Background and aim:
Adiponectin is considered by many to be part of the ‘common soil’ linking type 2 diabetes and coronary heart disease (CHD). We examined the relationship between adiponectin and insulin resistance, metabolic, inflammatory and haemostatic risk factors and hepatic function.
Methods and results:
The study was carried out in 3640 non-diabetic men aged 60–79 years drawn from general practices in 24 British towns and who were not on warfarin. Adiponectin was associated with waist circumference (inversely), alcohol intake (positively) and physical activity (nonlinearly); no association was seen with cigarette smoking, prevalent CHD or stroke. After adjustment for these factors, adiponectin was significantly inversely associated with insulin resistance, triglyceride, C-reactive protein (but not interleukin 6), tissue plasminogen activator and alanine aminotransferase and positively associated with high-density lipoprotein cholesterol (HDL-cholesterol) and Factor VIII, factors associated with diabetes. No association was seen with cholesterol, smoking, systolic blood pressure or coagulation factors. Risk of the metabolic syndrome decreased significantly with increasing adiponectin.
Adiponectin is inversely associated with factors strongly associated with the development of diabetes. Limited associations with the established major risk factors for CHD suggest adiponectin may be a stronger marker of risk for diabetes than for CHD.
Adiponectin, an adipose tissue-derived hormone, is thought to play an important role in the regulation of insulin sensitivity and glucose and lipid metabolism.1, 2 Adiponectin is exclusively produced by adipocytes and unlike other adipocyte hormones (adipokines), adiponectin concentrations are decreased in obesity, insulin resistance and type 2 diabetes.2, 3, 4 Furthermore, evidence (largely from animal models and experimental studies) suggests that adiponectin has potential antiatherogenic and anti-inflammatory properties. Low circulating adiponectin concentrations have been linked to endothelial dysfunction,5, 6, 7, 8 factors implicated in the pathogenesis of atherosclerosis and diabetes.9, 10 An increasing body of evidence has shown low-adiponectin levels to predict risk of developing diabetes.11, 12, 13, 14, 15, 16 Although an inverse association has been found between adiponectin and prevalent coronary heart disease (CHD) in cross-sectional studies,17, 18 prospective studies have produced conflicting results.19, 20, 21, 22 It remains uncertain whether adiponectin is a critical factor in the ‘common soil’23 leading to both diabetes and cardiovascular disease.
The modulation of insulin sensitivity or insulin resistance by adiponectin has been extensively studied.2, 24 In population-based studies, adiponectin is inversely associated with body mass index (BMI), insulin resistance, triglycerides, and positively associated with high-density lipoprotein (HDL)-cholesterol, components of the metabolic syndrome.25, 26, 27, 28, 29 Although adiponectin has been associated with markers of inflammation in particular, C-reactive protein (CRP)30, 31 associations with other proinflammatory cytokines such as interleukin 6 (IL-6) however have been less consistent31 and based on small selected populations. Moreover, whether the potential anti-inflammatory properties of adiponectin are mediated by its effect on insulin resistance remains unknown. In a large population based-study, we have therefore examined the relationships between adiponectin and a wide range of risk factors for diabetes and cardiovascular disease including insulin resistance and its components, the metabolic syndrome, inflammatory markers (CRP, white cell count, IL-6, fibrinogen) and several haemostatic risk factors: coagulation factors and markers (VII, VIII, fibrin D-dimer), and markers of endothelial dysfunction: von Willebrand factor (vWF) and tissue plasminogen activator antigen (t-PA). Given the more consistent reports thus far for the predictive ability of low adiponectin for incident diabetes relative to CHD, we hypothesized that adiponectin may be more related to established risk factors implicated in the development of diabetes such as insulin resistance, triglycerides, markers of endothelial dysfunction and inflammation than to established risk factors for CHD such as blood pressure and cholesterol.
Subjects and methods
The British Regional Heart Study is a prospective study of cardiovascular disease involving 7735 men aged 40–59 years selected from the age–sex registers of one general practice in each of 24 British towns, who were screened between 1978 and 1980.32 In 1998–2000, all surviving men, now aged 60–79 years, were invited for a 20th year follow-up examination. Ethics approval was provided by all relevant local research ethics committees. All men provided informed written consent to the investigation, which was carried out in accordance with the Declaration of Helsinki. All men completed a questionnaire (Q20), which included questions on their medical history, use of regular medication and lifestyle behaviour. The men were asked to fast for a minimum of 6 h, during which they were instructed to drink only water and to attend for measurement at a prespecified time between 0800 and 1800 h. All men were asked to provide a blood sample, collected using the Sarstedt Monovette system.A total of 4252 men (77% of survivors) attended for examination. We excluded 145 men currently on warfarin, which affects several coagulation factors and markers; and a further 467 men with a doctor diagnosis of diabetes and those with a fasting glucose of ⩾7 mmol/l (WHO criteria) who were considered to have prevalent diabetes. A total of 3640 men then were available for analysis.
