N C Jackson

University of Surrey, Guilford, England, United Kingdom

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Publications (40)170.44 Total impact

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    ABSTRACT: To investigate the effects of subcutaneous detemir on glucose flux, lipid metabolism and brain function, twelve people with type 1 diabetes received in random order 0.5Units/kgBW detemir or NPH insulin. Glucose concentration was clamped at 5mmol/L then increased to 10mmol/L. Glucose production rate (glucose Ra), glucose uptake (glucose Rd) and glycerol production (glycerol Ra) were measured with a constant iv infusion of [6,6(2) H2 ]glucose and [(2) H5 ]glycerol. Electroencephalography direct (DC) and alternating (AC) current potentials were measured. While detemir induced comparable effects on glucose Ra, glucose Rd and glycerol Ra during euglycaemia, compared with NPH, it triggered a distinct negative shift in DC-potentials, with significant treatment effect in frontal cerebrocortical channels (p<0.001). AC spectral power showed significant differences in theta and alpha frequencies during euglycaemia (p=0.03). Subcutaneous detemir exerts different effects on brain function when compared with NPH in people with type 1 diabetes.This may be an important mechanism behind the limitation of weight gain with detemir. This article is protected by copyright. All rights reserved.
    Diabetes Obesity and Metabolism 08/2015; DOI:10.1111/dom.12553 · 5.46 Impact Factor
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    ABSTRACT: We evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes(T1D). Randomized cross-over study comparing closed-loop with standard prandial insulin boluses versus closed-loop with prandial boluses reduced by 25%. Eight adolescents with T1D [M3; age 15.9(1.5)yrs; A1C 8.9(1.6)%; mean(SD); total daily dose 0.9(0.7, 1.1)IU/kg/d; median(IQR)] studied on two 36-hour-long visits. In random order, subjects received closed-loop with either standard or reduced insulin boluses administered with main meals [(50-80 g carbohydrates(CHO)] but not with snacks (15-30gCHO). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd). Time in target (70-180 mg/dl) was comparable [74(66,84)% vs 80(65,96)%, p = 0.87] and so was time above 180 mg/dl [21.8(16.3,33.5)% vs 18.0(4.1,34.2)%, p = 0.87] and below 70 mg/dl [0(0,1.5)% vs 0(0,1.8)%, p = 0.88]. Mean plasma glucose was identical during the two interventions [152(16) vs 152(17)mg/dl, reduced vs standard bolus, p = 0.98]. Hypoglycemia occurred once 1.5 h post-meal during closed-loop with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9(55.2,75.0) vs 72.5(63.6,80.3)IU, p = 0.01] and resulted in lower mean plasma insulin concentration [186(171,260) vs 252(198,336)pmol/l, p = 0.002]. Lower plasma insulin was also documented overnight [160(136,192) vs 191(133,252)pmol/l,p = 0.01, pooled nights]. Ra_total was similar [26.3(21.9,28.0) vs 25.4(21.0,29.2)µmol/kg/min, p = 0.19] as well as Rd [25.8(21.0,26.9) vs 25.2(21.2,28.8)µmol/kg/min, p = 0.46]. Twenty five percent reduction of prandial boluses during closed-loop maintains comparable glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with 25% reduction of prandial boluses will prevent postprandial hypoglycemia. ClinicalTrials.gov Identifier NCT01629251. This article is protected by copyright. All rights reserved.
