The purpose of this study was to determine the relationships between adipocyte hormones acylation stimulating protein (ASP), adiponectin, complement C3 (C3) (ASP precursor) and insulin, C-reactive protein (CRP), lipid profiles and insulin resistance in lean vs obese type 2 diabetes subjects.
Lean type 2 diabetes subjects (DL n=27) vs obese type 2 diabetes subjects (DO n=55) were compared to age-matched nondiabetic groups (Obese, OB n=55 and control, CTL n=50).
The DO group demonstrated significant increases in plasma ASP and C3 with decreases in plasma adiponectin as compared to CTL. Interestingly, these increases in ASP and C3 were as high, or greater, in the DL group in spite of normal weight. By contrast adiponectin in the DL group was comparable to CTL, in spite of marked insulin resistance. C3 correlated with insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR); ASP correlated with body mass index (BMI), glucose, insulin and plasma lipid parameters (non-esterified fatty acids (NEFA), triglyceride, cholesterol and apolipoprotein B). Adiponectin correlated with BMI, glucose, NEFA, triglyceride, high-density lipoprotein cholesterol and apolipoprotein A1 but not HOMA-IR, ASP or C3. CRP correlated only with HOMA-IR.
Increased ASP and C3 are both associated with diabetes and related lipid factors but are not regulated coordinately. Adiponectin appears to be more closely related to body size (decreased in obese subjects) than insulin resistance in these subjects.
Adipose tissue, long recognized as the major fat storage site, is also known to secrete bioactive substances ranging from signaling lipids to steroid hormones to peptide/protein hormones.1, 2, 3, 4 Recent research has disclosed a group of adipokines that include leptin, acylation stimulating protein (ASP), adiponectin, tumor necrosis factor-α, IL-6, resistin and peroxisome proliferator-activated receptor γ (PPAR γ)-angiopoietin-related protein (PGAR), among others. Many of these factors have been shown to play a central role in adipocyte metabolism from communication with a variety of tissues to allowing the adipocyte to sense its own energy stores, influencing energy expenditure as well as its own mass.1, 2, 3, 4
ASP is a small (9-kDa), basic protein identical to a fragment of the third component of the complement system, C3adesArg, and is generated through cleavage of its precursor protein complement C3 (C3) through combined action of adipsin, an adipose-specific serine protease enzyme, and cofactor B.5, 6 Both ASP and its precursor C3 have been suggested to be altered in disease states including diabetes and cardiovascular disease, but a detailed comparison between the two proteins has not been evaluated (for a review, see Cianflone et al.7). C-reactive protein (CRP) has also been implicated in complement, early atherosclerosis and in type 2 diabetes in association with ASP.8, 9
ASP is a potent stimulator of free fatty acid esterification into storage triglyceride in human adipocytes in vitro.5, 6, 10 Recent studies indicate that chylomicrons and insulin increase both ASP and C3 production in human adipocytes.11, 12, 13 While no direct role for C3 has been proposed, ASP appears to be an important determinant of postprandial lipemia in both human14 and mouse models.15, 16, 17, 18, 19 In complement C3(−/−) ASP-deficient mice, the lack of ASP results in delayed postprandial triglyceride clearance, which is normalized acutely through ASP injection. The mice are characterized by reduced adipose tissue with a compensatory upregulation of energy expenditure.17, 18, 19, 20, 21
Adiponectin is a hormone secreted exclusively from adipose tissue. It is thought to enhance insulin sensitivity by stimulating hepatic glucose utilization and reducing plasma nonesterified fatty acid levels (NEFA) (for a review, see Ukkola and Santaniem22). Furthermore, both the mRNA expression of adiponectin and circulating plasma levels have been shown to be decreased in obesity and type 2 diabetes in both animals and humans.1
While the relationship of many of these adipocyte hormones with diabetes has been examined in other studies, they are confounded by the presence of obesity in the vast majority of subjects with type 2 diabetes. In North America and Europe, the majority of subjects with type 2 diabetes are overweight and/or obese. On the other hand, obesity is far less common in China, although recent studies indicate that this is rapidly changing.23, 24 We used a Chinese diabetic population to compare the impact of body size on adipocyte hormones and the diabetic profile.
The aims of this study were to evaluate plasma ASP, its precursor C3, adiponectin and CRP in type 2 diabetic subjects, comparing lean diabetic subjects to obese diabetic subjects. We tested (i) whether plasma ASP, C3 or adiponectin concentrations are associated with insulin resistance in diabetes independent of obesity and (ii) whether the levels of plasma C3 directly affect the concentrations of ASP across all groups.