Cardiovascular risk factors and hepatic function
Anthropometric measurements including body weight, height and waist circumference (white cell) were carried out. Body mass index (BMI; weight/height2 in kg/m2) was calculated for each man at re-examination. Details of classification methods for smoking status, physical activity, BMI alcohol intake and social class and measurements of blood pressure and blood lipids have been described.32, 33, 34, 35 The men were asked to report the total number of alcoholic drinks/week and were classified into five groups based on their total daily intake: none, <1/day, 1–2/day, 3–4/day and ⩾5/day. One drink/unit (UK)=10 g alcohol. A physical activity score was derived for each man at Q20 and the men were grouped into six broad categories: inactive, occasional, light, moderate, moderately-vigorous and vigorous.33 From the combined information at screening and follow-up questionnaires the men were classified into five smoking groups: (i) those who had never smoked, (ii) ex-smokers >20 years, (iii) smokers at baseline who gave up between screening and Q20 (ex smokers <20 years) and (iv) current cigarette smokers. Blood pressure measured using a Dinamap 1846 was adjusted for observer variation. Total cholesterol, HDL-cholesterol and triglyceride were measured on a Hitachi 747 automated analyzer using established methods.35 Plasma glucose was measured by a glucose oxidase method using a Falcor 600 automated analyser.36 Serum insulin was measured using an enzyme-linked immunosorbent assay (ELISA) assay which does not cross-react with proinsulin.37 Triglycerides, blood glucose and insulin concentrations were adjusted for the effects of fasting duration and time of day.35 Insulin resistance was estimated according to the homoestasis model assessment (HOMA– the product of fasting glucose (mmol/l) and insulin (units/ml) divided by the constant 22.5).38 HOMA-IR showed a 0.98 correlation with fasting insulin. Alanine aminotransferase (ALT) were measured using a Hitachi 747 automated analyser.
Metabolic syndrome in non-diabetics
The metabolic syndrome was defined using the National Cholesterol Education Program definition,39 which included the presence of three or more of the following: (i) fasting plasma glucose of at least 110 mg/dl (6.1 mmol/l), (ii) serum triglycerides of at least 150 mg/d (1.7 mmol/l), (iii) serum HDL-cholesterol less than 40 mg/d (1.04 mmol/l), (iv) blood pressure of at least 130/85 mm Hg or on antihypertensive treatment or (v) waist circumference of more than 102 cm.
Haemostatic and inflammatory variables
Blood was anticoagulated with K2 EDTA (1.5 mg/ml) for measurement of haematocrit, white cell count and platelet count in an automated cell counter; and plasma viscosity at 37°C in a semi-automated capillary viscometer (Coulter Electronics, Luton, UK). Blood viscosity was calculated from haematocrit and plasma viscosity.39 Blood was also anticoagulated with 0.109 M trisodium citrate (9:1, v:v) for measurement of clottable fibrinogen (Clauss method); as well as coagulation factors VII, VIII and IX in an MDA-180 coagulometer (Organon Teknika, Cambridge, UK). Plasma levels of t-PA antigen and D-dimer were measured with ELIZA (Biopool AB, Umea, Sweden) as was vWF antigen (DAKO, High Wycombe, UK). CRP was assayed by ultra-sensitive nephelometry (Dade Behring, Milton Keynes, UK). IL-6 was assayed using a high-sensitivity ELISA (R & D Systems, Oxford, UK).
Plasma adiponectin concentrations were determined using ELISA (R&D Systems). Adiponectin was not available in 173 men.
Distributions of adiponectin, triglyceride, white cell count, CRP, fibrin D-dimer, IL-6 and ALT are highly skewed and natural log transformation was used. Analysis of covariance was used to obtain adjusted mean levels of metabolic and biological risk markers for the quintiles of adiponectin (Figure 1) and to obtain adjusted mean adiponectin (geometric) by lifestyle risk factor groups. Age, BMI and white cell are fitted as continuous variables; and physical activity, smoking, alcohol intake and pre-existing disease as categorical variables. Multivariate normal linear models and regression analysis are used to estimate the effect of adiponectin on metabolic risk factors, haemostatic and inflammatory risk markers (Table 3). Table 3 shows the differences in the metabolic, and biological risk factors (or logs where appropriate) for a 50% increase in adiponectin. For example, in the age- and white cell-adjusted model, a 50% increase in adiponectin concentration is associated with a 0.041 mmol/l increase in HDL-cholesterol concentration. The values are obtained using linear model assumptions and regression coefficient estimates. Multiple logistic regression was used to obtain adjusted odds ratio (OR) of having the metabolic syndrome by quintiles of adiponectin (fitted as categorical).
