Michael H. Cummings

Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM

SummaryWe 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 mevalpnic 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. There was also a significant positive association between plasma mevalonic acid and plasma C-peptide (r=0.82, p<0.05) concentrations in the diabetic patients. We conclude that in NIDDM, there is increased hepatic secretion of VLDL apoB which may partly explain the dyslipoproteinaemia seen in this condition. We suggest that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin on VLDL apoB secretion. Insulin resistance may also be the mechanism by which cholesterol synthesis, a regulator of apoB secretion, is increased in NIDDM.

Acute Hyperinsulinemia Decreases the Hepatic Secretion of Very-Low-Density Lipoprotein Apolipoprotein B-100 in NIDDM

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, [1-13C]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.

Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study

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.

Direct correlation between cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidemic subjects

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.

Simvastatin decreases the hepatic secretion of very‐low‐density lipoprotein apolipoprotein B‐100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications

Abstract. 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 27% (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 l‐[13C]‐leucine with monitoring of the isotopic enrichment of apoB by gas chromatography‐mass spectrometry; fractional secretion rate (FSR) was derived using a mono‐exponential 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= 0.007mgkg‐1day‐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. This effect does not appear to be directly related to the inhibition of cholesterol synthesis and may be due to decreased hepatic delivery of cholesterol esters via the LDL receptor‐independent pathway, but these mechanisms require further investigation.

Dyslipidaemia in Adult Growth Hormone (GH) Deficiency and the Effect of GH Replacement Therapy: A Review

Adult growth hormone (GH) deficiency is associated with a lipid profile known to be related to atherosclerosis. GH replacement therapy improves the lipid profile with the exception of lipoprotein (a) concentrations, which tend to increase after GH therapy. Plasma lipid concentrations depend on its plasma carriers, the lipoproteins. Possible mechanisms involved in the dyslipidaemia of GH-deficient patients and the effects of GH replacement therapy are discussed with a special focus on hepatic lipoprotein metabolism.

Growth hormone (GH) replacement therapy reduces serum sialic acid concentrations in adults with GH‐deficiency: a double‐blind placebo‐controlled study

Patients with adult GH‐deficiency are thought to have an increased risk of cardiovascular disease. Sialic acid (SA) concentrations have been proposed as a marker of atherosclerotic disease probably related to an inflammatory response of the arterial wall. SA as a marker of cardiovascular disease in adult GH‐deficiency and its relation to changes in fasting lipid profile and hormone concentrations have not yet been investigated.

Diabetes : chronic complications

Preface to Diabetiic Complications. Foreword to Diabetic Complications. Preface to the Current Edition. List of Contributors. 1. Diabetes and the Eye (Kevin Shotliff and Grant Duncan). 1.1 Introduction. 1.2 Epidemiology of diabetic retinopathy 1.3 Retinal anatomy. 1.4 Classification/clinical and histological features of diabetic retinopathy. 2. Diabetes and the Kidney (Richard J. MacIsaac and Gerald F. Watts). 2.1 Introduction. 2.2 Normal renal structure and function. 2.3 Stages in the development of diabetic renal disease. 2.4 Prevalence and significance of microalbuminuria. 2.5 Screening for diabetic renal disease. 2.6 Initiators and promoters of diabetic renal disease. 2.7 Renal morphology and diabetic nephropathy. 2.8 Prevention and treatment of diabetic renal disease. 2.9 Summary and conclusions. 3. Diabetes and Foot Disease (Darryl Meeking, Emma Holland and Deborah Land). 3.1 Introduction. 3.2 Diabetic foot ulceration. 3.3 Charcot foot. 3.4 The organization of foot care. 3.5 Conclusion. 4. Diabetes and Autonomic Neuropathy (Andres MacLeod). 4.1 Introduction. 4.2 Causative factors. 4.3 Tests of autonomic function. 4.4 Prevalence. 4.5 Screening for autonomic neuropathy. 4.6 Clinical syndromes. 4.7 Conclusion. 5. Diabetes and Sexual Health (Michael H. Cummings). 5.1 Male erectile dysfunction. 5.2 Aetiology. 5.3 Assessment of the diabetic male with ED. 5.4 Discussion and counselling. 5.5 Management of ED in the diabetic male. 5.6 Conclusions. 5.7 Sexual dysfunction in the female with diabetes. 6. Diabetes and the Heart (Miles Fisher and K.M. Shaw). 6.1 Introduction. 6.2 Nature of the problem. 6.3 Primary prevention of heart disease in diabetes. 6.4 Management of heart disease in diabetes. 6.5 Secondary prevention of heart disease in diabetes. 6.6 Conclusions. 7. Diabetes and the Brain (Iain Cranston). 7.1 Introduction. 7.2 Cerebrovascular disease and diabetes. 7.3 Primary prevention of stroke in diabetes. 7.4 Secondary stroke prevention. 7.5 Management of acute stroke in diabetic patients. 7.6 Diabetes and cognitive function. 7.7 Summary. 8. Diabetes and the Gastrointestinal System (Charles Murray and Anton Emmanuel). 8.1 Introduction. 8.2 Epidemiology. 8.3 Pathophysiology of GI dysfunction. 8.4 Oesophageal complications. 8.5 Stomach complications. 8.6 Small intestine. 8.7 Colon. 8.8 Anorectal function. 8.9 Pancreatic. 8.10 Hepatobiliary. 8.11 Biliary disorders. 8.12 Diabetic diarrhoea. 8.13 Conclusion. 9. Diabetes and Musculoskeletal Disease (D.L. Browne and F.C. McCrae). 9.1 Introduction. 9.2 Pathophysiology. 9.3 Musculoskeletal conditions associated with diabetes. 9.4 Upper limb diabetic complications. 9.5 Generalized conditions involving the skeletal system in diabetes. 9.6 Functional disability in diabetic patients. 9.7 Conclusion. 10. Diabetes and the Skin (Adam Haworth). 10.1 Introduction. 10.2 Necrobiotic disorders. 10.3 Necrobiosis lipoidica. 10.4 Acanthosis nigricans. 10.5 Eruptive xanthomata. 10.6 Diabetic thick skin. 10.7 Diabetic dermopathy. 10.8 Bullosis diabeticorum. 10.9 Infections. 10.10 Perforating disorders. 10.11 Glucagonoma syndrome. 10.12 Vitiligo. 10.13 Dermatological definitions. 10.14 Dermatological therapies. Index.

The Use of Stable Isotopes to Unravel the Hyperlipidemia of Adult Growth Hormone Deficiency

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.

Direct correlation between in vivo cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidaemic subjects

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-lowdensity 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 chromatographyelectron-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, Copyright