Characterisation of adiponectin multimers and the IGF axis in humans with a heterozygote mutation in the tyrosine kinase domain of the insulin receptor gene

in European Journal of Endocrinology

Objective

Low levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).

Methods

Blood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic–hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.

Results

Despite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.

Conclusion

The normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.

Abstract

Objective

Low levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).

Methods

Blood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic–hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.

Results

Despite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.

Conclusion

The normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.

Introduction

Adiponectin and leptin are prototypic adipokines secreted almost exclusively by adipocytes (1). Adiponectin levels are low in obesity and type 2 diabetes and consistently show strong correlation with several indices of insulin sensitivity (2), also in healthy populations (3). Conversely, increasing adiposity and common forms of insulin resistance are associated with increased leptin, probably due to leptin resistance in skeletal muscle (1). Correspondingly, high leptin-to-adiponectin ratios (LAR) show strong association with measures of insulin resistance in non-diabetic individuals (3).

Adiponectin circulates in blood in several multimeric subforms: low-molecular weight (LMW) trimers, medium-molecular weight (MMW) hexamers and high-molecular weight (HMW) multimers (1, 2). Of these, HMW adiponectin seems to be the most active and predominant form (1), and accordingly, HMW adiponectin shows the same strong inverse relationship with insulin resistance and type 2 diabetes as total adiponectin (4). Although the mechanisms by which adiponectin improves insulin sensitivity in humans in vivo remains to be proven (5), studies on rodents and cell cultures suggest that adiponectin stimulates glucose uptake and lipid oxidation via activation of AMP-activated protein kinase in liver and skeletal muscle (1). Based on recent studies that have shown higher than normal levels of plasma adiponectin in patients with chronic heart failure, renal failure, type 1 diabetes and anorexia nervosa, it has been hypothesised that adiponectin in these conditions may protect the organism against energy deprivation (6). Elevated levels of total and HMW adiponectin have been reported in severe insulin resistance (SIR) caused by insulin receptoropathies due to either mutations in the insulin receptor gene (INSR) or insulin receptor antibodies (5, 7, 8, 9). Moreover, leptin seems to be suppressed or absent, i.e. similar to that observed in lipodystrophies (5, 7). There is evidence that insulin suppresses plasma adiponectin in humans in vivo and down-regulates expression and/or secretion from adipocytes (5, 10, 11, 12). Assuming that this action of insulin is relatively intact in common forms of insulin resistance, fasting hyperinsulinaemia could be the cause of hypoadiponectinaemia in these conditions. In line with this, the apparently paradoxical hyperadiponectinaemia observed in SIR could be explained by complete insulin receptor dysfunction, which impairs not only insulin signalling to glucose transport but also other actions of insulin (5). To what extent a non-complete block of insulin receptor function, such as that seen in dominant-negative, heterozygous INSR mutations, affects adiponectin and its multimeric distribution and leptin levels remains to be established.

Treatment of diabetes in the context of SIR is a major challenge (13, 14). The IGF axis contributes to the regulation of glucose homeostasis (15). Accordingly, therapy with recombinant IGF1 has been shown to increase insulin sensitivity in obesity and type 2 diabetes and has been recommended as a potential therapy for SIR, e.g. in patients with INSR mutations (13, 14, 15). In obesity and type 2 diabetes, free IGF1 and total IGF2 are increased, while IGF-binding protein 1 (IGFBP1) and IGFBP2 are down-regulated (15, 16, 17). Moreover, in cross-sectional studies, IGFBP1 and IGFBP2 levels are associated with indices of insulin sensitivity (18, 19, 20). In contrast, little is known about the IGF1/IGFBP system in relation to SIR caused by INSR mutations (21). Insulin suppresses hepatic expression and secretion of IGFBP1 (15), and low levels of IGFBP1 in common forms of insulin resistance are likely to be caused by fasting hyperinsulinaemia. In parallel with paradoxically high adiponectin in the face of extreme fasting hyperinsulinaemia, IGFBP1 levels seem to be elevated in INSR mutants due to a blunted effect of insulin on the liver (9). However, this remains to be further examined.

We have recently reported a family with nine members carrying a dominant-negative mutation in the tyrosine kinase domain of INSR (22). They not only clinically presented with episodes of postprandial severe hypoglycaemia but also showed marked insulin resistance when metabolically characterised. Surprisingly, insulin signalling was only modestly impaired (23). Therefore, we hypothesised that insulin signalling was in part rescued by reduced insulin clearance, but a role for adaptive changes in the IGF1 axis and hybrids of IGF1R and insulin receptors was not investigated.

To gain further insights into the role of adiponectin, leptin and IGF axis in relation to SIR, we characterised the multimeric distribution of adiponectin, leptin, LAR, circulating IGFs, IGFBP1 and IGFBP2 in carriers of a dominant-negative INSR mutation and matched lean, healthy controls.

Materials and methods

Study subjects

Clinical and genetic data have been reported previously (22). Six family members carrying the Arg1174Gln mutation in the tyrosine kinase domain of the INSR gene and ten healthy control subjects matched according to age, sex and BMI participated in the study (Table 1). Compared with the original report (22), four additional control subjects were included. The Arg1174Gln carriers were clinically characterised by episodes of hypoglycaemia in the postprandial state, and all were without diabetes and showed no clinical features of SIR. The control subjects had normal glucose tolerance and no family history of diabetes. All subjects had normal results on screening blood tests of hepatic and renal function. All subjects were instructed to refrain from strenuous physical activity for a period of 48 h before the experiment. Informed consent was obtained from all subjects before participation. The study was approved by the local ethics committee and performed in accordance with the Helsinki-II Declaration.

Table 1

Clinical, biochemical and metabolic characteristics of study subjects. Metabolic rates are expressed as mg/min per m2. Data represent mean±s.e.m.