The mean (geometric) adiponectin levels in the 3640 men with no prevalent diabetes was 6.93 (4.43–11.14). Log adiponectin was significantly and negatively correlated with BMI (r=−0.15 (P<0.001) and waist circumference (r=–0.13; P<0.001). The correlation between log adiponectin and age was 0.03 (P<0.001).
Table 1 shows age-adjusted partial correlations between log adiponectin concentration and metabolic, inflammatory and haemostatic risk markers and liver enzymes. Adiponectin was negatively associated with triglyceride, HOMA-IR, CRP, t-PA, blood viscosity, ALT (hepatic function) and to a smaller extent with white cell count and IL-6 and was positively associated with HDL-cholesterol and Factor VIII. No significant associations were seen with systolic blood pressure, cholesterol, blood glucose, fibrinogen, fibrin D-dimer or vWF. As white cell tended to show stronger relations with the metabolic and inflammatory markers (data not shown) we adjusted the associations between adiponectin and these variables for white cell rather than BMI. The effect of adjustment for white cell is shown in Table 1. The relations between adiponectin and triglyceride, HDL-cholesterol, insulin, HOMA, CRP, t-PA, factor VIII, blood viscosity and ALT remained statistically significant though slightly weakened after adjustment.
To illustrate the relationships between adiponectin and the risk factors, we presented mean levels of metabolic, inflammatory and haemostatic markers by equal fifths of adiponectin, adjusted for age and then for age and white cell (Figure 1). To contrast magnitude of the response of the above variables to the increase in the adiponectin, graphs are shown on comparable scales, that is interval of presentation of a response variable is a mean ±/−0.5s.d. (interval is exponentiated where appropriate).
Table 2 shows geometric mean adiponectin concentrations by different lifestyle risk groups. In the age–white cell-adjusted analysis, there was a significant decrease in adiponectin concentration in those taking β-blockers and those who had a non-manual occupation. Non-drinkers showed higher levels than occasional or light drinkers but adiponectin levels tended to increase thereafter with the highest levels in moderate and heavy drinkers. There were no graded associations found between adiponectin concentrations and physical activity, though those participants involved in vigorous leisure time physical activity showed lower adiponectin concentration levels compared with those engaged in light and moderate physical activity. No associations were found between adiponectin and smoking or with prevalent CHD and stroke. Additional adjustment for each of the other factors in Table 2 made minor difference to the results although mean adiponectin levels was now higher in those with prevalent CHD. However, this difference was not significant.
Table 3 shows absolute differences (logged where necessary) in the metabolic and biological markers for a 50% increase in adiponectin with various levels of adjustment, that is adjustment for age, for age and waist circumference and additional adjustment for lifestyle risk factors and pre-existing diseases. Only factors, that were significant in age and waist circumference adjusted model in Table 1 are presented. Adjustment for white cell reduced the magnitude of associations between adiponectin and the metabolic and biological markers with the exception of factor VIII where adjustment increased the association between factor VIII and adiponectin. Additional adjustment for lifestyle factors, social class, pre-existing disease and use of β-blockers made minor differences to the relationships. Further adjustment for insulin resistance (HOMA-IR) reduced the magnitude of associations further particularly for triglyceride, t-PA and ALT although they remained significant.
We repeated the analyses excluding all men with prevalent cardiovascular disease. The main findings remained unchanged.
We examined the association between adiponectin and the metabolic syndrome. Mean adiponectin decreased significantly with increasing number of metabolic abnormalities (Figure 2) (P<0.0001). The odds of having the metabolic syndrome decreased significantly with increasing levels of adiponectin even after adjustment for BMI and potential confounders (Table 4). Men in the top quintile showed a 70% reduction in odds of having the metabolic syndrome compared to those in the lowest quintile.
