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Biomedical subjects

C N Hales

Publications and source records attributed to C N Hales.

At least 19 recordsLinked to original sources
PubMed2000

Left ventricular concentric remodeling rather than left ventricular hypertrophy is related to the insulin resistance syndrome in elderly men.

BACKGROUND: Associations between left ventricular (LV) geometry and the insulin resistance syndrome have been found, mostly in small studies of middle-aged hypertensives. The purpose of this study was to elucidate these associations through the use of a large sample of elderly men. METHODS AND RESULTS: We investigated 475 men (157 hypertensives) 71 years of age who were attending a population-based health survey in Uppsala County with echocardiography, oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, and lipid and 24-hour ambulatory blood pressure monitoring. LV relative wall thickness was significantly related to clamp insulin sensitivity index (r=-0.14), fasting insulin, 32-33 split proinsulin, triglycerides, nonesterified fatty acids, OGTT glucose and insulin levels, waist-to-hip ratio, body mass index, 24-hour blood pressure, and heart rate (r=0.10 to 0.22). Only 24-hour systolic pressure (r=0. 15), OGTT 2-hour insulin (r=-0.10), and heart rate (r=-0.14) were significantly related to LV mass index. Comparing subjects with various LV geometry (normal, concentric remodeling and concentric and eccentric hypertrophy) showed that 24-hour heart rate, OGTT glucose and insulin levels, waist-to-hip ratio, and body mass index were significantly higher (P<0.001 to 0.05) and clamp insulin sensitivity index was significantly lower (P<0.01) in the concentric remodeling geometry group than in the normal LV geometry group. The 24-hour blood pressure was significantly higher in the concentric hypertrophy group than in the normal LV geometry group (P<0.001). CONCLUSIONS: Several components of the insulin resistance syndrome were related to thick LV walls and concentric remodeling but less to LV hypertrophy in this population-based sample of elderly men.

Aged↗
PubMed2000

Effects of size at birth, gestational age and early growth in preterm infants on glucose and insulin concentrations at 9-12 years.

AIMS/HYPOTHESIS: To test the hypothesis that small size for gestation and poor postnatal growth in preterm infants is associated with higher fasting and post-load plasma glucose and insulin concentrations at 9-12 years of age. METHODS: Prospective follow-up at 9-12 years of 385 preterm children with birth weight less than 1850 g, who had anthropometry recorded at birth, 18 months and 7 years. Fasting plasma glucose, insulin, proinsulin and 32.33 split proinsulin concentrations and glucose and insulin concentrations 30 min after a standard glucose load were measured. RESULTS: Post-load glucose concentrations were negatively related to birth weight, independently of gestation or subsequent growth. Fasting split proinsulin and 30-min insulin concentrations were highest in children who showed the greatest increase in weight centile between birth and current follow-up, regardless of gestation. When weight during childhood was included, birthweight centile was, however, no longer statistically significant: concentrations of fasting, split, proinsulin and 30-min insulin were highest in those children who had shown the greatest increase in weight centile between 18 months of age and current follow-up, with no evidence of a greater effect in those who were smallest at 18 months. CONCLUSION/INTERPRETATION: Our findings suggest that fetal growth influences plasma glucose 30 min after a glucose load in preterm children at 9-12 years. In contrast, childhood weight gain is the most important factor influencing insulin concentrations and this effect is the same regardless of early size.

Blood Glucose↗
PubMed2000

Hypertension and its treatment influence changes in fasting nonesterified fatty acid concentrations: a link between the sympathetic nervous system and the metabolic syndrome?

In previous studies, a cross-sectional association has been described between blood pressure (BP) and nonesterified fatty acid (NEFA) concentrations. The direction of causality, and thus, the mechanism explaining this relationship, remains uncertain. Therefore, we analyzed a prospective population-based cohort of 937 subjects who underwent an oral glucose tolerance test (OGTT) on two occasions separated by 4.5 years. In cross-sectional analysis, NEFA measures were correlated with systolic and diastolic BP, both at baseline and at follow-up study. In longitudinal analysis, baseline systolic and diastolic BP predicted changes in fasting NEFA levels (both P < .01). However, baseline NEFA levels did not predict change in BR In multivariate analysis, the relationship between baseline BP and change in fasting NEFA was independent of age and sex. Obesity and its interaction with BP did not explain this association. Absolute changes in NEFA concentrations were greater among subjects who were hypertensive at baseline compared with the normotensive individuals. This change was greater in subjects treated with diuretics compared with those treated with beta-adrenergic antagonists (P < .01), an observation that provides support for a role of sympathetic nervous system (SNS) activity in explaining the relationship between BP and NEFA concentration.