Research design and methods
A total of 187 subjects were recruited from daily clinics at the Tongji Medical Centre, Tongji Hospital, Wuhan, Hubei, P.R. China. All participants gave informed consent and the study was approved by Tongji Hospital Ethics Committee.
Fasting blood samples and oral glucose tolerance test
Blood samples were drawn after an overnight fast from an antecubital vein. For those undergoing an oral glucose tolerance test (OGTT) for diagnostic purposes, samples were taken after a 75 g oral glucose load at 0, 60, 120 and 180 min and plasma glucose and insulin were determined. Fasting samples were used for measurement of all other parameters. The blood was centrifuged and the plasma was aliquoted and frozen immediately for future analysis of lipids and proteins.
Blood samples were analyzed as described below. Normal ranges within the laboratory are provided for each parameter. The blood glucose (3.9–6.4 mmol/l) was determined by glucose-oxidase method (AVE-852 half-auto biochemical analyzer). The plasma NEFA concentration (0.2–0.6 mmol/l) was determined by colorimetric enzymatic assay (WAKO Chemicals, Tokyo, Japan). Plasma triglycerides (TG) (0.34–1.7 mmol/l) were measured by GPO-PAP method and total cholesterol (2.86–5.98 mmol/l) was measured by COD-PAP method. Following precipitation of apolipoprotein B1 (Apo B) containing lipoproteins, the concentration of high-density lipoprotein cholesterol (HDL-C) (0.94–2.0 mmol/l) was also measured by colorimetric enzymatic assay.
Apolipoproteins A1 (Apo A1) (1.06–1.79 g/l) and B (0.59–1.55 g/l) were measured by immunoturbidimetric method. Insulin (10–20 IU/l) was measured by electrochemiluminescence immunoassay (Elecsys 1010, Roche Instrument Center AG). Plasma adiponectin concentration (2–20 μg/ml) was measured by ELISA (B-Bridge International, Phoenix, AZ, USA) and CRP (<10 mg/l) by nephelometry (Orion Diagnostica Turbox). C3 (0.55–2.50 g/l) was measured by an immunoturbidimetric assay (Lin-Fei Co, P.R. China), with ranges comparable to published control values for this assay (range 0.75–3.66 g/l) in a similar adult population.25, 26 Plasma ASP concentration (10.3–58.1 nmol/l) was measured via a sandwich ELISA immunoassay as previously described in detail.27, 28
Calculations and statistical analyses
Body mass index (BMI) was measured as weight (kg) per height (m2). Insulin resistance index was calculated by homeostasis model assessment, homeostasis model assessment of insulin resistance (HOMA-IR) as (fasting insulin IU/l) (fasting glucose mmol/l)/22.5 as previously reported by Matthews et al.29 Low-Density Lipoprotein cholesterol (LDL-C) (0.5–3.6 mmol/l) was calculated according to the Friedewald formula as LDL-C=(total cholesterol, mmol/l)−(triglyceride, mmol/l)/2.2−(HDL-C, mmol/l).30 Unless otherwise stated, data are given as means±standard error of the mean (s.e.m.). Statistical comparisons among all groups were performed using ANOVA analyses. All correlations were analyzed with Pearson's correlation coefficient. Non-normally distributed parameters were log transformed prior to analysis. P<0.05 was considered to be statistically significant for all analyses.
We analyzed data from a total of 187 Chinese subjects. Control nondiabetic subjects (n=105) were normal healthy adults with no known disease recruited at their yearly checkup. Diabetic subjects (n=82) were recruited at the time of their initial screening through the Endocrinology Clinic. Diabetes was defined according to 1999 World Health Organization criteria31 as fasting plasma glucose >7.0 mmol/l and/or a 2-h glucose >11.1 mmol/l after a glucose tolerance test. The type 2 diabetic participants were not taking any medication (including antidiabetic medication or herbal preparations) known to affect glucose tolerance, insulin sensitivity or insulin secretion at the time of blood sampling. Subjects (diabetic and nondiabetic controls) were excluded if they had any known disease (including cardiovascular disease, thyroid disease, high blood pressure or any other disease condition) or any current infectious condition. A BMI cutoff of 25 kg/m2 was used to define obesity according to guidelines established for Asian obesity,32 resulting in four groups: an obese diabetic group (DO, n=55), a lean diabetic group (DL, n=27) and control subjects divided into an obese (OB) group (BMI ⩾25 kg/m2, n=55) and a lean control (CTL) group (BMI <25 kg/m2, n=50). The clinical and laboratory data of the 187 subjects is shown in Table 1. There was no difference in age or gender distribution between all four groups. The control group was nonobese, with normal fasting glucose and insulin and a normal OGTT as shown in Table 1. By definition, both obese groups (DO and OB) had increased BMI compared to CTL, and the diabetic groups (DO and DL) had elevated glucose, insulin, HOMA-IR and abnormal (delayed) OGTT compared to CTL. The OB group also had significantly increased insulin and HOMA-IR as compared to CTL.