    Diabetes Obesity and Metabolism 08/2015; DOI:10.1111/dom.12549 · 5.46 Impact Factor
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    Atherosclerosis 07/2015; 241(1):e46. DOI:10.1016/j.atherosclerosis.2015.04.164 · 3.99 Impact Factor
  • Atherosclerosis 07/2015; 241(1):e103. DOI:10.1016/j.atherosclerosis.2015.04.360 · 3.99 Impact Factor
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    ABSTRACT: Aims/hypothesisPrevious studies have shown insulin detemir to be partially hepato-preferential at euglycemia and hypoglycemia. Using a novel non-steady state protocol, the differential effects of subcutaneous detemir and NPH insulin on glucose flux and lipid metabolism following insulin withdrawal were investigated.Materials and methodsFollowing a period of insulin withdrawal resulting in whole blood glucose of 7 mmol/l, eleven participants (5 males, age 41.0 years, BMI 25 kg/m2) with type 1 diabetes (HbA1c 57 mmol/mol, diabetes duration 14 years) received in random order 0.5 Units/kg BW subcutaneous insulin detemir or NPH insulin. Stable isotopes of glucose and glycerol were infused intravenously throughout the study protocol.ResultsGlucose concentration decreased following insulin treatment due to suppression of endogenous glucose production (Ra), which was similar with detemir and NPH insulin. Glucose rate of disappearance (Rd) was not increased significantly with either insulin. When the effect of detemir and NPH insulin on glucose flux at glucose concentrations between 9 to 6 mmol/l was examined glucose Ra was similar with the two insulins. However, glucose Rd was greater with NPH insulin when compared with detemir at glucose concentrations of 8.0, 8.5, 7.0 and 6.0 mmol/l (p < 0.05) The percentage change of glycerol Ra, a measure of lipolysis was greater in the NPH group than the detemir group (P = 0.04).Conclusions The results are also consistent with the hypothesis that detemir has a lesser effect on the periphery, as evidenced by a lesser effect on peripheral glucose uptake at specific glucose concentrations
    Diabetes Obesity and Metabolism 01/2015; 17(5). DOI:10.1111/dom.12434 · 5.46 Impact Factor
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    ABSTRACT: Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured. After 16 weeks, weight change was -0.69±1.85 kg with insulin detemir and +1.7±2.46 kg with NPH insulin (P<0.001). Total energy intake was significantly less with insulin detemir (2,016±501 kcal/day) than with NPH insulin (2,181±559 kcal/day) (P=0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P=0.039, P=0.047). After the meal, ghrelin and pancreatic polypeptide levels (P=0.002, P=0.001) were higher with insulin detemir. The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety.
    Diabetes care 05/2011; 34(7):1487-91. DOI:10.2337/dc11-0098 · 8.57 Impact Factor
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    ABSTRACT: Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7-9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4-6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU . kg(-1).min(-1) plus insulin requirement from study 1), BG of 7-9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU.kg(-1).min(-1) plus insulin requirement from study 1), BG of 4-6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 (P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI (P < 0.01) and HI (P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (R(a)), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose R(a) and lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI (P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7-9 mmol/l is sufficient to limit lipolysis and endogenous glucose R(a) and increase glucose R(d). Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.
    AJP Endocrinology and Metabolism 12/2009; 298(3):E697-705. DOI:10.1152/ajpendo.00407.2009 · 4.09 Impact Factor
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    ABSTRACT: Although low-density lipoprotein (LDL) cholesterol is often normal in patients with type 2 diabetes mellitus, there is evidence for a reduced fractional catabolic rate and consequently an increased mean residence time (MRT), which can increase atherogenic risk. The dyslipidemia and insulin resistance of type 2 diabetes mellitus can be improved by aerobic exercise, but effects on LDL kinetics are unknown. The effect of 6-month supervised exercise on LDL apolipoprotein B kinetics was studied in a group of 17 patients with type 2 diabetes mellitus (mean age, 56.8 years; range, 38-68 years). Patients were randomized into a supervised group, who had a weekly training session, and an unsupervised group. LDL kinetics were measured with an infusion of 1-(13)C leucine at baseline in all groups and after 6 months of exercise in the patients. Eight body mass index-matched nondiabetic controls (mean age, 50.3 years; range, 40-67 years) were also studied at baseline only. At baseline, LDL MRT was significantly longer in the diabetic patients, whereas LDL production rate and fractional clearance rates were significantly lower than in controls. Percentage of glycated hemoglobin A(1c), body mass index, insulin sensitivity measured by the homeostasis model assessment, and very low-density lipoprotein triglyceride decreased (P < .02) in the supervised group, with no change in the unsupervised group. After 6 months, LDL cholesterol did not change in either the supervised or unsupervised group; but there was a significant change in LDL MRT between groups (P < .05) that correlated positively with very low-density lipoprotein triglyceride (r = 0.51, P < .04) and negatively with maximal oxygen uptake, a measure of fitness (r = -0.51, P = .035), in all patients. The LDL production and clearance rates did not change in either group. This study suggests that a supervised exercise program can reduce deleterious changes in LDL MRT.