Adrenergic beta-Antagonists↗
PubMed2000

Effects of early protein restriction and adult obesity on rat pancreatic hormone content and glucose tolerance.

Rats were fed a diet containing either 20% ("control") or 8% ("reduced-protein") protein throughout pregnancy and lactation. Their female offspring were weaned onto the same respective diets. At 63 days of age one set of control and reduced-protein rats (n = 16 per group) underwent intraperitoneal glucose tolerance tests and one week later were killed and their pancreatic hormones extracted and measured. The reduced protein rats had better glucose tolerance (p < 0.001) and lower pancreatic insulin (p < 0.01) and amylin (p < 0.01) contents. Further sets of control and reduced-protein rats were then fed either chow or a cafeteria-style diet (n = 16 in each of the four groups). These rats underwent intraperitoneal glucose tolerance tests at 133 days of age, which showed the cafeteria-fed animals to have a worse glucose tolerance than the chow-fed animals irrespective of previous diet exposure (p < 0.0001). One week later reduced-protein rats still had lower pancreatic insulin contents (p < 0.05) (and a trend for lower amylin contents), but also had increased pancreatic glucagon contents (p < 0.05). There were no detectable differences in pancreatic somatostatin-like immunoreactivity or pancreatic polypeptide contents. These results are consistent with pancreatic beta- and alpha-cells being selectively susceptible to effects associated with early dietary protein restriction.

Amyloid↗
PubMed2000

Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects.

OBJECTIVE: Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. RESEARCH DESIGN AND METHODS: Insulin sensitivity (S(I)) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. RESULTS: Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S(I) (r = -0.19) (all P values <0.0001, adjusted for age, sex, ethnicity, glucose tolerance status, and smoking). In a multiple linear regression analysis (adjusting for age, sex, ethnicity, clinical center, glucose tolerance status, and smoking), heart rate was significantly and independently associated with AIR, proinsulin, and S(I). CONCLUSIONS: Proinsulin, acute insulin secretion, and S(I) are associated with heart rate in nondiabetic subjects.

Body Constitution↗
PubMed1999

Early growth determines longevity in male rats and may be related to telomere shortening in the kidney.

Maternal protein undernutrition can influence the growth and longevity of male offspring in the rat. We tested the hypothesis that these differences in longevity were associated with changes in the rate of telomere shortening. We found age-related shortening of telomeres in the liver and kidney but not in the brain of male rats. Growth retardation in postnatal life was associated with significantly longer kidney telomeres and an increased longevity. Conversely, growth retardation during the foetal life followed by postnatal catch-up growth was associated with a shorter life span and shorter kidney telomeres. These findings may provide a mechanistic basis for epidemiological studies linking early growth retardation to adult degenerative diseases.

Animals↗
PubMed1999

Identification of a novel complement-dependent serum-elicited inward current in the Xenopus oocyte provoking Ca2+ influx and subsequent activation of Cl- channels.

The membrane spanning complement channel is assumed to be a nonselective ion 'pore', although little evidence is available to support this hypothesis. In this paper we provide evidence that Ca2+ entry and Cl- exit occur rapidly after complement activation and precede the development of a long-lasting complement-dependent inward current. Addition of rabbit serum (a source of heterologous complement) and mouse anti-human insulin receptor antibody to a single Xenopus oocyte expressing human insulin receptor was shown to stimulate an initial hyperpolarising current followed by a sustained depolarising current. On voltage clamping the oocyte, a novel long-lasting inward current generated by serum addition was detected. Complement classical pathway-stimulated calcium influx into the oocyte was directly demonstrated using 45Ca influx measurements. In addition, we found that Ca2+ influx was required for the stimulation of the complement alternative pathway-dependent inward current. The novel conductance elicited by the classical pathway was outwardly rectifying, had a reversal potential of -35 +/- 8 mV (or -52 +/- 7 mV in the presence of chloride channel inhibitors), was inhibited by nifedipine, and was observed in the presence but not in the absence of the pore-forming complement component C9. As overactivation of complement does play a role in many inflammatory or autoimmune diseases, inhibition of early complement-mediated ion flux might restrict tissue damage and aid recovery from such diseases.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1999

The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed type II diabetes: the Insulin Resistance Atherosclerosis Study.

