Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat

Stefan, Norbert; Machicao, Fausto; Staiger, Harald; Machann, Jürgen; Schick, Fritz; Tschritter, Otto; Spieth, Christian; Weigert, Cora; Fritsche, Andreas; Stümvoll, Michael; Häring, Hans‐Ulrich

doi:10.1007/s00125-005-1948-3

Cited by 174 publications

(201 citation statements)

References 31 publications

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“…In addition, body fat may affect the expression of adiponectin and ADIPORs (29,36). The polymorphisms of ADIPORs have been inconsistently related to adiposity measurements in some studies (12,13,15). However, we did not find significant genetic associations with BMI in U.S. women.…”

Section: Discussioncontrasting

confidence: 73%

“…Limited evidence suggests that the genetic variability of ADIPOR1 may be more relevant to insulin resistance compared with ADIPOR2 (12). ADIPOR1 mRNA expression in human skeletal muscle cells was positively correlated with in vivo insulin secretion and plasma lipid concentrations, whereas the expression of ADIPOR2 was not associated with most of these metabolic parameters (9).…”

Section: Discussionmentioning

confidence: 98%

“…Several studies have documented that the variations in the ADIPOR1 gene were related with adiposity, insulin resistance (11)(12)(13), and the risk of type 2 diabetes (14 -17). Our findings that haplotypes possessing the tagging SNPs of the ADIPOR1 gene were associated with diabetes risk lend further credibility for the potential roles of the variability of the ADIPOR1 gene in the etiology of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of adiponectin receptor has been related to in vivo parameters of glucose and lipid metabolism (9) and was found to be lower in diabetic patients (10). The polymorphisms in the ADIPOR1 gene were recently associated with adiposity, insulin resistance, and high liver fat (11)(12)(13). A few studies have investigated the associations between the variations in ADIPOR1 and ADIPOR2 genes and the risk of type 2 diabetes but generated mixed results (14 -17).…”

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confidence: 99%

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Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women

Doria²,

Giorgi³

et al. 2007

Diabetes

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Adiponectin has been associated with low diabetes risk. The metabolic effects of adiponectin are mediated by adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2). We conducted a prospective, nested case-control study of 714 cases of type 2 diabetes and 1,120 control subjects. Six polymorphisms in ADIPOR1 and 16 polymorphisms in ADI-POR2 were determined. Haplotypes inferred from ADI-POR1 polymorphisms were significantly associated with diabetes risk (overall test, ؊2log-likelihood ‫؍‬ 15.1 on 5 df; P ‫؍‬ 0.0098). A single copy of haplotype 001100 (0, common allele; and 1, minor allele) was associated with 24% M any studies have documented that adiponectin, which is a hormonal cytokine secreted exclusively by adipose tissue, has strong insulin-sensitizing, anti-inflammatory, and antidiabetes effects (1,2). Adiponectin improves insulin sensitivity by affecting the metabolism of glucose and lipids in skeletal muscle and liver (3). In earlier analyses, we have found that blood adiponectin levels and variations in the adiponectin gene (ADIPOQ, also known as APM1) were associated with type 2 diabetes and cardiovascular risk (4 -6).Recent evidence indicates that the metabolic regulation of adiponectin is mainly mediated by two types of receptors, adiponectin receptors 1 (ADIPOR1) and 2 (ADI-POR2) (7,8). Downregulation of ADIPORs may blunt adiponectin-induced signaling (7). The expression of adiponectin receptor has been related to in vivo parameters of glucose and lipid metabolism (9) and was found to be lower in diabetic patients (10). The polymorphisms in the ADIPOR1 gene were recently associated with adiposity, insulin resistance, and high liver fat (11-13). A few studies have investigated the associations between the variations in ADIPOR1 and ADIPOR2 genes and the risk of type 2 diabetes but generated mixed results (14 -17). These studies, however, were largely limited by small sample size or a cross-sectional nature in design. The relation between ADIPOR genetic variability and diabetes risk has yet to be evaluated in prospective settings.In this study, we comprehensively examined the variations in ADIPOR1 and ADIPOR2 genes and the risk of type 2 diabetes in a nested, case-control study from the Nurses' Health Study cohort. We selected linkage disequilibrium (LD) tagging single nucleotide polymorphisms (SNPs) that capture the maximum variance in both genes and also included polymorphisms that were previously associated with diabetes risk. RESEARCH DESIGN AND METHODSThe Nurses' Health Study was established in 1976 when 121,700 female registered nurses aged 30 -55 years and residing in 11 large U.S. states completed a mailed questionnaire on medical history and lifestyle (18). The lifestyle factors, including smoking, menopausal status and postmenopausal hormone therapy, and body weight, have been updated by validated questionnaires every 2 years. Samples for the present case-control study were selected from a subcohort of 32,826 women who provided a blood sample between 1989 and 1990 and were free from diabetes, cardio...

