Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes

Kodera, Ryo; Shikata, Kenichi; Kataoka, Hitomi; Takatsuka, Tetsuharu; Miyamoto, Sadaaki; Sasaki, Motofumi; Kajitani, Nobuo; Nishishita, Sôichi; Sarai, Kei; Hirota, Daisho; Sato, Chikage; Ogawa, Daisuke; Makino, Hírofumi

doi:10.1007/s00125-010-2028-x

Cited by 329 publications

(287 citation statements)

References 49 publications

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“…This suggests that the normalisation of abnormally activated inflammatory signalling by GLP-1 contributes to the decreased production of inflammatory cytokines and chemokines. Consistent with our results, it was recently reported that exendin-4 treatment showed anti-inflammatory effects on glomerular endothelial cells and macrophages [43], and that liraglutide, a longacting GLP-1 analogue, also inhibited NF-κB activation in human umbilical vein endothelial cells [44]. Energy intake in excess of energy expenditure may cause obesity and insulin resistance, while dysregulation of energy E x -4 U n t r e a t e d E x -4 U n t r e a t e d E x -4 U n t r e a t e d E x -4 U n t r e a t e d E x -4 U n t r e a t e d E x -4 Nuclei were stained with 4′-6-diamidino-2-phenylindole.…”

Section: Discussionsupporting

confidence: 94%

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

et al. 2012

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Aims/hypothesis Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM). Methods We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signalregulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro. Results Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80 + and F4/80 + CD11b + CD11c + cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM. Conclusions/interpretation We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.

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Section: Discussionsupporting

confidence: 94%

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

et al. 2012

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“…With respect to the effects of GLP-1 on the kidney, it has been reported that in animal model, GLP-1R agonists have various extra-pancreatic actions such as regulating sodium excretion in the tubular cells of the kidney (Hirata et al 2009) and they have been shown to directly prevent the progression of DN through the suppression of inflammatory process via the activation of GLP-1R in kidney tis-sue (Kodera et al 2011).…”

Section: Introductionmentioning

confidence: 99%

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

Imamura

Hirai

2013

Tohoku J. Exp. Med.

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m 2 to 26.5 ± 0.8 kg/m 2 after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m 2 /year to 0.3 ± 1.9 mL/min/1.73 m 2 /year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

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“…GLP-1 has been reported to have various renoprotective effects [21][22][23][24][25][26][27][28][29][30][31], but renal expression of GLP-1 is suppressed in T2DM [32]. Sitagliptin elevates downregulated intrarenal GLP-1 expression in the T2DM rat model [32].…”

Section: Discussionmentioning

confidence: 99%

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

Kanozawa

Noguchi

Sugahara³

et al. 2017

Clin Exp Nephrol

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Background We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function. Methods Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/ day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months. Results Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon-like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient. Conclusion Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full-dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance.

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Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes

Abstract: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Cited by 329 publications

References 49 publications

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

The Glucagon-Like Peptide-1 Receptor Agonist, Liraglutide, Attenuates the Progression of Overt Diabetic Nephropathy in Type 2 Diabetic Patients

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

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