In this large cross-sectional study of men aged 60–79 years, adiponectin was strongly and inversely associated with BMI, waist circumference, insulin resistance (HOMA-IR), triglyceride, CRP (inflammatory marker), t-PA (a surrogate marker of endothelial dysfunction), ALT (hepatic function) and positively associated with HDL-C. These latter seven associations were independent of waist circumference and the potential confounding effects of lifestyle factors such as smoking, alcohol intake and physical activity and pre-existing disease. Most of the metabolic and biological risk factors shown to be significantly associated with adiponectin are strongly implicated in the development of, or have been shown to variably predict, type 2 diabetes, for example adiposity, high triglycerides and low HDL-cholesterol, inflammation, raised ALT,40 endothelial dysfunction, insulin resistance and the metabolic syndrome. Of the classical CHD risk factors, adiponectin did not associate with systolic blood pressure, cholesterol or fibrinogen, suggesting that adiponectin may play a more important role in insulin resistance and the development of diabetes. In line with this possibility, no significant association was seen between adiponectin and prevalent vascular disease, which is consistent with recent prospective case–control studies showing no association between adiponectin and CHD20, 22 and at variance with the first reported prospective study.19 Adiponectin was strongly associated with obesity, but was associated with few other lifestyle characteristics associated with CHD or diabetes. A positive association was seen between alcohol intake and adiponectin, which has been reported in other studies19 but no association was seen with cigarette smoking. We observed no consistent association between physical activity and adiponectin, although paradoxically levels were significantly reduced in the vigorously active group. Although it has been suggested that exercise may increase adiponectin levels, clinical studies on the effects of exercise training have been conflicting41, 42 and findings in population-based studies are inconsistent.19, 21
Insulin resistance and the metabolic syndrome
Strong associations were seen between adiponectin and HOMA-IR after adjustment for waist circumference and the magnitude of correlation was similar to that seen for BMI. These findings confirm previous population studies showing the association between adiponectin and insulin resistance to be independent of adiposity.22, 25, 28, 29, 43 The associations between adiponectin and insulin sensitivity has been well established in animal and human models.2, 24 The strongest associations, however, were seen between adiponectin and triglycerides and HDL-cholesterol (components of the insulin resistance syndrome) and these relationships were independent of adiposity and insulin resistance as has been reported in other studies.26, 27, 28, 43 The mechanisms by which adiponectin may affect blood lipids are substantially unknown. There is some evidence that such effects may be mediated via reduced hepatic lipase activity, an enzyme which contributes to a lowering of HDL-C concentrations26 – low adiponectin is associated with increased hepatic lipase activity in vivo independent of insulin resistance.44 No association was seen between adiponectin and blood pressure, consistent with other population based studies.21 We have also observed a strong inverse relationship between adiponectin and the presence of the metabolic syndrome which we and others have shown to be much more strongly associated with incident diabetes than with cardiovascular events.45, 46
Adiponectin was significantly but modestly associated with the inflammatory marker CRP independent of adiposity, but the association with the proinflammatory cytokine IL-6 and with white cell count was dependant on adiposity. No association was seen with fibrinogen. The significant inverse relationship between adiponectin and CRP confirms other recent smaller studies reporting an inverse relationship between adiponectin and CRP independent of adiposity in non-diabetics.21, 30, 31 Studies that have reported inverse associations between IL-6 and adiponectin have generally been carried out in obese subjects,31, 47 and the association of IL6 with adiponectin, which was dependent on adiposity in the present study, suggests that adiponectin expression may be negatively regulated by IL-6 in adipose tissue. The mechanisms linking adiponectin and CRP are not clear. Adipose tissue is the source of circulating adiponectin and may be the common pathway contributing to the adiponectin–CRP relationship. Although the relationship between adiponectin and CRP was present independent of waist circumference, adjusting for more robust measures of fat mass (perhaps visceral fat mass) may have attenuated the relationship. Alternatively, as adiponectin leads to a reduction in hepatic fat accumulation and is anti-inflammatory, its association with CRP, independent of adiposity, may relate to specific hepatic-mediated effects, as CRP is synthesized by the liver. The anti-inflammatory effects of adiponectin might be mediated by its effect on blood lipids. HDL particles, and in particular its apoAI protein, are widely accepted to exhibit anti-inflammatory properties.48 Adjustment for HDL-cholesterol attenuated the association between adiponectin and CRP but the trend was still statistically significant. A more central role for adiponectin in inflammatory processes is supported by evidence largely from in vitro and animal studies, suggesting that adiponectin may play a role in the modulation of inflammatory vascular response by acting through the NF-κB pathway,49 inhibiting the expression of adhesion molecules on endothelial cells50 and suppressing macrophage function. The finding of an independent inverse association between adiponectin and CRP suggests that decreased production of adiponectin may contribute to the systemic and vascular inflammation commonly found in obesity.