The lipid profiles of the four groups are shown in Table 2. In the DO group, most lipid parameters (TG, TC and LDL-C and total Apo B) were significantly increased relative to controls with decreases in HDL-C and Apo A1. In the DL subjects, TG, TC and Apo B were also significantly increased while in the OB subjects TG was increased and HDL-C and Apo A1 were reduced relative to controls. Interestingly, plasma NEFA was increased in both diabetic groups (DO and DL) but not in OB subjects relative to CTL subjects (P<0.0001 by ANOVA).
We then examined several hormones known to be involved in fat regulation, energy metabolism, insulin resistance and immune function. The results for adiponectin, ASP, C3 as well as CRP are shown in Table 3. Plasma adiponectin concentrations were significantly lower in the DO group than in the CTL group (P<0.0001 by ANOVA). In spite of the presence of insulin resistance in the DL group, plasma adiponectin was not significantly changed vs CTL. On the other hand, the obese nondiabetic (OB) group also had significantly decreased adiponectin levels. This relationship between BMI and adiponectin is demonstrated in Figure 1 (top panel). While there is clearly a significant correlation, there is no significant difference between the diabetic and the nondiabetic groups (nondiabetic (CTL+OB): slope=−0.449, r=0.563, P<0.0001 and diabetic (DL+DO): slope=−0.337, r=0.315, P=0.004, P=not significantly different between the two groups for either slope or intercept).
Plasma ASP concentrations were significantly higher in both obese groups: the nondiabetic OB (+43%) and the diabetic DO (+33%) (P=0.0024 by ANOVA), consistent with the increase in fat mass in the obese subjects. Interestingly, although the DL group was nonobese, plasma ASP was markedly increased (+56%) relative to the CTL group, to a level comparable or higher than both obese groups (OB and DO) (Table 3). As a consequence, although ASP demonstrated a significant positive correlation with BMI in the nondiabetic subjects (CTL+OB, Figure 1, bottom left, slope=2.373, r=0.259, P=0.0007), there was no such correlation in the diabetic subjects, where ASP was uniformly elevated at all BMI (Figure 1, bottom right).
Serum C3 concentrations were also significantly higher in both diabetic groups DO and DL vs CTL (P=0.0001 by ANOVA), although not significantly increased in the OB group. C3 is present in the plasma at molar amounts, far in excess of ASP (>225-fold). As C3 is the precursor to ASP, we also examined the ratio of ASP to C3 as an indication of the conversion rate, as suggested by Kotler et al.33 As shown in Table 3, only the OB group demonstrated a significant increase (37%) in % ASP/C3 (P=0.05), suggesting increased conversion of C3 to ASP. There was no difference in % ASP/C3 in any other subject group as compared to CTL. Lastly, CRP was also measured in the four groups. Owing to the wide variation in CRP values (even in healthy subjects), the small number of values that exceeded the 95th percentile were excluded from the analysis. Although there was a tendency for the diabetic and obese groups to be higher than the control group, this was not statistically significant.
In regression analysis (Pearson's correlation), we correlated each of the hormones with all plasma variables in the complete cohort of subjects, as well as each group individually (Table 4). Adiponectin correlated with BMI (r=−0.487, P<0.001), glucose (r=0.168, P=0.02) as well as lipid variables such as plasma NEFA (r=0.156, P=0.04), triglycerides (r=−0.205, P=0.005), HDL-C (r=0.187, P=0.01) and Apo A1 (r=0.186, P=0.05). Surprisingly, there was no significant correlation with insulin or HOMA-IR.
In the complete cohort, ASP correlated with BMI (r=0.241, P=0.001), glucose (r=0.170, P=0.02), insulin (r=0.172, P=0.02) and a number of lipid variables: NEFA (r=0.143, P<0.05), triglyceride (r=0.180, P=0.015), total cholesterol (r=0.206, P=0.005) and Apo B (r=0.229, P=0.016). Interestingly, C3 was primarily and very strongly associated with insulin status, correlating with glucose (r=0.283, P<0.0001), insulin (r=0.301, P<0.0001) and HOMA-IR (r=0.266, P=0.0002). On the other hand, CRP correlated only with HOMA-IR (r=0.277, P=0.05). Of note, while each of the hormones correlated with different lipid and glucose homeostasis variables, the results of multivariate correlations showed there were no relationships between ASP, adiponectin, C3 and CRP.