AIMS/HYPOTHESIS: Proinsulin concentrations are increased relative to insulin concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance or due to a defect in insulin secretion. METHODS: We investigated the association between fasting insulin, intact proinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and with acute insulin response (AIR) in 182 newly diagnosed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. RESULTS: Insulin sensitivity correlated inversely with fasting insulin (r(s) = -0.42) and intact proinsulin (r(s) = -0.32) (p < 0.001). The intact proinsulin:insulin ratio was not correlated with insulin sensitivity. AIR correlated positively with intact proinsulin (r(s) = 0.23) and inversely with the intact proinsulin:insulin ratio (r(s) = -0.29, p < 0.001). Fasting glucose correlated positively with intact proinsulin (r(s) = 0.34) and the intact proinsulin:insulin ratio (r(s) = 0.24, p < 0. 001). The intact proinsulin:insulin ratio increased by decreasing AIR (quartiles of AIR from high to low: 7.8, 8.2, 9.7 and 12.1 %, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensitivity. CONCLUSION/INTERPRETATION: Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type II diabetes. In contrast, both low AIR and high fasting glucose concentrations were associated with a disproportionate increase in proinsulin concentration. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects.

Adult↗
PubMed1999

Frequent salad vegetable consumption is associated with a reduction in the risk of diabetes mellitus.

This cross-sectional study was undertaken to investigate the association between the reported frequency of consumption of vegetables and fruits, the choice of staple carbohydrate, and glucose intolerance. One thousand one hundred twenty-two subjects aged 40-64 years in a population-based study underwent an oral glucose tolerance test, and their food consumption was assessed using a food-frequency questionnaire. The crude prevalence of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) was 4.5%, and that of impaired glucose tolerance (IGT) 16.8%. The age-standardized prevalence rates were 2.3 and 11.2%, respectively. Frequent consumption of vegetables throughout the year was inversely associated with the risk of having NIDDM (odds ratio [OR] = 0.16; 95% confidence interval [CI] = 0.04-0.69). This association was maintained after adjustment for age, gender, and family history. Vegetable consumption during the summer months had a much weaker inverse association with the risk of having NIDDM that failed to reach statistical significance. A nonsignificant inverse association between frequent consumption of fruits and NIDDM was observed. Frequent self-reported pasta and rice consumption was associated with a reduction in the risk of having IGT and NIDDM. (OR = 0.62, 95% CI = 0.44-0.87, and OR = 0.51, 95% CI = 0.27-0.99, respectively) but this relationship was not independent of age. Whether these associations reflect specific effects of particular nutrients or are a reflection of the patterning of lifestyle factors remains to be determined.

Adult↗
PubMed1999

The long-term consequences of intra-uterine protein malnutrition for glucose metabolism.

Our initial observations, in epidemiological studies, linking indices of poor early (fetal and infant) growth to the subsequent development of poor glucose tolerance and the insulin resistance syndrome in adult life, have been confirmed in studies in a wide variety of populations around the world. These findings led us 5 years ago to propose the 'thrifty phenotype' hypothesis. Tests of this hypothesis in an animal model in which the pregnant and/or lactating rat dams are fed on an isoenergetic diet containing just under half the normal protein content are consistent with the ideas put forward. They have also allowed us to refine the hypothesis in the light of the new data as follows: (1) the growth of the fetus (and possibly infant) is quantitatively and qualitatively altered by its nutritional environment (which may include maternal diet-dependent changes in maternal hormones); (2) these changes serve to select between the growth rates of different tissues according to priorities which differ between males and females (nutritional thrift) and to alter organ function to constitute a thrifty offspring adapted to survival in poor nutritional circumstances (thrifty phenotype); (3) an individual so constituted suffers adverse consequences in adult life if he/she experiences good or supranormal nutrition; (4) both poor insulin secretion and insulin resistance can result from these adaptive processes; (5) the adverse consequences include loss of glucose tolerance and hypertension. The precise outcome of growth retardation during early life may vary according to the type and timing of the factors responsible for the retardation. It remains to be determined to what extent these potentially adverse effects can be delayed or prevented by a suitable postnatal diet. Experiments in animal models are largely consistent with the concepts proposed from human epidemiological studies. They show that the metabolism of the liver, muscle and adipose tissue may be programmed by maternal nutrition during gestation and lactation. The combination of early growth restriction and subsequent adult obesity reproduced in the rat are the main features of the insulin resistance syndrome.

