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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0166
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 3219-3223
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Elevated Plasma Adiponectin in Humans with Genetically Defective Insulin Receptors

R. K. Semple, M. A. Soos, J. Luan, C. S. Mitchell, J. C. Wilson, M. Gurnell, E. K. Cochran, P. Gorden, V. K. K. Chatterjee, N. J. Wareham and S. O’Rahilly

Departments of Clinical Biochemistry (R.K.S., M.A.S., J.C.W., S.O.) and Medicine (C.S.M., M.G., V.K.K.C.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Clinical Endocrinology Branch (E.K.C., P.G.), National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892; and Medical Research Council Epidemiology Unit (J.L., N.J.W.), Institute of Public Health, University of Cambridge, Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom

Address all correspondence and requests for reprints to: Dr. R. Semple, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: rks16{at}cam.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity.

Objective: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance.

Design/Setting: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States.

Participants: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls.

Outcome Measures: Fasting plasma insulin, adiponectin, and leptin were measured.

Results: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6–36.6 (normal adult range for body mass index 20 kg/m2 = 3–19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12–11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0–16: normal adult range for body mass index of < 25 kg/m2 = 2.4–24.4 (female) and 0.4–8.3 ng/ml (male)].

Conclusions: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WHITE ADIPOSE TISSUE (WAT) can elaborate a variety of molecules with paracrine and endocrine actions of proven or potential relevance to body weight and fuel metabolism. Best established of these so-called adipokines is leptin, a cytokine-like peptide hormone secreted in proportion to total body fat mass (1), which is a centrally acting suppressor of appetite in humans (2). Leptin administration to lipodystrophic, leptin-deficient humans (3) markedly improves insulin sensitivity, as does transplantation of normal, but not leptin-deficient, WAT into totally lipodystrophic mice (4).

Adiponectin, a second adipokine, is one of the most abundant plasma proteins in humans. It is a multimeric hormone with homology to complement factor 1q that circulates in adults at levels that are inversely related to the total WAT mass, in contrast to leptin (reviewed in Ref. 5). Also unlike leptin, circulating levels of adiponectin have been shown to correlate negatively with insulin sensitivity in a wide range of human populations (5) as well as murine models of insulin resistance and obesity (6) and to be elevated on treatment with thiazolidinediones (5). Both infusion of adiponectin (6) and transgenic overexpression of a mutant species with enhanced bioactivity (7) markedly improve insulin sensitivity in insulin-resistant mice. These findings have led to the suggestion that defects in adiponectin production and/or action may be an etiological factor in at least some cases of human insulin resistance.

We have previously used a population of patients with a variety of syndromes of severe insulin resistance (SIR) to identify several novel genetic defects in human insulin resistance (8, 9, 10). Having developed an in-house two-step, time-resolved fluorometric assay for adiponectin and confirmed the inverse association between adiponectin and insulin levels in a large normal population, we measured total plasma adiponectin in 75 subjects with a range of syndromes of SIR. Strikingly and unexpectedly, the subgroup of patients with mutations in the insulin receptor had elevated plasma adiponectin levels. In contrast, plasma leptin, an index of the composite effect of the amount of whole-body adipose tissue and intact insulin signaling, was almost invariably very low in this subgroup.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Research design

Subjects with SIR were recruited for genetic and biochemical studies with full informed consent in line with procedures approved by either the local research ethics committee in Cambridge, UK, or the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases. All mutations described have previously been characterized and reported, with the exceptions of five novel heterozygous dominant-negative peroxisome proliferator-activated receptor-{gamma} (PPARG) mutations (Chatterjee, V. K. K., and M. Gurnell, unpublished data) and the insulin receptor G359S missense mutation (Semple, R., and S. O’Rahilly, unpublished data). Subjects with biochemically defined SIR in whom no pathogenic mutation has yet to be discovered are at present enrolled in high-throughput genetic screening of candidate genes for insulin resistance. As part of this screen, 90% of the insulin receptor gene has been sequenced to date, with no mutations found in this group.