    Metabolism: clinical and experimental 11/2008; 57(11):1608-14. DOI:10.1016/j.metabol.2008.06.018 · 3.61 Impact Factor
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    ABSTRACT: Alterations of protein turnover may contribute to the progressive decline of muscle mass with aging. Our objective was to examine the effects of near-physiological recombinant human GH and/or testosterone (T) administration to older men on whole body protein kinetics and muscle gene expression. A 6-month randomized, double-blind, placebo-controlled trial in 21 healthy elderly men aged 65-75 yr, was performed. Participants were randomized to receive placebo GH and placebo T, rhGH and placebo T (GH), T and placebo GH (T), or rhGH and T (GHT). The leucine rate of appearance (index of proteolysis), nonoxidative leucine disposal rate (an index of protein synthesis), and leucine oxidation rate were measured with an infusion of l-[1-(13)C] leucine. Muscle biopsies for the measurement of gene expression were performed. Body composition and aerobic capacity (maximal oxygen capacity) were measured. Serum IGF-I levels increased significantly with GH and GHT (P < 0.001) compared with placebo. T increased significantly only in the T group (P = 0.028). Leucine rate of appearance and nonoxidative leucine disposal rate increased with GH (P = 0.015, P = 0.019) and GHT (P = 0.017, P = 0.02), but leucine oxidation did not change significantly in any treatment group. Midthigh muscle mass and maximal oxygen capacity increased (P < 0.04) with GHT only. Expression of muscle function genes did not change significantly, but the within-group comparisons revealed a significant increase of androgen receptor expression in the GHT group (P = 0.001). This study showed that 6-month treatment with low-dose GH alone or with T in healthy elderly men produces comparable increments in whole body protein turnover and protein synthesis.
    Journal of Clinical Endocrinology &amp Metabolism 05/2008; 93(8):3066-74. DOI:10.1210/jc.2007-2695 · 6.31 Impact Factor
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    ABSTRACT: It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.
    Diabetologia 02/2007; 50(2):404-13. DOI:10.1007/s00125-006-0498-7 · 6.88 Impact Factor
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    ABSTRACT: To assess the effects of low dose recombinant growth hormone (GH), testosterone (T) and combined GH and T, on lipid profiles and very low density lipoprotein apolipoprotein B (VLDL apoB) metabolism. Sixty-nine healthy elderly men (65-80 yr) were studied in a six month double-blind, placebo-controlled trial. Participants were randomised to placebo GH and placebo T (P), GH and placebo T (GH), T and placebo GH (T) or GH and T (GHT). Plasma lipid profiles were assessed before treatment and at 6 months. VLDL apoB absolute secretion rate (ASR) and fractional catabolic rate (FCR) were measured in a subset of 21 men: P (n=5); GH (n=5); T (n=6); GHT (n=5), with an infusion of 1-(13)C leucine. Fat mass (FM) was measured by DEXA and intra-abdominal fat (IAF) by CT scan. IGF-I levels increased in the GH and GHT (P<0.001) groups: testosterone increased in the T (P=0.029) and GHT (P=0.05) groups. There was no change in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B or lipoprotein(a) in the GH, GHT or T groups. In the subset of 21 men, IGF-I levels increased similarly with GH and GHT (P<0.01) but T levels increased only with T (P<0.03). FM and IAF decreased significantly only with GHT (P<0.01, P=0.01). Treatment with GH, T or GHT had no effect on VLDL apoB ASR or VLDL FCR. Co-administration of GH and T in near physiological doses in healthy elderly men resulted in favourable changes in body composition without altering the plasma lipid profile or VLDL apoB metabolism.