Adiponectin was strongly and inversely associated with t-PA antigen, which has been reported in other studies.21, 51 It is hypothesized that increased abdominal adipose tissue is responsible for a mild chronic inflammatory state, which may induce insulin resistance and endothelial dysfunction, markers of which include t-PA antigen levels.52 Hypoadiponectinemia may directly contribute to the development of endothelial dysfunction by allowing vascular proinflammatory reactions to occur more readily.5 However, no association was seen with vWF, another potential marker of endothelial dysfunction. In part, t-PA antigen is also a measure of increased circulating complexes of t-PA with its inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Hence, the association of adiponectin with increased levels of t-PA antigen may also or simply reflect elevated PAI-1. In this respect, it should be noted that PAI-1 may be synthesized directly from adipocytes or hepatocytes so the association of t-PA with adiponectin may simply reflect adiposity directly or liver adiposity. In line with this notion, evidence of a link between adiponectin and directly measured endothelial dysfunction is inconsistent,6, 7, 8, 53 whereas other data support a link between elevations in adiponectin and reduced liver fat.54 The inverse correlation between adiponectin and ALT in this study supports to some extent this latter possibility.
We observed no significant associations between adiponectin and markers of activated coagulation such as fibrinogen, fibrin D-dimer and vWF. However, an inverse association was seen with blood viscosity independent of adiposity and insulin resistance. Blood viscosity has been associated with increased risk of CHD,55 but its role in diabetes is less established although elevated blood viscosity is associated with insulin sensitivity and the metabolic syndrome.56 Elevated factor VIII has been linked with development of diabetes57 and although there was a significant association between adiponectin and factor VIII, the association was positive thus raised factor VIII is unlikely to contribute to the increased risk of diabetes associated with low adiponectin.
There are now increasing data as noted above to suggest links between adiponectin and reduced liver fat accumulation, indirectly approximated by elevated ALT levels. Moreover, a marked rise in adiponectin by glitazones has been directly correlated with a reduction in hepatic fat accumulation.54 Thus adiponectin's action to reduce hepatic fat by enhancing fatty acid oxidation, may partially explain its inverse association to parameters such as ALT, triglyceride, CRP and, as discussed above, t-PA (via reduced hepatic PAI-1 synthesis).
Potential biases and limitations
The study population is not strictly a random population sample, being influenced by survival and response, both of which will tend to lead to under-representation of selected groups of individuals such as obese subjects. Although this may affect the average levels of the inflammatory and haemostatic markers in the population, there is no reason to believe that under-representation per se should bias the relationships between adiponectin and the biological markers studied. If selection bias were to occur this would tend to result in the strength of the associations to be underestimated. Although we cannot extend our findings to other ethnic groups, younger subjects or women, significant associations between adiponectin and inflammatory markers in women have also been reported, consistent with our own findings.31, 47 Although we have observed strong relationships between adiponectin and insulin resistance, dyslipidemia and inflammation, factors shown to be associated with CHD and in particular diabetes, the cross-sectional nature of our study cannot prove a causal association between adiponectin and these risk factors, nor can it provide direct evidence as to whether these factors indeed mediate the relationship between adiponectin and diabetes. However, the strong significant inverse associations between adiponectin and insulin resistance, metabolic abnormalities and with several factors associated with risk of diabetes (particularly triglyceride, markers of inflammation, and raised ALT and t-PA antigen levels) suggest that these factors may contribute to the increased risk of diabetes associated with low adiponectin.
Adiponectin was significantly and inversely associated with inflammation, endothelial markers, ALT and in particular hypertriglyceridaemia/ low HDL-cholesterol, insulin resistance (HOMA-IR) and having the metabolic syndrome, factors strongly associated with the development of type 2 diabetes. These associations were independent of adiposity measures. By contrast, associations with classical risk factors for CHD such as blood cholesterol, smoking, systolic blood pressure or fibrinogen were lacking. The findings suggest that adiponectin may play a more important role in insulin resistance and the development of diabetes than in CHD.
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The British Regional Heart Study is a British Heart Foundation Research Group and also receives support from the Department of Health (England). JT and measurements and laboratory analyses in this study were supported by British Heart Foundation Project Grants. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health (England).
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Wannamethee, S., Tchernova, J., Whincup, P. et al. Associations of adiponectin with metabolic and vascular risk parameters in the British Regional Heart Study reveal stronger links to insulin resistance-related than to coronory heart disease risk-related parameters. Int J Obes 31, 1089–1098 (2007). https://doi.org/10.1038/sj.ijo.0803544
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