Control groupArg1174Gln groupP value
Male/female6/45/1NS
Age (years)46.8±2.041.7±5.60.48
BMI (kg/m2)24.4±0.725.4±1.00.52
Fat-free mass 49.0±2.948.5±2.00.91
HbA1c (%)5.1±0.15.7±0.20.039
Total cholesterol (mmol/l)5.2±0.25.7±0.40.36
LDL-cholesterol (mmol/l)3.0±0.23.6±0.30.14
HDL-cholesterol (mmol/l)1.6±0.11.5±0.20.66
Plasma triglycerides (mmol/l)1.3±0.31.3±0.2NS
Serum C-peptide (pmol/l)424±42553±640.16
Plasma glucose basal (mmol/l)5.3±0.15.6±0.20.21
Plasma glucose clamp (mmol/l)5.2±0.15.3±0.10.39
Serum insulin basal (pmol/l)18±2177±310.0011
Serum insulin clamp (pmol/l)332±101313±127*0.0011
Serum C-peptide basal (pmol/l)424±42553±640.16
Serum C-peptide clamp (pmol/l)394±57527±1010.42
Insulin clearance (ml/min per m2)759±110192±45<0.001
Plasma FFA basal (nmol/l)529±56382±770.23
Plasma FFA clamp (nmol/l)17±4118±48*0.0061
GDR basal75±376±30.66
GDR clamp352±21200±34*0.0067
Glucose oxidation basal48±448±60.59
Glucose oxidation clamp128±7100±14*0.11
Lipid oxidation basal39±237±30.74
Lipid oxidation clamp10±221±6*0.19
NOGM basal 27±427±50.74
NOGM clamp225±18100±24*0.0048

*P<0.05 and P<0.01 vs basal. NOGM, non-oxidative glucose metabolism.

Study design

All study subjects were admitted to the Diabetes Research Centre at Odense University Hospital, Denmark. After a 10 h overnight fast, the subjects underwent a euglycaemic–hyperinsulinaemic clamp (2 h equilibrium period followed by 3 h insulin infusion, 40 mU/m2 per min) combined with indirect calorimetry and muscle biopsies. Please refer to our previous report (22) for further details about calculation of glucose disposal rates (GDR), glucose oxidation, lipid oxidation, non-oxidative glucose metabolism (NOGM) and insulin clearance. Blood samples were drawn in the basal and insulin-stimulated state. Plasma glucose, serum insulin, C-peptide and FFA were measured using commercial assays as described previously (22). Fat-free mass was determined by the bioimpedance method.

Total adiponectin and adiponectin multimers

Serum total adiponectin was measured using a validated in-house time-resolved immunofluorometric assay (TR-IFMA) as described previously (24), having an intra-assay coefficient of variance (CV) <5% and interassay CV <10%. The three major subforms of circulating adiponectin, HMW, MMW and LMW subforms were isolated by fast protein liquid chromatography (FPLC), followed by immunoassay of the obtained fractions corresponding to the three major subforms. The FPLC method has been described previously in detail elsewhere (25). The intra-assay CV values for the relative concentrations of the HMW, MMW and LMW subforms were <4, 6 and 3% respectively. The interassay CV values were 6, 12 and 7% respectively (25).

Leptin

Leptin was determined by a validated in-house TR-IFMA (26) based on commercial reagents (R&D Systems, Abingdon, UK: two MABs (cat. no. MAb 398 for coating and BAM 398 for detection) and recombinant human leptin as standard (cat. no. 398-LP)) and carried out essentially as the adiponectin TR-IFMA. The recovery of exogenous leptin added to serum averaged 96.8±0.2%, the intra-assay CV averaged <5% and the interassay CV averaged <10% (>50 assay setups).

Total IGF1, IGF2, free IGF1 and IGFBP1 and -2

All measurements were performed in duplicate or triplicate (free IGF1) within the same assay run. With the exception of free IGF1 (see below), all intra-assay CVs were <5%. Serum total IGF1 and total IGF2 were determined after acid ethanol extraction using non-competitive TR-IFMAs as described previously (27). Serum-free IGF1 was determined using ultrafiltration by centrifugation, as described previously (28). The intra-assay CV including ultrafiltration and immunoassay averaged 19%. Serum IGFBP1 was determined with an in-house RIA as described by Westwood et al. (29, 30), with modifications. Serum IGFBP2 was measured using an in-house TR-IFMA as described previously (30).

Statistical analysis

Data calculation and statistical analysis were performed using the SPSS for Windows Version 10.0 program. Data are presented as mean±s.e.m. Differences between the groups or within the groups were evaluated using the Mann–Whitney U test for unpaired data and the Wilcoxon signed rank test for paired data respectively (two sided). Correlation analysis was performed using Spearman's correlation analysis. Significance was accepted at the level of P<0.05.

Results

Clinical and metabolic characteristics

As reported previously (22), Arg1174Gln carriers had pronounced fasting hyperinsulinaemia and slightly elevated HbA1c levels (within the normal range) compared with lean, healthy controls (Table 1). Nevertheless, fasting plasma glucose and serum C-peptide were similar between groups. Exogenous insulin infused at a rate of 40 mU/m2 per min raised serum insulin to fourfold higher levels in the Arg1174Gln group than in controls due to reduced clearance of insulin (Table 1). There was no effect of insulin on serum C-peptide in either group. In both groups, insulin infusion increased GDR, glucose oxidation and NOGM and suppressed lipid oxidation and plasma FFA (Table 1). However, the effect of exogenous insulin on GDR and NOGM was significantly reduced in the Arg1174Gln group.