    Growth Hormone & IGF Research 10/2006; 16(5-6):308-17. DOI:10.1016/j.ghir.2006.08.001 · 1.33 Impact Factor
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    ABSTRACT: Epidemiological studies suggest that hypopituitary patients have an increased risk for cardiovascular mortality. The dyslipidaemia associated with this condition is often characterised by an increase in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol (LDL-C) and may contribute to these findings. The underlying mechanisms are not fully elucidated. LDL apolipoprotein B (apoB) production rate and metabolic clearance rate were measured in seven patients with hypopituitarism (including GH deficiency) under stable conventional replacement therapy (three males and four females; age 40-16.1 years; body mass index 29.0-6.1 kg/m(2) (means +/- s.d.)) and seven age-, gender- and body mass index-matched control subjects with an infusion of 1-(13)C-leucine. Fasting lipid profile and lipid composition of LDL were also measured. Fasting TC, triglycerides (TG), high-density lipoprotein-C, LDL-C and free fatty acid concentrations were not different between hypopituitary patients and control subjects. LDL-TG (P < 0.006) and LDL-TG/LDL apoB ratio (P < 0.02) were significantly increased in hypopituitary patients. LDL apoB pool size was not statistically different between patients and control subjects. In the hypopituitary patients, LDL apoB metabolic clearance rate (P < 0.05) and LDL apoB production rate (P < 0.02) were lower than in the control subjects. The present results suggest that LDL apoB turnover and LDL composition is altered in hypopituitary patients. Whether these findings explain the increased risk for cardiovascular disease in hypopituitary patients remains to be established.
    European Journal of Endocrinology 04/2006; 154(3):459-66. DOI:10.1530/eje.1.02105 · 3.69 Impact Factor
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    ABSTRACT: We hypothesised that loss of peripheral fat in HIV patients would result in decreased plasma adipocytokines, in particular adiponectin, and that this decrease would be associated with changes in VLDL, IDL and LDL apolipoprotein B kinetics. Plasma adiponectin, leptin and other cytokines were measured in uninfected control subjects (n=12) and three HIV-positive groups comprising treatment-naïve patients (n=15) and patients on triple antiretroviral therapy containing protease inhibitors (PI, n=15) or non-nucleoside reverse transcriptase inhibitors (NNRTI, n=25). VLDL, IDL and LDL apolipoprotein B kinetics were measured with an infusion of [1-(13)C] leucine. Regional body fat was measured with a dual energy X-ray absorptiometry scan. Insulin resistance was calculated using homeostasis model assessment (HOMA). Adiponectin (median [interquartile range]) was reduced in the treatment-naive (5.4 microg/ml [4.7-8.5]), PI (5.0 microg/ml [3.3-6.4]) and NNRTI (5.0 microg/ml [3.1-6.7]) groups compared with controls (9.7 microg/ml [6.9-13.3]) (p<0.05). In all subjects adiponectin correlated positively with HDL-cholesterol levels, the VLDL, IDL and LDL apolipoprotein B fractional clearance rates, and with the limb fat:lean body mass ratio (all p<0.01). Adiponectin correlated negatively with plasma triglyceride levels and HOMA (p<0.001). In a linear regression model that included HOMA, adiponectin was an independent predictor of VLDL and HDL-cholesterol levels and the IDL fractional clearance rate. TNF was higher in treatment-naive and PI subjects, and soluble TNF receptor superfamily, members 1A and 1B (previously known as TNF receptors 1 and 2) was higher in PI patients than in control subjects (p<0.05). Adiponectin levels are significantly reduced in treated and untreated HIV patients and are predictive of VLDL and IDL apolipoprotein B fractional clearance rates. Adiponectin may have a direct effect on lipoprotein metabolism, which may be independent of insulin.
    Diabetologia 03/2006; 49(3):538-42. DOI:10.1007/s00125-005-0085-3 · 6.88 Impact Factor
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    ABSTRACT: Exercise is a potent stimulator of growth hormone (GH) secretion. We hypothesised that after a short bout of intense exercise GH may increase lipolysis during recovery. In 7 moderately trained young male subjects (21.8 +/- 0.5 years) and 7 moderately trained older male subjects (56.0 +/- 1.0 years) [(2)H(5)] glycerol was infused for 370min to measure glycerol production rate (R(a)), a measure of lipolysis. At 130 min subjects exercised on a cycle ergonometer for 20 min at 70% V(O2 max), followed by rest for 220 min. On a separate occasion the study was repeated in the young subjects with a 1h GH infusion (4microgkg(-1)h(-1)) at 130 min instead of exercise. In response to exercise, catecholamines (p < 0.02) and glycerol R(a) (p < 0.01) increased, peaking during exercise. GH concentration increased in response to exercise (p < 0.01), peaking after exercise (150-160 min) in both groups with no significant difference in peak response between groups. A post-exercise rise in glycerol R(a) was demonstrated in both groups peaking at 265-295 min in the older group (p < 0.002, peak vs. basal) and continuing to rise until 370 min in the young group (p < 0.01, peak vs. basal). The timing and magnitude of this was reproduced with the GH infusion. There was a significant correlation between the peak GH response to exercise and the post-exercise rise in glycerol R(a) measured as area under the curve (r=0.57, p < 0.04). In conclusion, this study provides evidence that the GH response to acute exercise may increase lipolysis during recovery.
