Serum Adiponectin and Progression of Diabetic Nephropathy in Patients With Type 1 Diabetes

Saraheimo, Markku; Forsblom, Carol; Thorn, Lena M.; Wadén, Johan; Rosengård-Bärlund, Milla; Heikkilä, Outi; Hietala, Kustaa; Gordin, Daniel; Frystyk, Jan; Flyvbjerg, Allan; Groop, Per‐Henrik

doi:10.2337/dc07-2306

Cited by 79 publications

(65 citation statements)

References 23 publications

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“…Indeed, it has been debated whether the use of AICAR could be compromised in patients with diabetic nephropathy because research indicates that the drug may increase adiponectin [13]. Although adiponectin is generally described as a protective adipokine [16] and thought to protect podocyte function in early onset kidney disease [18,[42][43][44], the role of adiponectin in the later stages of human renal failure is unclear [18] with some studies suggesting that it is harmful [19,20]. Thus, our finding that AICAR attenuated HFD-induced kidney disease in an adiponectin-independent manner may indicate that the drug is a more suitable therapeutic agent for patients with advanced nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…Although adiponectin is generally described as a protective adipokine [16], several clinical studies have reported a paradoxical inverse association between circulating adiponectin levels and renal function [17,18]. Specifically, increased adiponectin levels correlate with diabetic nephropathy [19,20], advanced chronic kidney disease (CKD) [21][22][23] and increased risk of mortality [24]. As we cannot exclude the compromising role of adiponectin in CKD patient groups, it is critical to assess if AICAR-mediated actions are adiponectin dependent to determine its suitability as a drug to target obesity-related pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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Aims/hypothesis In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m 2 ) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 + T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H 2 O 2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. Conclusions/interpretation AICAR may promote metabolic health and protect against obesity-induced systemic diseases Catherine Godson and Kumar Sharma are joint senior authors.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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“…Based upon these well established associations, one would expect an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin concentrations in patients with elevated UAE [12][13][14][15][16][17][18]. The reasons for such unexpected findings are unknown.…”

Section: Introductionmentioning

confidence: 90%

“…Most [12][13][14][15][16][17][18], although not all [38][39][40] previous studies have reported a direct correlation between circulating adiponectin and UAE rate. This finding was somewhat 'unexpected' if insulin resistance was regarded as the common soil of both variables, and pointed to the role of confounding factors, including diabetes, kidney disease and related treatments, possibly affecting previous studies [12][13][14][15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

et al. 2011

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Aims/hypothesis Insulin resistance is associated with reduced serum adiponectin and increased albuminuria levels. Thus, one would anticipate an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin in patients with elevated albuminuria. These findings may have been confounded by the presence of diseases and related treatments known to affect circulating adiponectin and albuminuria. We therefore studied the relationship between circulating adiponectin and albuminuria in the absence of such confounders. Methods To this purpose, the relationship between adiponectin isoforms and albumin:creatinine ratio (ACR) was investigated in a family-based sample of 634 non-diabetic untreated white individuals with normal kidney function. We also investigated whether the two variables share a common genetic background and addressed the specific role of the gene encoding adiponectin on that background by genotyping several ADIPOQ single nucleotide polymorphisms (SNPs). Results ACR was directly associated with high molecular weight (HMW) adiponectin isoform (p=0.024). The two variables shared some genetic correlation (ρ g = 0.38, p=0.04). ADIPOQ promoter SNP rs17300539 was associated with HMW adiponectin (p=4.8×10 −5 ) and ACR (p=0.0027). The genetic correlation between HMW adiponectin and ACR was no longer significant when SNP rs17300539 was added to the model, thus reinforcing the role of this SNP in determining both traits.Conclusions/interpretation Our study shows a positive, independent correlation between HWM adiponectin and ACR. ADIPOQ variability is associated with HMW adiponectin and ACR, and explains some of the common genetic background shared by these traits, thus suggesting that ADIPOQ and HMW adiponectin modulate albuminuria levels.

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“…We acknowledge the assistance of the FinnDiane Study Group [13] and, especially, the skilled technical assistance of S. Lindh and A. Sandelin. SNP genotyping based on Sequenom technology was performed at the Finnish Genome Center.…”

Section: Acknowledgementsmentioning

confidence: 99%

DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

et al. 2010

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Aims/hypothesis The AGE receptors 1, 2 and 3, which are encoded by DDOST, PRKCSH and LGALS3, respectively, may be involved in the pathogenesis of diabetic complications. We sought to find out whether these genes are associated with diabetic nephropathy, cardiovascular disease and type 1 diabetes or related quantitative traits. Methods Using the Tagger program, we selected 28 single nucleotide polymorphisms (SNPs) based on the HapMap Centre d'Etude du Polymorphisme (Utah residents with northern and western European ancestry) data. The SNPs were genotyped in 2,719 Finnish patients with type 1 diabetes and tested for association with diabetic nephropathy (821 cases, 1,060 controls), cardiovascular disease and related quantitative traits. For association analysis with type 1 diabetes, 703 non-diabetic control participants were genotyped. Results We found evidence of genotype association between diabetic nephropathy and the SNPs rs2170336 in DDOST (p=0.03), rs311788 in PRKCSH (p=0.04) and rs311778 in PRKCSH (p=0.02). However, these associations did not reach the significance limit of 0.0008 adjusted for multiple testing. None of the DDOST, PRKCSH or LGALS3 SNPs were associated with quantitative traits related to diabetic nephropathy, including AER and estimated GFR. No associations were found between the SNPs and cardiovascular disease, blood pressure, serum lipid levels or type 1 diabetes. Conclusions/interpretation The common SNPs tested in DDOST, PRKCSH and LGALS3 do not seem to be associated with diabetic micro-or macrovascular complications or with type 1 diabetes in Finnish patients.

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Serum Adiponectin and Progression of Diabetic Nephropathy in Patients With Type 1 Diabetes

Cited by 79 publications

References 23 publications

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

DDOST, PRKCSH and LGALS3, which encode AGE-receptors 1, 2 and 3, respectively, are not associated with diabetic nephropathy in type 1 diabetes

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