Biomedical subjects

Ian F Godsland

Publications and source records attributed to Ian F Godsland.

10 recordsLinked to original sources

PubMed2006

Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system.

OBJECTIVES: Leptin, an important hormonal regulator of body weight, has been shown to stimulate the sympathetic nervous system (SNS) in vitro although the physiological relevance remains unclear. Increased SNS activity has been implicated in the pathogenesis of insulin resistance and an increased cardiovascular risk. We have therefore investigated the relationship between leptin, insulin resistance and cardiac autonomic activity in healthy young adults. 130 healthy men and women age 20.9 years were studied. Insulin sensitivity was assessed using the IVGTT and minimal model with simultaneous measures of leptin. Cardiac autonomic activity was assessed using spectral analysis of heart rate variability. RESULTS: Women showed significantly higher fasting leptin, heart rate and cardiac sympathetic activity, and lower insulin sensitivity. Men showed inverse correlations between insulin resistance and heart rate, and between insulin resistance and cardiac sympatho-vagal ratio. Women, in contrast, showed no SNS relationship with insulin resistance, but rather an inverse correlation between leptin and the sympatho-vagal ratio, suggesting that leptin in women is associated with SNS activity. The correlation remained significant after adjustment for BMI and waist-to-hip ratio (beta=-0.33 and p=0.008). CONCLUSION: Insulin resistance and SNS activity appear to be linked, although the relationship showed marked gender differences, and the direction of causality was unclear from this cross-sectional study. Leptin appears to exert a greater effect on the SNS in women, possibly because of their greater fat mass.

Adult↗

PubMed2006

Evaluation of nonlinear regression approaches to estimation of insulin sensitivity by the minimal model with reference to Bayesian hierarchical analysis.

Minimal model analysis of intravenous glucose tolerance test (IVGTT) glucose and insulin concentrations offers a validated approach to measuring insulin sensitivity, but model identification is not always successful. Improvements may be achieved by using alternative settings in the modeling process, although results may differ according to setting, and care must be exercised in combining results. IVGTT data (12 samples, regular test) from 533 men without diabetes was modeled by the traditional nonlinear regression (NLR) approach, using five different permutations of settings. Results were evaluated with reference to the more robust Bayesian hierarchical (BH) approach to model identification and to the proportion of variance they explained in known correlates of insulin sensitivity (age, BMI, blood pressure, fasting glucose and insulin, serum triglyceride, HDL cholesterol, and uric acid concentration). BH analysis was successful in all cases. With NLR analysis, between 17 and 35 IVGTTs were associated with parameter coefficients of variation (PCVs) for minimal model parameters S(I) (insulin sensitivity) and S(G) (glucose effectiveness) of >100%. Systematic use of each different approach in combination reduced this number to five. Mean (interquartile range) S(I)(NLR) was then 3.14 (2.29-4.63) min(-1).mU(-1).l x 10(-4) and 2.56 (1.74-3.83) min(-1).mU(-1).l x 10(-4) for S(I)(BH) (correlation 0.86, P < 0.0001). S(I)(NLR) explained, on average, 10.6% of the variance in known correlates of insulin sensitivity, whereas S(I)(BH) explained 8.5%. In a large body of data, which BH analysis demonstrated could be fully identified, use of alternative modeling settings in NLR analysis could substantially reduce the number of analyses with PCVs >100%. S(I)(NLR) compared favorably with S(I)(BH) in the proportion of variance explained in known correlates of insulin sensitivity.

Bayes Theorem↗

PubMed2006

Less than 50% of variation in HDL cholesterol between and within individuals, is explained by established predictors.

Variation in serum high density lipoprotein cholesterol (HDL-C) concentrations is believed to be largely explained by triglycerides, but this has been mainly explored in cross-sectional analyses. Eight hundred and eighty one white male participants in a health screening program attended on a total of 2158 occasions for measurements that included fasting HDL-C, low density lipoprotein cholesterol (LDL-C) and homeostasis model assessment insulin resistance (HOMA-R). Baseline, change between-visit and repeated-measures regression models were used to analyse predictors of between- and within-individual variation in HDL-C. Independent predictors of between-individual variation included serum triglycerides (20.3 or 19.6% of the variance explained, depending on the model used), body mass index (BMI: 4.7 and 4.3%), cigarette smoking (3.3 and 1.5%) and alcohol consumption (0.4 and 1.1%). Within-individual variation in HDL-C was explained by changes in serum triglycerides (4.7 and 7.5%) and BMI (5.3 and 2.9%). In multivariate models, 24.3 and 24.9% of between-individual variation in HDL-C, and 7.9 and 8.8% of within-individual variation could be explained, depending on the model used. Sixty percent of the variation in HDL-C was due to unobserved factors. The majority of variation in HDL-C remains to be explained by influences other than the conventional variables: triglyceride and LDL cholesterol concentrations, insulin resistance, smoking and alcohol.