    Growth Hormone & IGF Research 12/2005; 15(6):397-404. DOI:10.1016/j.ghir.2005.08.003 · 1.33 Impact Factor
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    ABSTRACT: Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors. We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients (n=13) and patients taking two nucleoside analogues plus either a PI (n=15) or an NNRTI (n=24). LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups (P<0.05). In the TN patients, LDL ASR was lower (P<0.05) and there was a trend for a lower FCR and higher RT compared with the controls (P=0.07). LDL apoB pool size was greater in the PI group compared with the controls (P<0.05). In the PI group, patients on ritonavir (RTV)-containing regimens had a lower LDL apoB ASR (P=0.009) and a trend to a lower LDL apoB FCR and increased RT compared with non-RTV-containing PI regimens (P=0.05). There was a positive correlation between LDL apoB FCR and limb fat/lean body mass (P=0.004) in all subjects. Decreased LDL FCR, despite unchanged LDL cholesterol, was demonstrated in both treated and untreated HIV patients. It was more marked with RTV-containing regimens and was associated with reduced limb fat. The increased LDL RT may lead to an increased risk of atherogenesis thus contributing to the risk for cardiovascular disease in these patients.
    Antiviral therapy 02/2005; 10(5):663-70. · 3.14 Impact Factor
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    ABSTRACT: The relationship between antiretroviral treatment of HIV infection, body fat distribution, insulin resistance, and very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) apolipoprotein-B (apoB) kinetics was investigated in 55 HIV-infected patients taking two nucleoside analogs plus either a protease inhibitor (n = 15) or a nonnucleoside reverse transcriptase inhibitor (n = 25), 15 antiretroviral therapy-naive patients, and 12 HIV-negative controls. Compared with the controls, high-density lipoprotein cholesterol was reduced in all groups (P < 0.01). Plasma triglyceride was increased in patients taking protease inhibitors (P < 0.05). VLDL and IDL apoB fractional catabolic rate (FCR) was lower in all treatment groups (P < 0.05) compared with controls. Trunk fat, VLDL apoB absolute secretion rate, and insulin resistance were not different between groups. Peripheral fat was lower in the treated patients (P < 0.05) and correlated with duration of therapy (r = -0.55; P < 0.001). There was a positive correlation between peripheral fat and VLDL apoB FCR (P = 0.002) and IDL apoB FCR (P = 0.002) and a negative correlation with VLDL apoB pool size, VLDL cholesterol, and triglyceride (P < 0.03; P < 0.01; P < 0.002). These results suggest that mild dyslipidemia resulting from antiretroviral therapy is caused by a decrease in VLDL and IDL apoB FCR, which is associated with a loss of peripheral fat.
    Journal of Clinical Endocrinology &amp Metabolism 02/2005; 90(2):755-60. DOI:10.1210/jc.2004-1273 · 6.31 Impact Factor
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    ABSTRACT: There is evidence of a metabolic role for IGF-I in type 1 diabetes, but it is unclear whether IGF-I acts indirectly by reducing GH secretion or has direct effects. Using stable isotopes we have investigated, on three separate occasions, the effect of a pulse of recombinant human GH, a sc injection of recombinant human IGF-I, and a placebo on glucose, lipid, and protein metabolism in subjects with type 1 diabetes during a basal insulin infusion and a hyperinsulinemic euglycemic clamp. Endogenous GH secretion was suppressed with octreotide. IGF-I reduced the hepatic glucose production rate (Ra), increased peripheral glucose uptake, and reduced protein breakdown during the basal insulin infusion (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo) and the hyperinsulinemic euglycemic clamp (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo). IGF-I had no effect on glycerol Ra, an index of lipolysis. GH increased glucose and glycerol Ra during the basal insulin infusion (P < 0.005 vs. placebo study), but the effects were no different from placebo during the clamp. In conclusion, IGF-I had a direct effect on glucose and protein metabolism, which was maintained during the hyperinsulinemic euglycemic clamp. This suggests that IGF-I acts in concert with insulin and may have an important role in maintaining glucose homeostasis and protein metabolism in type 1 diabetes.