Donohue syndrome, Rabson-Mendenhall syndrome, and type A insulin resistance represent arbitrary divisions of a continuum of severity of insulin receptor defects. The classification used here was based on the original descriptions of these groups. Hyperandrogenism, insulin resistance, and acanthosis nigricans was defined based on the eponymous clinical features as well as a body mass index (BMI) greater than 30 kg/m2. MIR-AN was the designation given to males with acanthosis nigricans and severe hyperinsulinemia, and other SIR syndromes encompassed a range of complex syndromes that featured SIR. Hyperinsulinemia was defined with reference to a BMI-matched Caucasian control population. The phenotypes of the lipodystrophic syndromes caused by mutations in PPARG [Online Inheritance in Man (OMIM) no. 604367], lamin A/C (OMIM no. 151660), acylglycerol phosphate acyltransferase-2 (OMIM no. 608594), and Berardinelli-Seip congenital lipodystrophy-2 (OMIM no. 269700) were in accord with previous descriptions. The lipodystrophy caused by AKT2 mutations, although not reported in detail previously, was in keeping with Kobberling-type lipodystrophy, or familial partial lipodystrophy-1 (OMIM no. 608600).

Venous blood was drawn in the fasting state except in those infants highly dependent on iv feeding and plasma immediately extracted and stored at –20 C. Insulin, leptin, and adiponectin were all assayed on a 1235 AutoDELFIA (PerkinElmer Lifesciences, Boston, MA) automatic immunoassay system using two-step time-resolved fluorometric assays. Reagents for the insulin assay were supplied by Dako Ltd. (Ely, UK) for Wallac Oy (Turku, Finland). A prototype of the assay has previously been described (11). Leptin and total adiponectin were assayed after automatic dilution in duplicate. R&D Systems Europe, Ltd. (Abingdon, UK) supplied lyophilized recombinant human leptin and adiponectin as well as coating antibody MAB 398 and biotinylated detection antibody BAM-398 (leptin assay), and reagents from the adiponectin duo set, coating antibody 840 965, and biotinylated detection antibody 840966 (adiponectin assay). Europium-labeled streptavidin was obtained from PerkinElmer Life Sciences (Wallac Oy, Finland). Between-batch coefficients of variation for the leptin assay were 7.1% at 2.7 ng/ml, 3.9% at 14.9 ng/ml, and 5.7% at 54.9 ng/ml (n = 30). For the adiponectin assay, they were 5.2% at 3.49 mg/liter, 6.95% at 8.85 mg/liter, and 11.9% at 15.8 mg/liter (n = 20).

BMI-adjusted normative insulin, adiponectin, and leptin data were derived from a Caucasian population from the MRC Ely Study cohort, representative of an ethnically homogeneous Caucasian population in this area of eastern England (12). All venous blood samples were drawn in the fasting state, and those with diabetes on the basis of either fasting blood glucose or oral glucose tolerance testing were excluded from the analysis. A complete data set (fasting plasma insulin, plasma leptin, and plasma adiponectin) was available for 872 nondiabetic participants. The distribution of insulin and adiponectin was skewed and therefore normalized by logarithmic transformation for statistical analyses. Simple regressions between fasting plasma insulin or BMI and adiponectin were performed using the regress command in Stata/SE 8.2 for Windows (StataCorp., College Station, TX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After logarithmic transformation, fasting plasma adiponectin in 872 nondiabetic but otherwise unselected subjects was found to correlate inversely and highly significantly with both BMI (r = –0.19, P = 1.2 x 10–8) and fasting plasma insulin (r = –0.25, P = 1.9 x 10–13) in line with findings from previous studies. Although no direct comparison was made between the assay described and previously published assays, the 90% confidence range for the control population (2.9–14.9 mg/liter) is also in agreement with previous reports.

Table 1Go shows the genetic, phenotypic, and biochemical profiles of the various etiological subgroups within the SIR cohort and the control group. A total of 75 subjects was studied. Most subjects were adult, although the insulin receptor (INSR) group was enriched for younger subjects, in keeping with the early presentation of this degree of insulin resistance. Unsurprisingly, fasting plasma insulin is very elevated in all subgroups, with the most extreme hyperinsulinemia seen in the group with insulin receptor defects.


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  		TABLE 1. Characteristics of the SIR subjects studied

 
Figure 1AGo shows the plasma adiponectin levels in SIR subjects grouped by etiological subclass. In all but one subgroup, plasma adiponectin levels were well below the BMI-adjusted normal range. However, in stark contrast, all but one of the subjects with insulin receptor mutations had elevated adiponectin levels. Plasma leptin levels, however, were almost invariably very low in the INSR subgroup, commensurate with those in generalized lipodystrophy, as shown in Fig. 1BGo. There was no clear difference in plasma leptin between groups of subjects with partial lipodystrophy caused by mutations in lamin A/C, AKT2, and PPARG, whereas plasma leptin was higher in the idiopathic SIR group, in keeping with the significant number of overweight subjects with the hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome in this group.