Alcohol Drinking↗

PubMed2006

Impaired insulin secretion after prenatal exposure to the Dutch famine.

OBJECTIVE: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.

Blood Glucose↗

PubMed2005

Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure.

OBJECTIVES: The aim of this study was to determine the significance of insulin resistance as an independent risk factor for impaired prognosis in patients with chronic heart failure (CHF). BACKGROUND: In CHF, impaired insulin sensitivity (S(I)) indicates abnormal energy metabolism and is related to decreased exercise capacity and muscle fatigue. The relationship between insulin resistance (i.e., low S(I)) and survival in patients with CHF has not been established. METHODS: We prospectively studied 105 male patients with CHF due to ischemic (63%) or non-ischemic (37%) etiology. All patients were in clinically stable condition (age 62 +/- 1 year, New York Heart Association [NYHA] functional class 2.6 +/- 0.1, left ventricular ejection fraction [LVEF] 28 +/- 2%, peak oxygen uptake [Vo(2)] 18.2 +/- 0.7 ml/kg/min). Insulin sensitivity was assessed from glucose and insulin dynamic profiles during an intravenous glucose tolerance test using the minimal model technique. RESULTS: During a mean follow-up period of 44 +/- 4 months, 53 patients (50%) died. Patients with S(I) below the median value (median: 1.82 min(-1) x microU x ml(-1).10(4); n = 52) had worse survival (at two years 61% [range 47% to 74%]) than patients with S(I) above the median value (n = 53; at two years 83% [range 73% to 93%]; risk ratio [RR] 0.38, 95% confidence interval [CI] 0.21 to 0.67; p = 0.001). Both patient groups were similar in terms of age, NYHA functional class, and body composition parameters (dual-energy X-ray absorptiometric scan; p > 0.2), but patients with a lower S(I) had a lower LVEF (24 +/- 2% vs. 33 +/- 3%) and peak Vo(2) (16.8 +/- 1.0 ml/kg/min vs. 19.7 +/- 1.0 ml/kg/min; both p < 0.05). On univariate Cox analysis, higher S(I) predicted better survival (RR 0.56, 95% CI 0.35 to 0.89; p = 0.015). On stepwise multivariate analysis, S(I) predicted mortality independently of other variables. CONCLUSIONS: In patients with CHF, lower S(I) relates to higher mortality, independent of body composition and established prognosticators. Impaired S(I) may have implications in the pathophysiology of CHF disease progression. Therapeutically targeting impaired insulin sensitivity may potentially be beneficial in patients with CHF.

Chronic Disease↗

PubMed2004

Biology: risk factor modification by OCs and HRT lipids and lipoproteins.

The many effects that the oestrogens and progestagens used in oral contraceptive (OC) and postmenopausal hormone replacement therapies (HRTs) have on lipoprotein metabolism are of importance because of the involvement of lipoproteins in endothelial damage and arterial occlusion. Lipoproteins promoting endothelial damage include: low density lipoprotein (LDL), particularly the small dense subfraction (sdLDL), remnants of very low density lipoprotein (VLDL) and chylomicron metabolism, and lipoprotein (a). High density lipoprotein (HDL) has pleiotropic effects that prevent or alleviate endothelial damage. Orally administered oestrogens increase hepatic triglyceride synthesis and VLDL secretion and increase the proportion of sdLDL. Oestrogens increase the rates of elimination of LDL, VLDL remnants and chylomicrons, suppress the synthesis of key enzymes of lipoprotein metabolism, hepatic and lipoprotein lipase, and increase synthesis of the principal apoprotein of HDL, apoAI. In general, progestagens oppose these effects according to type and dose. In OC and HRT users, this leads to a range of different lipoprotein profiles, which may differ from those evaluated with respect to vascular disease risk in population studies. Accumulating evidence suggests that the clinical implications of steroid induced changes in the lipoprotein profile will need to be evaluated independently of population-based evidence.

Cholesterol, HDL↗

PubMed2004

Inflammation markers and erythrocyte sedimentation rate but not metabolic syndrome factor score predict coronary heart disease in high socioeconomic class males: the HDDRISC study.