    Journal of Clinical Endocrinology &amp Metabolism 02/2004; 89(1):425-32. DOI:10.1210/jc.2003-031274 · 6.31 Impact Factor
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    ABSTRACT: Protein loss leading to reduced lean body mass is recognized to contribute to the high levels of morbidity and mortality seen in critical illness. This prospective, randomized, controlled study compared the effects of conventional parenteral nutrition (TPN), glutamine-supplemented (0.4 g.kg-1.day-1) TPN (TPNGLN), and TPNGLN with combined growth hormone (GH, 0.2 IU.kg-1.day-1) and IGF-I (160 microg.kg-1.day-1) on protein metabolism in critical illness. Nineteen mechanically ventilated subjects [64 +/- 3 yr, body mass index (BMI) 23.8 +/- 1.3, kg/m2] were initially studied in the fasting state (study 1) and subsequently after 3 days of nutritional with/without hormonal support (study 2). All had recently been admitted to the ICU and the majority were postemergency abdominal surgery (APACHE II 17.5 +/- 1.0). Protein metabolism was assessed using a primed constant infusion of [1-13C]leucine. Conventional TPN contained mixed amino acids, Intralipid, and 50% dextrose. TPNGLN, unlike TPN alone, resulted in an increase in plasma glutamine concentration ( approximately 50%, P < 0.05). Both TPN and TPNGLN decreased the rate of protein breakdown (TPN 15%, P < 0.002; TPNGLN 16%, P < 0.05), but during these treatments the patients remained in a net negative protein balance. Combined treatment with TPNGLN + GH/IGF-I increased plasma IGF-I levels (10.3 +/- 0.8 vs. 48.1 +/- 9.1 nmol/l, study 1 vs. study 2, P < 0.05), and in contrast to therapy with nutrition alone, resulted in net protein gain (-0.75 +/- 0.14 vs. 0.33 +/- 0.12 g protein.kg-1.day-1, study 1 vs. study 2, P < 0.05). Therapy with GH/IGF-I + TPNGLN, unlike nutrition alone, resulted in net positive protein balance in a group of critically ill patients.
    AJP Endocrinology and Metabolism 02/2004; 286(1):E151-7. DOI:10.1152/ajpendo.00122.2003 · 4.09 Impact Factor
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    ABSTRACT: We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dual-tracer dilution methodology. Six healthy lean male subjects (age 33 +/- 3 yr, body mass index 22.7 +/- 0.6 kg/m(2)) underwent a 4-h IVGTT (0.3 g/kg glucose enriched with 3-6% D-[U-(13)C]glucose and 5-10% 3-O-methyl-D-glucose) preceded by a 2-h investigation under basal conditions (5 mg/kg of D-[U-(13)C]glucose and 8 mg/kg of 3-O-methyl-D-glucose). A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a one-compartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 +/- 3.8 vs. 10.4 +/- 3.9 vs. 11.1 +/- 2.7 x 10(-2) ml small middle dot kg(-1) small middle dot min(-1) per mU/l; P = nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective (P < 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52-82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/transport was least responsive to insulin and was maximally activated by 62% (34-96%) above basal at 80 min compared with maximum 279% (116-565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP (P < 0.02) with half-times of 207 (84-510), 12 (7-22), and 29 (16-54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP (r = 0.96, P < 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity (r = 0.73, P = 0.10) and disposal sensitivity (r = 0.55, P = 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.
    AJP Endocrinology and Metabolism 05/2002; 282(5):E992-1007. DOI:10.1152/ajpendo.00304.2001 · 4.09 Impact Factor

Publication Stats

812 Citations
170.44 Total Impact Points

Institutions

  • 2008–2015
    • University of Surrey
      • Postgraduate Medical School (PGMS)
      Guilford, England, United Kingdom
    • ICL
      Londinium, England, United Kingdom
  • 2006–2007
    • King's College London
      Londinium, England, United Kingdom
  • 2005
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2004–2005
    • The Kings College
      Gatlinburg, Tennessee, United States
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1999–2002
    • City University London
      Londinium, England, United Kingdom