The salient findings of the present study are (1) circulating ASP levels were increased in DL subjects to a level comparable to that in the two obese groups (OB and DO), even though the subjects were lean; (2) plasma C3 was also significantly increased in both diabetic groups (DO and DL); (3) by contrast, circulating adiponectin levels were reduced only in the two obese groups, DO and OB, but not in the lean diabetic DL group. Finally, ASP, C3 and adiponectin did not correlate with each other, in spite of being derived from a similar tissue source (adipose) and correlating with similar parameters (glucose/insulin and lipids). HOMA-IR did not correlate with ASP or adiponectin but correlated strongly to C3 and CRP. Thus these data suggest that changes in these hormones may be induced not only by obesity, but also independently by diabetic status (even in the absence of obesity).
A number of previous articles have demonstrated the strong inverse relationship between obesity and adiponectin as well as between diabetes and adiponectin.34, 35, 36, 37, 38 However, in most cases, the diabetic groups had increased BMI, and the effects of obesity vs diabetic status have not been directly addressed. For example, a recent study in 73 type 2 diabetic Japanese subjects demonstrated decreased adiponectin in diabetic subjects. While the concentration of adiponectin ranged from 2 to 35 μg/ml (within normal ranges), and BMI ranged from 16.2 to 31.3 kg/m2, there was no indication of the segregation of adiponectin levels between lean and obese.39 In the present study, we have directly assessed adiponectin levels in lean diabetic subjects as compared to obese diabetic subjects, and assessed this correlation across all subjects as a continuous parameter. The results indicate that plasma adiponectin is more closely related to the obesity state than the diabetic state, correlating with BMI but not indices of insulin resistance (HOMA-IR). On the other hand, there were strong consistent associations between adiponectin and plasma lipids, particularly plasma triglycerides (negative), HDL-C, Apo A1 and NEFA (positive). This strong association of adiponectin with HDL metabolism has been previously noted40, 41, 42, 43, 44, 45, 46, 47 and in fact in a study with >500 subjects, it was proposed as a useful marker/risk factor in cardiovascular disease assessment.40 While the physiological nature of this correlation has not been determined, this may be tied to the proposed functions of adiponectin at the vascular wall which include modulation of endothelial function, inhibition of vascular smooth muscle proliferation, suppression of macrophage transformation and modulation of inflammation (for a review, see Ukkola and Santaniem22). The recent identification of two related adiponectin receptors48 will likely lead to a better understanding of the role of adiponectin.
Several lines of evidence suggest that both C3 and its cleavage product ASP may be linked to insulin resistance and/or hyperinsulinemia49, 50 (for a review, see Cianflone et al.7). Elevated C3 concentration levels have been reported in individuals with obesity,51 type 2 diabetes,52 hypertension,53 dyslipidemia,25 and coronary artery disease,54 all of which are known to be associated with obesity (for a review, see Cianflone et al.7). In the present study, we found that both ASP and C3 concentration were increased in diabetic subjects in the absence of obesity, suggesting that it is the diabetic state (or associated abnormalities), not just the presence of obesity, which results in increased levels of these proteins. Related to that, the lean diabetic subjects also demonstrated increased NEFA, Apo B and total cholesterol. In the present study, plasma C3 and CRP were closely related to insulin resistance. This may have pathophysiological and clinical relevance. Recently, it has been suggested by Pickup and Crook55 and Pickup et al.56 as well as others,57, 58 that insulin resistance, and ultimately type 2 diabetes, may in part be a manifestation of a chronic acute-phase response. This concept was largely developed from the observations that plasma concentrations of other inflammatory cytokines and acute-phase proteins such as TNF-α, IL-6, and/or CRP are increased in individuals with type 2 diabetes.59 It is known that C3 mRNA expression is upregulated by TNF-α and IL-6,2 other adipocyte-derived cytokines implicated in the pathophysiology of insulin resistance.56 Insulin, as well, increases adipocyte production of C3.11, 12, 13 On the other hand, an elevated C3 concentration may play a causative role in the development of insulin resistance by either direct or indirect effects (mediated through ASP, discussed below), although this functional relationship between C3 and insulin action has not been examined.