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women

Doria²,

Giorgi³

et al. 2007

Diabetes

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“…8 Our group recently described a common polymorphism in the promoter region of AdipoR1 located 8503 bp upstream of the translational start codon (rs6666089; minor allele frequency 0.267), which was linked to lower insulin sensitivity, higher HbA1 and higher liver fat in a European population. 9 Adipokines function not only in the periphery but also in the central nervous system: adiponectin is found in the cerebrospinal fluid of rodents and humans. [10][11][12] Furthermore, AdipoR1 and AdipoR2 are expressed in the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

A polymorphism in the gene encoding AdipoR1 affects olfactory recognition

et al. 2010

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Polymorphisms in the gene encoding adiponectin receptor 1 (AdipoR1) are associated with insulin resistance, fatty liver, increased risk for type 2 diabetes and cardiovascular disease. AdipoR1 is expressed in the central nervous system and in the olfactory mucosa of mice and humans. We therefore hypothesized that a common polymorphism in AdipoR1 might alter olfactory function. We investigated a group of 222 healthy subjects (male: n ¼ 147, female: n ¼ 75) for olfactory recognition, and genotyped them for the polymorphism rs6666089 in the human AdipoR1 gene. This polymorphism has been previously shown to be associated with insulin resistance. Olfactory recognition was tested using standardized sniffing sticks, and parameters of glucose metabolism and serum adiponectin levels were assessed. We found a significant olfactory impairment in carriers of the AdipoR1 polymorphism rs6666089 (olfactory recognition: GG: 89.4 ± 1.2%, GA: 86.9 ± 1.4%, AA: 77.2 ± 4.8%, additive model, P ¼ 0.0004, adjusted for age). Adiponectin levels had no impact on olfactory recognition. Fasting plasma glucose, fasting plasma insulin, body mass index and HbA1c did not differ between the genotype groups. In conclusion, the presence of a genetic variation in AdipoR1 is associated with decreased olfactory recognition in healthy subjects. Adiponectin signalling may have an important role in olfactory function and regulation of appetite.

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Identification and Characterization of Metabolically Benign Obesity in Humans

Stefan

Kantartzis²,

Machann³

et al. 2008

Arch Intern Med

908

616

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Background: Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist.Methods: In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], Ͻ25.0), overweight (BMI, 25.0-29.9), obese-insulin sensitive (IS) (BMI, Ն30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, Ն30.0 and placement in the lower 3 quartiles of insulin sensitivity).Results: Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (PϽ.05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (PϽ.001) and particularly the liver (4.3%±0.6% vs 9.5%±0.8%) and the intima-media thickness of the common carotid artery (0.54±0.02 vs 0.59±0.01 mm) were lower and insulin sensitivity was higher (17.4±0.9 vs 7.3±0.3 arbitrary units) in the obese-IS vs the obese-IR group (PϽ.05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2±0.9 AU and 0.51±0.02 mm, respectively). Conclusions:A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.

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Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat

Cited by 174 publications

References 31 publications

Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women

Variations in Adiponectin Receptor Genes and Susceptibility to Type 2 Diabetes in Women

A polymorphism in the gene encoding AdipoR1 affects olfactory recognition

Identification and Characterization of Metabolically Benign Obesity in Humans

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