Adiponectin and leptin

Despite fasting hyperinsulinaemia and marked insulin resistance, total plasma adiponectin levels in Arg1174Gln carriers were not different from those observed in lean, healthy controls (Table 2). However, the absolute concentrations of LMW adiponectin were reduced in Arg1174Gln carriers (P<0.05), whereas HMW and MMW adiponectin did not differ between groups (Fig. 1A). When evaluating the relative distribution of the adiponectin subforms, the HMW fraction was increased in Arg1174Gln carriers (P<0.05), whereas the LMW fraction was reduced compared with lean, healthy subjects (P<0.001) both before and after exogenous insulin (Fig. 1B). The MMW fraction was also decreased in Arg1174Gln carriers, but only after infusion of insulin (P=0.04). Administration of insulin in physiological concentrations over 3 h caused a small but significant reduction in total adiponectin (7%; P=0.02) and MMW adiponectin (9%; P=0.02) in lean, healthy controls, whereas no effect of exogenous insulin was observed in Arg1174Gln carriers despite fourfold higher insulin levels at the end of the clamp. No differences in serum leptin levels or LAR ratios were found between Arg1174Gln carriers and lean, healthy individuals (Table 2). However, in Arg1174Gln carriers, exogenous insulin caused a small reduction in serum leptin levels (P=0.03).

Table 2

Adiponectin, leptin and LAR. Data represent mean±s.e.m.

Control groupArg1174Gln groupP value
Plasma adiponectin basal (mg/l)12.1±1.511.5±1.80.91
Plasma adiponectin clamp (mg/l) 11.3±1.6*11.3±1.70.91
Serum leptin basal (μg/l)6.9±1.95.6±1.00.91
Serum leptin clamp (μg/l)6.6±1.74.7±1.2*0.52
LAR basal0.61±0.1980.55±0.130.72
LAR clamp0.62±0.170.48±0.140.66

*P<0.05 vs basal. LAR, leptin-to-adiponectin ratio.

Figure 1

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Figure 1

Absolute levels (A) and fractions (B) of HMW, MMW and LMW adiponectin in ten healthy subjects (Con) and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene (Mut) before (white bars) and at the end (black bars) of a 3 h, 40 mU/m2 per min euglycaemic–hyperinsulinaemic clamp. Data are mean±s.e.m. *P<0.05 and §P<0.001 vs Con; #P<0.05 vs basal.

Citation: European Journal of Endocrinology 166, 3; 10.1530/EJE-11-0790

IGF axis

Arg1174Gln carriers showed increased circulating levels of total IGF1 (P=0.007), total IGF2 (P=0.01) and free IGF1 (P=0.007) compared with lean, healthy individuals (Fig. 2). However, despite insulin resistance, and fasting hyperinsulinaemia, serum levels of IGFBP1 and IGFBP2 in Arg1174Gln carriers did not differ from those observed in lean, healthy individuals (Fig. 3). Moreover, the ability of exogenous insulin to acutely suppress IGFBP1 (P=0.03) and increase IGFBP2 (P=0.05) was intact in Arg1174Gln carriers.

Figure 2

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Figure 2

Baseline serum levels of total IGF1 (A), total IGF2 (B) and free IGF1 (C) in ten healthy controls (white bars) and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene (black bars). Data are mean±s.e.m. ##P<0.001 and #P<0.05 vs controls.

Citation: European Journal of Endocrinology 166, 3; 10.1530/EJE-11-0790

Figure 3

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Figure 3

Serum levels of IGFBP1 (A) and IGFBP2 (B) in ten healthy controls and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene before (white bars) and at the end (black bars) of a 3 h 40 mU/m2 per min euglycaemic–hyperinsulinaemic clamp. Data are mean±s.e.m. *P<0.05 and **P<0.001 vs basal.

Citation: European Journal of Endocrinology 166, 3; 10.1530/EJE-11-0790

Correlation analysis

In Arg1174Gln carriers, total adiponectin and absolute concentrations of MMW and LMW subforms were closely correlated with insulin action on GDR (all r=0.94; P=0.005), glucose oxidation (all r=0.83; P=0.04), lipid oxidation (all r=−0.94; P=0.005) and FFA (all r=−0.94; P=0.005). HMW adiponectin also correlated with insulin action on GDR (r=0.89; P=0.02), lipid oxidation (r=−0.89; P=0.02) and FFA (r=−0.89; P=0.02). Furthermore, IGFBP1 was strongly associated with basal FFA (r=0.99; P<0.001) and basal leptin correlated with HDL-cholesterol (r=−0.89; P=0.02) in Arg1174Gln carriers.

In lean, healthy controls, no correlations between adiponectin or its subforms and measures of glucose and lipid metabolism were observed. However, IGFBP1 correlated inversely with fasting insulin (r=−0.70; P=0.02) and positively with insulin-stimulated GDR (r=0.70; P=0.03) and NOGM (r=0.70; P=0.03), whereas IGFBP2 was negatively related to HbA1c (r=−0.79; P=0.004) and FFA clamp (r=−0.79; P=0.006) in controls. Moreover, total IGF1 was positively associated with HbA1c (r=0.72; P=0.02) in controls. Basal leptin correlated positively with glucose oxidation (r=0.67; P=0.05) and FFA (r=0.68; P=0.046) during clamp.

Total IGF1 and free IGF1 were strongly associated in both Arg1174Gln carriers (r=1.00; P<0.001) and controls (r=0.81; P=0.009). Moreover, IGFBP2 correlated inversely with basal serum leptin in Arg1174Gln carriers (r=−0.89; P=0.02) as well as in healthy control subjects (r=−0.83; P=0.005).