In contrast to the association of C3 with insulin/glucose homeostasis, plasma ASP correlated primarily with lipid/lipoprotein factors. While these associations are similar to those previously reported (for a review, see Cianflone et al.7), there are very few studies with a direct comparison of C3 to ASP. Our study found no correlation between fasting C3 and ASP, in agreement with data reported elsewhere,9, 60 but unlike the study by Weyer et al.50 Therefore although ASP and its precursor C3 correlate with various plasma parameters, they do not necessarily correlate with each other, suggesting differential regulation of C3 production compared to conversion/generation of ASP.
The finding that fasting ASP concentrations were markedly increased in both DL and OB suggests a role beyond linkages with OB. In the DL, in spite of BMI comparable to the CTL group, ASP was increased by more than 50%. In both the present study and other studies (for a review, see Cianflone et al.7), ASP consistently correlates with plasma lipids, particularly NEFA and indices of Apo B lipoproteins (such as plasma Apo B, LDL-C, total cholesterol, etc.), factors commonly related to metabolic syndrome, diabetes and cardiovascular disease. Whether the increase in plasma ASP is a cause or consequence of abnormal lipid metabolism cannot be determined simply by correlation studies, but examination of ASP function is supportive of linkages. Based on a number of studies in mice and adipocytes, ASP enhances adipose fat storage through increased fatty acid esterification (for review see Kalant et al.2 and Cianflone et al.7). ASP deficiency (C3 knockout mice) results in decreased adipose tissue and delayed postprandial TG clearance,17, 18, 19, 20, 21 while acute administration of ASP increases postprandial TG clearance.15, 16, 17, 19 Related to glucose metabolism, ASP increases glucose transport in adipocytes and myotubes through translocation of GLUT1, GLUT3 and GLUT4.61, 62, 63 As well, ASP has recently been demonstrated to stimulate insulin secretion from islet cells both ex vivo and in vivo.64 While we have no direct evidence of ASP resistance in vivo in diabetes or obesity, the presence of chronically elevated levels of ASP, in conjunction with insulin resistance and plasma lipid abnormalities, would be consistent with that hypothesis49, 65, 66, 67 as discussed elsewhere.7 In patients with cardiovascular disease, we have demonstrated that subjects with increased plasma Apo B (HyperapoB) and increased ASP are characterized by cellular resistance to the action of ASP as measured by decreased ASP cellular binding and decreased stimulation of both triglyceride synthesis (fatty acid esterification) and glucose transport.68 Further, subcutaneous and omental adipocyte membranes from obese subjects (especially male subjects) demonstrate reduced ASP binding and affinity.16 Thus, a high plasma ASP might be a marker for ASP resistance.69 Reduced adipose tissue response to ASP could contribute to an increased fatty acid flux, which leads to stimulation of hepatic Apo B lipoprotein production, explaining the associations between plasma ASP and lipid parameters.7 As previously pointed out by us and others, the action of ASP is a function not only of the prevailing ASP concentration, but also of the sensitivity of the ASP receptor in target tissues to ASP.1 With the identification of an ASP receptor, C5L2, in adipose tissue and other insulin-sensitive tissues,70 we can now examine directly the role of ASP in diabetes and test the hypothesis of ‘ASP resistance’.
In conclusion, we found abnormalities of C3 and ASP in diabetic subjects independent of obesity. On the other hand, adiponectin appears to be more closely related to body size than insulin resistance in these subjects. None of these hormones correlated with each other and each was associated with different lipid/glucose parameters, suggesting independent regulation and contribution to the diabetic state. Adiponectin and ASP may be important mediators of relationships between insulin resistance, obesity and cardiovascular disease and are candidate targets for future diabetes therapy. However, the precise mechanisms that determine interindividual variability of adiponectin, C3 and ASP in diabetes remain to be identified.
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This study was supported by Grant # OOP69600 from CIHR (to KC) and the FRSQ-NSFC Quebec–China exchange program (to KC). KC is Canada Research Chair in Adipose Tissue. We acknowledge the contribution of the Laboratory of Endocrinology and the Laboratory of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology for supporting this work. We thank Lin Feng, Feng Xiao and Jun Wei for technical assistance and for their help in recruiting the subjects. Ping Yin provided statistical advice.
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The Effect of Atorvastatin (and Subsequent Metformin) on Adipose Tissue Acylation-Stimulatory-Protein Concentration and Inflammatory Biomarkers in Overweight/Obese Women With Polycystic Ovary Syndrome
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