 mg, P < 0.001; and FH, 51.4 +/- 17.9 mg/kg per day vs. controls, 9.4 +/- 1.1 mg/kg per day, P < 0.02, respectively). We conclude that FH is associated with increased hepatic secretion of VLDL apo B and that this may contribute to the elevated concentration of LDL-cholesterol. The findings are also consistent with the hypothesis that in FH increased hepatic cholesterol availability (due to increased uptake of LDL-cholesterol via the receptor-independent pathway) stimulates hepatic secretion of VLDL apo B.
The regulation of apolipoprotein B-100 (apo B) metabolism in man is not fully understood. In vitro studies suggest a key role for the hepatic availability of cholesterol substrate. We therefore examined whether there was a direct association between plasma mevalonic acid (MVA) concentration (an index of in vivo cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein (VLDL) apo B in eight normolipidemic, healthy adult subjects. Hepatic secretion of VLDL apo B was estimated by endogenous labeling of apo B with an 8-hour primed, constant infusion of 1-13C-leucine. Isotopic enrichment of VLDL apo B was measured by gas chromatography-mass spectrometry (GCMS), from which the fractional secretion rate (FSR) was derived by a modified monoexponential function. Plasma concentration of MVA was measured by gas chromatography-electron-capture mass spectrometry in blood samples taken at 9 AM. The absolute secretion rate (ASR) of VLDL apo B (mean +/- SD) was 9.7 +/- 2.6 mg/kg/d, and MVA concentration was 5.0 +/- 2.5 ng/mL. There was a highly significant positive correlation between ASR of VLDL apoB and plasma MVA (r = .88, P = .004), which persisted after adjusting for apo E phenotype. The findings suggest that in vivo cholesterol synthesis is a determinant of hepatic secretion of apo B in normolipidemic subjects.
1. We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable-isotope gas chromatography-mass spectrometry method in six obese subjects [three males, three females, age 41.5 +/- 3.4 years (mean +/- SEM), weight 105.0 +/- 4.8 kg, plasma total cholesterol concentration 6.2 +/- 0.4 mmol/l, triacylglycerol 2.8 +/- 0.8 mmol/l, high-density lipoprotein cholesterol 1.0 +/- 0.2 mmol/l] and six lean control subjects (three males, three females, age 41.8 +/- 3.7 years, weight 68.2 +/- 4.9 kg, total cholesterol concentration 4.5 +/- 0.3 mmol/l, triacylglycerol 0.8 +/- 0.2 mmol/l, high-density lipoprotein cholesterol 1.3 +/- 0.1 mmol/l). 2. Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects (P = 0.02, P = 0.03, P = 0.04, respectively). VLDL apoB pool size and absolute secretion rate were significantly higher in the obese subjects than in control subjects (323.4 +/- 99.8 mg versus 53.6 +/- 17.1 mg, P = 0.004; and 42.3 +/- 13.8 mg kg fat-free mass-1 day-1 versus 10.7 +/- 0.4 mg kg fat-free mass-1 day-1, P = 0.01), but there was no significant difference in the fractional catabolic rate of VLDL apoB.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P = 0.002), triglycerides by 15% [corrected] (P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% (P = 0.002); high-density lipoprotein cholesterol increased by 17% (P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[13C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a monoexponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007 mg kg-1 day-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0) mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration (P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.
Using a stable isotope method, we measured the hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in a 26-year-old women who had dyslipidemia due to cholesteryl ester storage disease (CESD) and in five normolipidemic subjects. [1-13C]Leucine was administered by a primed constant intravenous infusion and the enrichment of VLDL apoB was determined by gas chromatography-mass spectrometry. The absolute secretion rate (ASR) of VLDL apoB in the patient was more than twice the mean ASR of the normolipidemic group (17.1 vs 8.0 +/- 0.8 mg/kg body wt. per day). The plasma mevalonic acid concentration, a measure of intrahepatic cholesterol synthesis, was also greater in the patient than in the normolipidemic subjects (8.3 vs 4.4 +/- 1.8 micrograms/L). The findings are consistent with the hypothesis that in CESD increased intrahepatic synthesis of cholesterol stimulates hepatic secretion of VLDL apoB and this may partly account for the dyslipidemia.
We highlight the case of a 35-year-old male who suffered a respiratory arrest as a result of methaemoglobinaemia secondary to skin contamination and inhalation of petrol octane booster following a road traffic accident. It is important that petrol octane booster is stored safely in leak-proof containers and that suitable warnings are displayed to alert the user of potential toxicity.
To assess whether the Lowry-tetramethylurea method for measuring apolipoprotein B-100 (apo-B) in very low density lipoprotein (VLDL) could be replaced by direct assay of VLDL apo-B using a highly practicable immunological method. Seventy five fasting blood samples were collected from patients attending the lipid clinic at this hospital. Plasma was separated immediately and VLDL isolated by preparative ultracentrifugation at solution density 0.93-1.006 kg/l. Apo-B was precipitated from an aliquot of the VLDL fraction using the tetramethylurea (TMU) technique and protein mass determined by the Lowry method (LM); mean apo-B 83.02 micrograms/ml (SD 74.85). Apo-B was also measured in VLDL using direct immunoturbidimetry on the Cobas-Fara analyser; mean apo-B 82.32 micrograms/ml (SD 72.88). There was a very close correlation between methods (immunoturbidimetry = 0.94.LM + 3.95, r = 0.97, p < 0.001). The mean difference between methods (constant error) was small (0.70 microgram/ml) and not significant (p = 0.742). Random error was 13.01 micrograms/ml by analysis of variance. It is concluded that immunoturbidimetry, a more rapid and convenient test, may replace the LM and TMU techniques for measuring VLDL apo-B concentration and that this method could be applied to research studies requiring analysis of large numbers of samples.
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