Discussion

Recent studies have shown apparently paradoxical high adiponectin in humans with SIR caused either by INSR mutations or insulin receptor antibodies (7, 8). Here, we have characterised the multimeric distribution of adiponectin and the IGF axis in carriers of a dominant-negative mutation in the tyrosine kinase domain of INSR (Arg1174Gln). The major findings are that total adiponectin and absolute levels of HMW adiponectin are not decreased in these insulin receptor-deficient patients despite fasting hyperinsulinaemia and marked insulin resistance. The plasma levels of other markers for common insulin resistance, such as leptin, IGFBP1 and IGFBP2, were also completely normal in Arg1174Gln carriers. Our results are consistent with the hypothesis that high fasting levels of insulin cannot suppress these markers of common insulin resistance in patients with dysfunctional insulin receptors (5). Circulating levels of total IGF1, IGF2 and free IGF1 were elevated, probably reflecting a compensatory increase. Interestingly, the distribution of adiponectin complexes showed an increased ratio of HMW adiponectin and decreased levels of LMW adiponectin, and total plasma adiponectin and its subforms strongly correlated with insulin action on glucose metabolism and lipid oxidation in Arg1174Gln carriers. These findings indicate that the preservation of adiponectin levels together with an improved distribution and adaptive increases in IGF1 and -2 may contribute to rescue insulin action in insulin receptor-deficient patients.

Based on fasting insulin levels above 150 pmol/l, all but one of the Arg1174Gln carriers could be categorised as having SIR (9). Moreover, all but one of these six carriers of an INSR mutation showed plasma adiponectin above 7 mg/l, and they all showed plasma IGFBP1 above 20 μg/l. Based on the observations done mostly in patients with homozygous or compound heterozygous mutations in INSR mutations (7), these criteria have been proposed to separate cases of dysfunctional insulin receptors from other causes of SIR (9). However, in agreement with the normal rather than high levels of adiponectin in the Arg1174Gln carriers, the lowest adiponectin levels were previously observed in two patients with heterozygote INSR (7). Nevertheless, it appears that also in Arg1174Gln carriers, chronic fasting hyperinsulinaemia fails to suppress adiponectin similar to that observed in cases with biallelic INSR mutations. Indeed, our data confirm that measures of adiponectin and IGFBP1 may help to point out dysfunctional insulin receptors in cases with SIR. However, compared with common forms of insulin resistance such as obesity and type 2 diabetes, other measures may be better discriminators. Thus, Arg1174Gln carriers are characterised by highly increased fasting insulin-to-C-peptide ratios (well above 0.1) due to a fourfold decrease in the clearance of insulin from the circulation (22).

Compared with individuals with common insulin resistance, the levels of adiponectin were surprisingly normal in the Arg1174Gln carriers in the face of highly elevated fasting insulin levels. Evidence from genetically modified mouse models (5) evidence from studies showing the presence of high adiponectin levels in type 1 diabetes (12) and evidence from studies showing infusion of insulin for 3–5 h suppresses plasma adiponectin in healthy subjects (10, 11); all indicate that insulin negatively regulates adiponectin expression and/or secretion from adipocytes. In line with this the apparently paradoxical hyperadiponectinaemia observed in SIR could be explained by complete insulin receptor dysfunction, which impairs not only insulin signalling to glucose transport but also other actions of insulin (5). Accordingly, fasting hyperinsulinaemia is believed to be the cause of reduced plasma adiponectin in common forms of insulin resistance. In support of this hypothesis, humans with loss-of-function mutation in Akt2 show SIR together with low levels of adiponectin (7). Assuming that carriers of a dominant-negative INSR mutation have about 25% fully functional insulin receptors (31), it was expected that the tenfold higher insulin levels would be enough to suppress plasma adiponectin below normal levels. This was, however, not the case, and our findings agree with reports of normal adiponectin levels (6–10 mg/l) in the presence of extreme fasting hyperinsulinaemia (>1500 pmol/l) in two other cases of heterozygote INSR mutations (7). In support of an attenuated response to insulin in Arg1174Gln carriers, a 3 h insulin infusion raised insulin levels to 1300 pmol/l but failed to suppress plasma adiponectin. Thus, it appears that 25% fully functional insulin receptors in adipocytes are not sufficient to induce a suppression of plasma adiponectin despite tenfold elevated insulin levels. This suggests that other mechanisms may be operating to keep plasma adiponectin high in insulin receptor-deficient individuals.

In the majority of studies, total and HMW adiponectin are reduced in obesity and type 2 diabetes and show stronger association with insulin resistance, risk of type 2 diabetes and coronary artery diseases than MMW and LMW adiponectin (32, 33, 34, 35, 36, 37, 38). In this context, the finding of normal total and HMW adiponectin and the relative increase in the fraction of HMW adiponectin and the decrease in absolute levels and fraction of LMW adiponectin may play a beneficial role for the Arg1174Gln carriers. However, in a recent study, LMW adiponectin was the only decreased subform in obesity and type 2 diabetes (39). This indicates that the role of LMW adiponectin in the pathogenesis of insulin resistance and type 2 diabetes remains to be fully defined, and hence, further studies are required to safely conclude that high HMW and low LMW adiponectin represent an improved multimeric distribution of adiponectin. This is, to some extent, also reflected by the observation that all three subforms of adiponectin showed tight correlation with measures of insulin action on glucose and lipid metabolism in the small group of Arg1174Gln carriers, but not in the controls. This suggests the possibility that adiponectin may play a relatively greater role for preservation of insulin sensitivity in insulin receptor-deficient individuals and that the paradoxically high levels of adiponectin in insulin recepteropathies may represent a compensatory increase rather than simply being the consequence of dysfunctional insulin receptors.