Animals↗
PubMed1999

Prospective cohort study of the relationship of markers of insulin resistance and secretion with weight gain and changes in regional adiposity.

OBJECTIVE: To examine whether fasting insulin concentrations and markers of first-phase insulin secretion are associated with weight gain and changes in distribution of adiposity over 4.4y. DESIGN: Longitudinal prospective population-based cohort study of middle-aged Caucasians. SUBJECTS: 767 subjects (40-65y at baseline) were followed up for a mean of 4.4y. MEASUREMENTS: 75 g oral glucose tolerance test performed at baseline and follow-up. Insulin was measured at fasting, and 30 and 120 min post-glucose load using a highly specific assay. RESULTS: Fasting insulin levels were correlated with baseline weight (r = 0.32, P<0.001), as was the 30 min insulin incremental response (r = 0.17, P<0.001). Mean weight gain over the 4.4y of follow-up was 2.17 kg (range: -6.17-10.5 kg) for men and 2.49 kg (range: -7.41-12.39 kg) for women. In women, the 30 min insulin incremental response was negatively associated with percentage weight gain (P<0.001), but there was no relationship between fasting insulin levels and weight gain. The baseline fasting insulin was positively correlated with percentage increase in waist- hip ratio (r = 0.12, P = 0.01). In stratified analysis, this relationship was confined to women over the age of 50 y. However, in men, none of these relationships were demonstrable. CONCLUSION: In middle-aged women reduced first-phase insulin secretion was associated with an increased risk of future weight gain, whereas fasting hyperinsulinaemia was associated with an increase in waist-hip ratio over time.

Adult↗
PubMed1999

Cross-sectional but not longitudinal associations between non-esterified fatty acid levels and glucose intolerance and other features of the metabolic syndrome.

AIMS: Cross-sectional studies have demonstrated an association between high non-esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the direction of causality in these studies is uncertain. The aim of this study was to examine whether NEFA levels predicted the development of glucose intolerance in a prospective population-based cohort study. METHOD: Four hundred and eighty-one women and 345 men participated in a prospective cohort study in which NEFA concentrations and glucose tolerance were measured at baseline and then repeated at follow-up 4.5 years later. RESULTS: The data do not show longitudinal relationships between baseline NEFA levels and either glucose intolerance or other features of the metabolic syndrome at follow-up. In contrast, strong cross-sectional associations were observed between NEFA measures and glucose intolerance (and other features of the metabolic syndrome) in both baseline and follow-up studies. At follow-up, fasting NEFA levels and two measures of NEFA suppression were markedly different in subjects with features of the metabolic syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs. metabolic syndrome for each NEFA value, P< 0.001). CONCLUSIONS: These results support the hypothesis that plasma NEFA levels change as a consequence of the metabolic syndrome and do not support the notion that increased NEFA levels cause either the metabolic syndrome or diabetes.

Adult↗
PubMed1999

The effect of insulin on delta5 desaturation in hepG2 human hepatoma cells and L6 rat muscle myoblasts.