OBJECTIVE: To evaluate prediction of coronary heart disease (CHD) by quantitative measures of the metabolic syndrome and inflammation in a cohort of high socio-economic status males. METHODS: Incident CHD was identified in a cohort of 649 male participants in a company health programme during a mean follow-up of 10.6 years. Using factor analysis, metabolic syndrome and sub-clinical inflammation scores were derived from baseline measurements, which included an oral glucose tolerance test-derived measure of insulin resistance. Factor scores were then included as predictor variables in a Cox regression analysis of incident CHD. RESULTS: Forty-two cases of definite CHD were identified on follow-up. The conventional risk factors, cigarette smoking, blood pressure, total cholesterol and low HDL cholesterol were clearly distinguished as significant predictors of incident CHD. Erythrocyte sedimentation rate was also an independent predictor (coefficient 0.0480, z score 2.39, p=0.017). The metabolic syndrome factor included insulin resistance, body mass index, serum triglycerides, glucose tolerance, serum uric acid and fasting plasma glucose. The inflammation factor included serum globulin, blood leukocyte count, low albumin, haemoglobin and cholesterol, but not erythrocyte sedimentation rate. The inflammation factor score was a significant predictor of CHD (coefficient 0.4601, z score 2.43, p=0.015) but the metabolic syndrome factor was not (coefficient 0.2488, z score 1.24, p=0.2). CONCLUSIONS: Erythrocyte sedimentation rate and a factor analysis-derived measure of sub-clinical inflammation were important in the development of CHD in this relatively low-risk group, but neither metabolic syndrome factor score nor its individual components predicted CHD.

Biomarkers↗

PubMed2003

The minimal model: an evolving methodology.

After more than 20 years, minimal model analysis of intravenous glucose tolerance test glucose and insulin concentrations continues to be widely employed in studies of insulin sensitivity and insulin resistance. Moreover, problems encountered in solving the minimal model equations continue to find new solutions. Bayesian techniques enable prior knowledge to be incorporated into parameter estimation routines. They offer particular advantages in the measurement of insulin sensitivity with the minimal model, and provide an elegant means of improving model identification success rates and parameter precision. This comment describes the study by Agbaje and colleagues in this issue of Clinical Science that exemplifies a new phase in the evolution of minimal model practice.

Bayes Theorem↗

PubMed2003

Insulin resistance and beta-cell dysfunction in normoglycaemic European women with a history of gestational diabetes.

OBJECTIVE: Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM. PATIENTS AND MEASUREMENTS: We performed an insulin-modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose. RESULTS: Post-GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25.3 kg/m2 (23.8-27.1 kg/m2) vs. 23.1 kg/m2 (21.9-24.3 kg/m2), P = 0.03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0.6 x 10-4/min/pmol/l (0.3-1.2 x 10-4/min/pmol/l) vs. 1.5 x 10-4/min/pmol/l (1.2-1.8 x 10-4/min/pmol/l), P = 0.01] and by homeostatic model assessment [72% (49-107%) vs. 153% (113-206%), P = 0.004]; and by their higher fasting triglycerides [1.0 mmol/l (0.7-1.5 mmol/l) vs. 0.7 mmol/l (0.6-0.8 mmol/l), P = 0.001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post-GDM group (P = 0.01). Concomitant beta-cell dysfunction in the post-GDM women was revealed by their lower disposition index [0.05/min (0.02-0.10/min) vs. 0.11/min (0.09-0.14/min), P = 0.02] compared to controls. The differences in insulin sensitivity, but not those of beta-cell function, were partly, though not completely, attributable to differences in regional and total adiposity. CONCLUSIONS: European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced beta-cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.

Adult↗

PubMed2002

Insulin resistance in moderate chronic heart failure is related to hyperleptinaemia, but not to norepinephrine or TNF-alpha.

OBJECTIVES: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNFalpha) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNFalpha or leptin relate to insulin sensitivity. DESIGN: 41 patients with CHF (age 60+/-2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6+/-1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNFalpha and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. RESULTS: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1+/-9.7 vs. 41.4+/-6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28+/-0.84 vs. 4.83+/-0.68 ng/ml), norepinephrine (3.45+/-0.34 vs. 1.87+/-0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280+/-141 vs. 639+/-52 pg/ml) and 2 (2605+/-184 vs. 1758+/-221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3+/-3 vs. 24.3+/-2 pg/ml per 100 g, P<0.001). TNFalpha was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNFalpha. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised coefficient=-0.59, P<0.001), independent of body fat mass, age and peak VO2. CONCLUSION: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNFalpha and norepinephrine are not related to insulin resistance in moderate CHF.

Adipose Tissue↗