To our knowledge, this is the first case–control study of the IGF axis in carriers of a dominant-negative INSR mutation. We report increased levels of total IGF1, total IGF2 and free IGF1. While total IGF2 and free IGF1 have been reported to be increased in obesity and type 2 diabetes (15, 16, 17), in most studies no change or even a decrease in total IGF1 has been reported (15, 16, 17, 40, 41). Moreover, lower levels of total IGF1 may increase the risk of type 2 diabetes (42) and are associated with poorer glycaemic control in type 2 diabetes (41). In obesity and type 2 diabetes, the increase in free IGF1 and total IGF2 is considered as compensatory to insulin resistance, with the increase in free IGF1 being mainly a consequence of reduced IGFBP1 (15). Whether the increase in total IGF1 in Arg1174Gln carriers is caused by increased synthesis or reduced clearance cannot be determined from this study. Previously, low levels of total IGF1 have been reported in a case with biallelic INSR mutations (43). In this case, increased clearance of IGF1 was found and proposed to explain the failure of IGF1 therapy. The higher levels of both total and free IGF1 in the Arg1174Gln carriers suggest that IGF1 therapy of carriers of dominant-negative INSR mutations would have only limited beneficial effects. The higher free IGF1, despite normal IGFBP1, seems to be directly explained by the increase in total IGF1. Thus, a strong correlation between total and free IGF1 was preserved in Arg1174Gln carriers. The elevated total and free IGF1 levels may help to preserve not only insulin sensitivity (40) but also β-cell function (15) in the Arg1174Gln carriers. In this context, it is of interest that so far none of the ten family members in three generations carrying the Arg1174Gln mutation in INSR have developed fasting hyperglycaemia or type 2 diabetes (22). Of course, we cannot exclude that these family members share other gene variants that are in linkage disequilibrium with the INSR mutation and that protects against β-cell failure despite marked insulin resistance.

The intact acute regulation of IGFBP1 and IGFBP2 by insulin suggests that 25% normal insulin receptors in the tissues secreting IGFBP1 and IGFBP2 are sufficient, although the elevated levels of clamp insulin may also elicit insulinomimetic effects on IGF1 receptors or hybrids in, e.g. the liver (15). However, similar to adiponectin, the highly elevated fasting insulin levels in Arg174Gln carriers were not sufficient to cause reduced levels of IGFBP1 and IGFBP2, as observed in common forms of insulin resistance. This suggests that the effects of chronically elevated insulin levels on circulating markers of insulin resistance cannot simply be extrapolated from the effects of prolonged insulin infusion.

Of interest, we found a strong inverse relationship between fasting levels of IGFBP2 and leptin, both in the Arg1174Gln carriers and in the control subjects. Thus, the normal serum leptin does not seem to be the cause of normal serum IGFBP2 in these insulin receptor-deficient individuals. At first sight, this contrasts with the recent finding that leptin administration to ob/ob mice (which lack leptin) induces hepatic IGFBP2 mRNA and increases circulating IGFBP2 and that this response reduces glucose and insulin resistance (44). Moreover, pharmacological IGFBP2 levels were shown to reverse both type 1 and type 2 diabetes in mice (44), and based on the findings in mice, leptin therapy for type 1 diabetes in humans is currently debated (45). Indeed, serum IGFBP2 increased in two of three patients with lipodystrophy in response to leptin therapy for 6 months (46). However, consistent with our results, another recent study demonstrated the same inverse relationship between leptin and plasma IGFBP2 in humans (46). In addition, low IGFBP2 and high leptin are consistently associated with decreased insulin sensitivity even in healthy populations (15). This suggests that the ability of leptin to increase IGFBP2 is restricted to leptin-deficient conditions, although this also warrants further studies on humans.

In conclusion, in carriers of a dominant-negative INSR mutation, markers of common insulin resistance such as adiponectin, leptin, IGFBP1 and IGFBP2 are normal in the context of highly elevated fasting insulin levels and marked insulin resistance. Together with adaptive changes in the IGF axis and a potentially improved multimeric distribution of adiponectin, this may help to preserve insulin action in insulin receptor-deficient patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by grants from the Novo Nordisk Foundation and The Danish Medical Research Council.

Acknowledgements

Lone Hansen, Charlotte B Olsen, Hanne Pedersen, Kirsten N Rasmussen and Susanne Sørensen are thanked for skilled technical assistance.

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    SempleRKSoosMALuanJMitchellCSWilsonJCGurnellMCochranEKGordenPChatterjeeVKWarehamNJO'RahillyS. Elevated plasma adiponectin in humans with genetically defective insulin receptors. Journal of Clinical Endocrinology and Metabolism20069132193223. doi:10.1210/jc.2006-0166.

  • 8

    SempleRKHalbergNHBurlingKSoosMASchrawTLuanJCochranEKDungerDBWarehamNJSchererPEGordenPO'RahillyS. Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes20075617121717. doi:10.2337/db06-1665.

  • 9

    SempleRKCochranEKSoosMABurlingKASavageDBGordenPO'RahillyS. Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care200831977979. doi:10.2337/dc07-2194.

  • 10

    HøjlundKFrystykJLevinKFlyvbjergAWojtaszewskiJFBeck-NielsenH. Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes. Diabetologia20064912831291. doi:10.1007/s00125-006-0240-5.

  • 11

    MöhligMWegewitzUOsterhoffMIskenFRistowMPfeifferAFSprangerJ. Insulin decreases human adiponectin plasma levels. Hormone and Metabolic Research200234655658. doi:10.1055/s-2002-38248.

  • 12

    LethHAndersenKKFrystykJTarnowLRossingPParvingHHFlyvbjergA. Elevated levels of high-molecular-weight adiponectin in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism20089331863191. doi:10.1210/jc.2008-0360.

  • 13

    McDonaldAWilliamsRMReganFMSempleRKDungerDB. IGF-I treatment of insulin resistance. European Journal of Endocrinology2007157 (Suppl 1) S51S56. doi:10.1530/EJE-07-0271.

  • 14

    SempleRKWilliamsRMDungerDB. What is the best management strategy for patients with severe insulin resistance?Clinical Endocrinology201073286290. doi:10.1111/j.1365-2265.2010.03810.x.

  • 15

    RajpathakSNGunterMJWylie-RosettJHoGYKaplanRCMuzumdarRRohanTEStricklerHD. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes/Metabolism Research and Reviews200925312. doi:10.1002/dmrr.919.

  • 16

    FrystykJSkjaerbaekCVestboEFiskerSØrskovH. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes/Metabolism Research and Reviews199915314322. doi:10.1002/(SICI)1520-7560(199909/10)15:5<314::AID-DMRR56>3.0.CO;2-E.