In humans there is a correlation between the ratio of arachidonic acid (20:4n-6) to cis 8,11,14 eicosatrienoic acid (20:3n-6) in skeletal muscle phospholipids and insulin sensitivity. This has been interpreted as indicating a link between the activity of the delta5 desaturase enzyme and muscle insulin sensitivity. The present study addressed the possibility that insulin regulates delta5 desaturase activity using L6 rat myoblasts and hepG2 human hepatoma cells. Both cell lines responded to insulin by increasing the amount of D-[U-14C] glucose incorporated into glycogen. In L6 cells, insulin stimulated cis 8,11,14 eicosatrienoic acid uptake and arachidonic acid production but had no effect on the percentage conversion of cis 8,11,14 eicosatrienoic acid to arachidonic acid. In hepG2 cells, insulin had no effect on cis 8,11,14 eicosatrienoic acid uptake or arachidonic acid production. These results suggest that insulin has no direct effect on delta5 desaturase activity in the liver but can alter arachidonic acid production in muscle by altering substrate availability.

Animals↗
PubMed1999

Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS).

Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.

Arteriosclerosis↗
PubMed1999

LDL particle size in relation to insulin, proinsulin, and insulin sensitivity. The Insulin Resistance Atherosclerosis Study.

OBJECTIVE: LDL particles are heterogeneous in terms of size and density; small dense LDL particles are considered more atherogenic than larger LDL particles. The aim of this study was to investigate the interrelationships among LDL size, insulin, proinsulin (intact and split), and insulin sensitivity in a tri-ethnic population with varying degrees of glucose tolerance (n = 1,549) in the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Proinsulin levels were measured using highly sensitive assays without detectable cross-reactivity with insulin, and LDL size was determined by gradient-gel electrophoresis. RESULTS: In univariate analyses, LDL size was related to various features of the insulin resistance syndrome, including fasting insulin (r = -0.18), intact proinsulin (r = -0.24), split proinsulin (r = -0.24), the proinsulin-to-insulin ratio (r = -0.14), and insulin sensitivity (r = 0.21; all P < 0.0001). In a multivariate regression model (adjusted for age, BMI, ethnicity, and clinic), triglyceride levels (P = 0.0001), HDL cholesterol (P = 0.0001), sex (P = 0.002), and proinsulin (P = 0.01) were significantly related to LDL size. In the same model stratified by sex, LDL size was significantly inversely related to proinsulin in men (P = 0.005 and P = 0.04 after further adjustment for the glucose tolerance status), but not in women (P > 0.15). CONCLUSIONS: We found an inverse relation of proinsulin to LDL particle size in a large tri-ethnic population with varying degrees of glucose tolerance. This relation was independent of age, BMI, and triglyceride and HDL cholesterol concentrations, and was more pronounced in men than in women.

Arteriosclerosis↗
PubMed1999

Fasting proinsulin concentrations predict the development of type 2 diabetes.

OBJECTIVE: The development of specific assays allows the different molecules in the proinsulin processing pathway to be measured separately. 32,33 Split proinsulin is the predominant form of proinsulin and accounts for the disproportionate hyperproinsulinemia seen in individuals with prevalent type 2 diabetes. This study was established to examine whether the concentration of this molecule predicts diabetes. RESEARCH DESIGN AND METHODS: A population-based longitudinal cohort study was conducted in Ely, Cambridgeshire. At baseline, 1,122 individuals completed a 75-g oral glucose tolerance test (OGTT). At the 4.5-year follow-up study, repeat OGTTs were performed on 937 of the cohort of 1,071 individuals who had been nondiabetic at baseline. RESULTS: A total of 26 people progressed to diabetes as determined by the OGTTs. The risk of progression was strongly related to the fasting glucose concentration (relative risk [RR] comparing top with bottom quartile 17.6 [95% CI 2.4-130.4]) and fasting 32,33 split proinsulin (RR 16.4 [2.2-121.9]), but less strongly to the fasting insulin (RR 4.41 [1.5-12.9]) or intact proinsulin (RR 5.2 [1.5-17.3]). In multivariate analyses, these associations were independent of age, sex, BMI, and baseline glucose tolerance category. Subjects in the top quartile for fasting glucose and total proinsulin with a family history of diabetes were a high-risk subgroup (incidence 65.8 per 1,000 person-years of follow-up [pyfu]); 30% of them progressed to diabetes at follow-up. CONCLUSIONS: Fasting 32,33 split proinsulin independently predicts the development of diabetes. This prediction was better than that observed for either the insulin or intact proinsulin concentrations. The combination of family history, fasting glucose, and total proinsulin identified a subgroup of individuals at high risk of progression who might benefit from targeted interventions.

Adult↗