Figure 1
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  		FIG. 1. A, Fasting plasma adiponectin. B, Fasting plasma leptin in syndromes of SIR. Genes affected are named according to standard National Center for Biotechnology Information abbreviations. CGL, Congenital generalized lipodystrophy; AGL, acquired generalized lipodystrophy; NK, genetic defect not known; LMNA, lamin A/C. The control group comprised 872 nondiabetic subjects. Horizontal bars represent the means of each group. Statistical comparisons between the control group and other groups were performed using the Kolmogorov-Smirnov test. ****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is well established that plasma adiponectin is lower in obese subjects and those with idiopathic insulin resistance, in whom there is an incompletely characterized defect in intracellular signaling downstream from the insulin receptor (5). The finding that loss-of-function mutations in the insulin receptor itself, although leading to extreme insulin resistance, are associated with normal or elevated plasma adiponectin is therefore striking. This discordance is particularly notable because mutations in AKT2, which lies at a key point in the signal transduction cascade downstream from the insulin receptor, result in partial lipodystrophy with low leptin and also low adiponectin. The explanation for the dissociation between insulin sensitivity and plasma adiponectin in INSR subjects is not yet clear.

Under clamp conditions in vivo in human subjects, insulin has been shown to depress plasma adiponectin (13), and transcriptional down-regulation of adiponectin gene expression in response to insulin is also seen in the murine 3T3-L1 adipocyte cell line (14). Furthermore, plasma adiponectin has been found to be higher in those with type 1 diabetes than healthy BMI-matched controls (15) and to increase with duration of type 2 diabetes (16), suggesting a correlation with insulin deficiency. Thus, elevated adiponectin with impaired insulin receptor function may reflect loss of tonic inhibition of adiponectin expression by insulin signaling in adipocytes. This signaling presumably occurs down an arm of the signal transduction pathway that is relatively less affected by insulin resistance than signaling to glucose transport and that does not appear to be AKT2 dependent.

Another possible explanation relates to the role played by the insulin receptor in adipocyte differentiation and function. It is likely that IGF-I receptor-mediated early preadipocyte differentiation is intact or even enhanced in subjects with INSR mutations but that later insulin receptor-mediated, triglyceride accretion is severely impaired. This could lead to the expansion of a pool of nonlipidated cells with the capacity to produce adiponectin but that are unable to secrete leptin, which correlates closely with total body fat mass (1) and hence adipocyte triglyceride content. However, this requires further scrutiny in human subjects with insulin receptor mutations, including studies of fat distribution and the microscopic morphology of adipose tissue.

Adipose-specific deletion of the insulin receptor in mice produces reduced adipose tissue mass and a dimorphic population of adipocytes, with increased expression of adiponectin in adipocytes as well as elevated plasma adiponectin (17), suggesting that the role of the insulin receptor in adiponectin production is at least in part cell autonomous. Plasma leptin levels were normal, however, implying that the effect of Insr mutations on leptin is indirect. Although adiponectin was also elevated in muscle-specific Insr knockout mice, this was approximately commensurate with an increase in adipose tissue mass (18), in contrast to the discordant effects on adipose tissue mass and plasma adiponectin seen in adipose-specific Insr knockout animals and the human subjects described here.

Whether high levels of adiponectin in subjects with INSR mutations are functionally important is not clear. Adiponectin promotes fatty acid oxidation (6) and has been shown significantly to ameliorate hepatic steatosis in mice (19). This suggests that it could play a role in the fasting hypoglycemia and hypotriglyceridemia commonly seen in subjects with INSR mutations.

The data presented here suggest that in adults with SIR, high/normal adiponectin may be used as a simple biochemical discriminator of those subjects with pathogenic insulin receptor mutations, facilitating directed genetic screening of the large insulin receptor gene only in those subjects with the highest probability of harboring a pathogenic mutation.


   Footnotes
 
This work was supported by the Wellcome Trust (to S.O. and V.K.K.C.) and the U.K. Medical Research Council (to N.J.W. and J.L.).

Author disclosure statement: None of the authors has any interests to declare.

First Published Online May 16, 2006

Abbreviations: BMI, Body mass index; INSR, insulin receptor; OMIM, Online Inheritance in Man; PPARG, peroxisome proliferator-activated receptor-{gamma}; SIR, severe insulin resistance; WAT, white adipose tissue.

Received January 25, 2006.

Accepted May 10, 2006.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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