  • 17

    FrystykJ. Free insulin-like growth factors – measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Hormone & IGF Research200414337375. doi:10.1016/j.ghir.2004.06.001.

  • 18

    MadduxBAChanADe FilippisEAMandarinoLJGoldfineID. IGF-binding protein-1 levels are related to insulin-mediated glucose disposal and are a potential serum marker of insulin resistance. Diabetes Care20062915351537. doi:10.2337/dc05-1367.

  • 19

    ArafatAMWeickertMOFrystykJSprangerJSchöflCMöhligMPfeifferAF. The role of insulin-like growth factor (IGF) binding protein-2 in the insulin-mediated decrease in IGF-I bioactivity. Journal of Clinical Endocrinology and Metabolism20099450935101. doi:10.1210/jc.2009-0875.

  • 20

    HealdAHKaushalKSiddalsKWRudenskiASAndersonSGGibsonJM. Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Experimental and Clinical Endocrinology & Diabetes2006114371376. doi:10.1055/s-2006-924320.

  • 21

    Ogilvy-StuartALSoosMAHandsSJAnthonyMYDungerDBO'RahillyS. Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin receptors. Journal of Clinical Endocrinology and Metabolism20018633193326. doi:10.1210/jc.86.7.3319.

  • 22

    HøjlundKHansenTLajerMHenriksenJELevinKLindholmJPedersenOBeck-NielsenH. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes20045315921598. doi:10.2337/diabetes.53.6.1592.

  • 23

    HøjlundKWojtaszewskiJFBirkJHansenBFVestergaardHBeck-NielsenH. Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene. Diabetologia20064918271837. doi:10.1007/s00125-006-0312-6.

  • 24

    FrystykJTarnowLKrarupHTParvingHHFlyvbjergA. Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia20054819111918. doi:10.1007/s00125-005-1850-z.

  • 25

    AndersenKKFrystykJWolthersODHeuckCFlyvbjergA. Gender differences of oligomers and total adiponectin during puberty: a cross-sectional study of 859 Danish school children. Journal of Clinical Endocrinology and Metabolism20079218571862. doi:10.1210/jc.2006-2310.

  • 26

    AsfergCMøgelvangRFlyvbjergAFrystykJJensenJSMarottJLAppleyardMJensenGBJeppesenJ. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. American Journal of Hypertension201023327333. doi:10.1038/ajh.2009.244.

  • 27

    FrystykJDinesenBØrskovH. Non-competitive time-resolved immunofluorometric assays for determination of human insulin-like growth factor I and II. Growth Regulation19955169176.

  • 28

    FrystykJSkjærbækCDinesenBØrskovH. Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Letters1994348185191. doi:10.1016/0014-5793(94)00602-4.

  • 29

    WestwoodMGibsonJMDaviesAJYoungRJWhiteA. The phosphorylation pattern of insulin-like growth factor-binding protein-1 in normal plasma is different from that in amniotic fluid and changes during pregnancy. Journal of Clinical Endocrinology and Metabolism19947917351741. doi:10.1210/jc.79.6.1735.

  • 30

    KrassasGEPontikidesNKaltsasTDumasAFrystykJChenJWFlyvbjergA. Free and total insulin-like growth factor (IGF)-I, -II, and IGF binding protein-1, -2, and -3 serum levels in patients with active thyroid eye disease. Journal of Clinical Endocrinology and Metabolism200388132135. doi:10.1210/jc.2002-021349.

  • 31

    TaylorSI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes19924114731490. doi:10.2337/diabetes.41.11.1473.

  • 32

    AsoYYamamotoRWakabayashiSUchidaTTakayanagiKTakebayashiKOkunoTInoueTNodeKTobeTInukaiTNakanoY. Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin. Diabetes20065519541960. doi:10.2337/db05-1525.

  • 33

    HaraKHorikoshiMYamauchiTYagoHMiyazakiOEbinumaHImaiYNagaiRKadowakiT. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care20062913571362. doi:10.2337/dc05-1801.

  • 34

    NakashimaRKameiNYamaneKNakanishiSNakashimaAKohnoN. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese–Americans. Journal of Clinical Endocrinology and Metabolism20069138733877. doi:10.1210/jc.2006-1158.

  • 35

    HeidemannCSunQvan DamRMMeigsJBZhangCTworogerSSMantzorosCSHuFB. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women. Annals of Internal Medicine2008149307316.

  • 36

    BasuRPajvaniUBRizzaRASchererPE. Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes: differential regulation from nondiabetic subjects. Diabetes20075621742177. doi:10.2337/db07-0185.

  • 37

    MurdoloGHammarstedtASchmelzMJanssonPASmithU. Acute hyperinsulinemia differentially regulates interstitial and circulating adiponectin oligomeric pattern in lean and insulin-resistant, obese individuals. Journal of Clinical Endocrinology and Metabolism20099445084516. doi:10.1210/jc.2009-0431.

  • 38

    Lara-CastroCLuoNWallacePKleinRLGarveyWT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes200655249259. doi:10.2337/diabetes.55.01.06.db05-1105.

  • 39

    SchoberFNeumeierMWeigertJWurmSWanningerJSchäfflerADadaALiebischGSchmitzGAslanidisCBuechlerC. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release. Biochemical and Biophysical Research Communications2007361968973. doi:10.1016/j.bbrc.2007.07.106.

  • 40

    SestiGSciacquaACardelliniMMariniMAMaioRVatranoMSuccurroELauroRFedericiMPerticoneF. Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance. Diabetes Care200528120125. doi:10.2337/diacare.28.1.120.

  • 41

    EzzatVADuncanERWheatcroftSBKearneyMT. The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. Diabetes Obesity and Metabolism200810198211. doi:10.1111/j.1463-1326.2007.00709.x.

  • 42

    SandhuMSHealdAHGibsonJMCruickshankJKDungerDBWarehamNJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet200235917401745. doi:10.1016/S0140-6736(02)08655-5.

  • 43

    LongoNSinghRElsasLJ. Decreased half-life of insulin-like growth factor I in Rabson–Mendenhall syndrome. Journal of Inherited Metabolic Disease200124546550. doi:10.1023/A:1012411709972.

  • 44

    HedbackerKBirsoyKWysockiRWAsilmazEAhimaRSFarooqiISFriedmanJM. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metabolism2010111122. doi:10.1016/j.cmet.2009.11.007.

  • 45

    KrausDHermanMAKahnBB. Leveraging leptin for type I diabetes?PNAS201010747934794. doi:10.1073/pnas.1000736107.

  • 46

    ClaudioMBenjamimFRiccardoBMassimilianoCFrancescoBLucianoC. Adipocytes IGFBP-2 expression in prepubertal obese children. Obesity20101820552057. doi:10.1038/oby.2010.7.

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  • View in gallery

    Absolute levels (A) and fractions (B) of HMW, MMW and LMW adiponectin in ten healthy subjects (Con) and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene (Mut) before (white bars) and at the end (black bars) of a 3 h, 40 mU/m2 per min euglycaemic–hyperinsulinaemic clamp. Data are mean±s.e.m. *P<0.05 and §P<0.001 vs Con; #P<0.05 vs basal.

  • View in gallery

    Baseline serum levels of total IGF1 (A), total IGF2 (B) and free IGF1 (C) in ten healthy controls (white bars) and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene (black bars). Data are mean±s.e.m. ##P<0.001 and #P<0.05 vs controls.

  • View in gallery

    Serum levels of IGFBP1 (A) and IGFBP2 (B) in ten healthy controls and six carriers of a dominant-negative mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene before (white bars) and at the end (black bars) of a 3 h 40 mU/m2 per min euglycaemic–hyperinsulinaemic clamp. Data are mean±s.e.m. *P<0.05 and **P<0.001 vs basal.

References

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2

FinucaneFMLuanJWarehamNJSharpSJO'RahillySBalkauBFlyvbjergAWalkerMHøjlundKNolanJJEuropean Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease Risk Study Group) Savage DB. Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia20095223452349. doi:10.1007/s00125-009-1508-3.

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TrujilloMESchererPE. Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. Journal of Internal Medicine2005257167175. doi:10.1111/j.1365-2796.2004.01426.x.

4

BlüherMBrennanAMKelesidisTKratzschJFasshauerMKralischSWilliamsCJMantzorosCS. Total and high-molecular weight adiponectin in relation to metabolic variables at baseline and in response to an exercise treatment program: comparative evaluation of three assays. Diabetes Care200730280285. doi:10.2337/dc06-1362.

5

CookJRSempleRK. Hypoadiponectinemia – cause or consequence of human "insulin resistance"?Journal of Clinical Endocrinology and Metabolism20109515441554. doi:10.1210/jc.2009-2286.

6

BehreCJ. Adiponectin and its role. Scandinavian Journal of Clinical & Laboratory Investigation200868678680. doi:10.1080/00365510802267077.

7

SempleRKSoosMALuanJMitchellCSWilsonJCGurnellMCochranEKGordenPChatterjeeVKWarehamNJO'RahillyS. Elevated plasma adiponectin in humans with genetically defective insulin receptors. Journal of Clinical Endocrinology and Metabolism20069132193223. doi:10.1210/jc.2006-0166.

8

SempleRKHalbergNHBurlingKSoosMASchrawTLuanJCochranEKDungerDBWarehamNJSchererPEGordenPO'RahillyS. Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes20075617121717. doi:10.2337/db06-1665.

9

SempleRKCochranEKSoosMABurlingKASavageDBGordenPO'RahillyS. Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. Diabetes Care200831977979. doi:10.2337/dc07-2194.

10

HøjlundKFrystykJLevinKFlyvbjergAWojtaszewskiJFBeck-NielsenH. Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes. Diabetologia20064912831291. doi:10.1007/s00125-006-0240-5.

11

MöhligMWegewitzUOsterhoffMIskenFRistowMPfeifferAFSprangerJ. Insulin decreases human adiponectin plasma levels. Hormone and Metabolic Research200234655658. doi:10.1055/s-2002-38248.

12

LethHAndersenKKFrystykJTarnowLRossingPParvingHHFlyvbjergA. Elevated levels of high-molecular-weight adiponectin in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism20089331863191. doi:10.1210/jc.2008-0360.

13

McDonaldAWilliamsRMReganFMSempleRKDungerDB. IGF-I treatment of insulin resistance. European Journal of Endocrinology2007157 (Suppl 1) S51S56. doi:10.1530/EJE-07-0271.

14

SempleRKWilliamsRMDungerDB. What is the best management strategy for patients with severe insulin resistance?Clinical Endocrinology201073286290. doi:10.1111/j.1365-2265.2010.03810.x.

15

RajpathakSNGunterMJWylie-RosettJHoGYKaplanRCMuzumdarRRohanTEStricklerHD. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes/Metabolism Research and Reviews200925312. doi:10.1002/dmrr.919.

16

FrystykJSkjaerbaekCVestboEFiskerSØrskovH. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes/Metabolism Research and Reviews199915314322. doi:10.1002/(SICI)1520-7560(199909/10)15:5<314::AID-DMRR56>3.0.CO;2-E.

17

FrystykJ. Free insulin-like growth factors – measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Hormone & IGF Research200414337375. doi:10.1016/j.ghir.2004.06.001.

18

MadduxBAChanADe FilippisEAMandarinoLJGoldfineID. IGF-binding protein-1 levels are related to insulin-mediated glucose disposal and are a potential serum marker of insulin resistance. Diabetes Care20062915351537. doi:10.2337/dc05-1367.

19

ArafatAMWeickertMOFrystykJSprangerJSchöflCMöhligMPfeifferAF. The role of insulin-like growth factor (IGF) binding protein-2 in the insulin-mediated decrease in IGF-I bioactivity. Journal of Clinical Endocrinology and Metabolism20099450935101. doi:10.1210/jc.2009-0875.

20

HealdAHKaushalKSiddalsKWRudenskiASAndersonSGGibsonJM. Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Experimental and Clinical Endocrinology & Diabetes2006114371376. doi:10.1055/s-2006-924320.

21

Ogilvy-StuartALSoosMAHandsSJAnthonyMYDungerDBO'RahillyS. Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin receptors. Journal of Clinical Endocrinology and Metabolism20018633193326. doi:10.1210/jc.86.7.3319.

22

HøjlundKHansenTLajerMHenriksenJELevinKLindholmJPedersenOBeck-NielsenH. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes20045315921598. doi:10.2337/diabetes.53.6.1592.

23

HøjlundKWojtaszewskiJFBirkJHansenBFVestergaardHBeck-NielsenH. Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene. Diabetologia20064918271837. doi:10.1007/s00125-006-0312-6.

24

FrystykJTarnowLKrarupHTParvingHHFlyvbjergA. Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia20054819111918. doi:10.1007/s00125-005-1850-z.

25

AndersenKKFrystykJWolthersODHeuckCFlyvbjergA. Gender differences of oligomers and total adiponectin during puberty: a cross-sectional study of 859 Danish school children. Journal of Clinical Endocrinology and Metabolism20079218571862. doi:10.1210/jc.2006-2310.

26

AsfergCMøgelvangRFlyvbjergAFrystykJJensenJSMarottJLAppleyardMJensenGBJeppesenJ. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. American Journal of Hypertension201023327333. doi:10.1038/ajh.2009.244.

27

FrystykJDinesenBØrskovH. Non-competitive time-resolved immunofluorometric assays for determination of human insulin-like growth factor I and II. Growth Regulation19955169176.

28

FrystykJSkjærbækCDinesenBØrskovH. Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Letters1994348185191. doi:10.1016/0014-5793(94)00602-4.

29

WestwoodMGibsonJMDaviesAJYoungRJWhiteA. The phosphorylation pattern of insulin-like growth factor-binding protein-1 in normal plasma is different from that in amniotic fluid and changes during pregnancy. Journal of Clinical Endocrinology and Metabolism19947917351741. doi:10.1210/jc.79.6.1735.

30

KrassasGEPontikidesNKaltsasTDumasAFrystykJChenJWFlyvbjergA. Free and total insulin-like growth factor (IGF)-I, -II, and IGF binding protein-1, -2, and -3 serum levels in patients with active thyroid eye disease. Journal of Clinical Endocrinology and Metabolism200388132135. doi:10.1210/jc.2002-021349.

31

TaylorSI. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes19924114731490. doi:10.2337/diabetes.41.11.1473.

32

AsoYYamamotoRWakabayashiSUchidaTTakayanagiKTakebayashiKOkunoTInoueTNodeKTobeTInukaiTNakanoY. Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin. Diabetes20065519541960. doi:10.2337/db05-1525.

33

HaraKHorikoshiMYamauchiTYagoHMiyazakiOEbinumaHImaiYNagaiRKadowakiT. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care20062913571362. doi:10.2337/dc05-1801.

34

NakashimaRKameiNYamaneKNakanishiSNakashimaAKohnoN. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese–Americans. Journal of Clinical Endocrinology and Metabolism20069138733877. doi:10.1210/jc.2006-1158.

35

HeidemannCSunQvan DamRMMeigsJBZhangCTworogerSSMantzorosCSHuFB. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women. Annals of Internal Medicine2008149307316.

36

BasuRPajvaniUBRizzaRASchererPE. Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes: differential regulation from nondiabetic subjects. Diabetes20075621742177. doi:10.2337/db07-0185.

37

MurdoloGHammarstedtASchmelzMJanssonPASmithU. Acute hyperinsulinemia differentially regulates interstitial and circulating adiponectin oligomeric pattern in lean and insulin-resistant, obese individuals. Journal of Clinical Endocrinology and Metabolism20099445084516. doi:10.1210/jc.2009-0431.

38

Lara-CastroCLuoNWallacePKleinRLGarveyWT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes200655249259. doi:10.2337/diabetes.55.01.06.db05-1105.

39

SchoberFNeumeierMWeigertJWurmSWanningerJSchäfflerADadaALiebischGSchmitzGAslanidisCBuechlerC. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release. Biochemical and Biophysical Research Communications2007361968973. doi:10.1016/j.bbrc.2007.07.106.

40

SestiGSciacquaACardelliniMMariniMAMaioRVatranoMSuccurroELauroRFedericiMPerticoneF. Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance. Diabetes Care200528120125. doi:10.2337/diacare.28.1.120.

41

EzzatVADuncanERWheatcroftSBKearneyMT. The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. Diabetes Obesity and Metabolism200810198211. doi:10.1111/j.1463-1326.2007.00709.x.

42

SandhuMSHealdAHGibsonJMCruickshankJKDungerDBWarehamNJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet200235917401745. doi:10.1016/S0140-6736(02)08655-5.

43

LongoNSinghRElsasLJ. Decreased half-life of insulin-like growth factor I in Rabson–Mendenhall syndrome. Journal of Inherited Metabolic Disease200124546550. doi:10.1023/A:1012411709972.

44

HedbackerKBirsoyKWysockiRWAsilmazEAhimaRSFarooqiISFriedmanJM. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metabolism2010111122. doi:10.1016/j.cmet.2009.11.007.

45

KrausDHermanMAKahnBB. Leveraging leptin for type I diabetes?PNAS201010747934794. doi:10.1073/pnas.1000736107.

46

ClaudioMBenjamimFRiccardoBMassimilianoCFrancescoBLucianoC. Adipocytes IGFBP-2 expression in prepubertal obese children. Obesity20101820552057. doi:10.1038/oby.2010.7.

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