Pleiotropic Effects of Glucagon-like Peptide-1 (GLP-1)-Based Therapies on Vascular Complications in Diabetes

Yamagishi, Sho‐ichi; Matsui, Takanori

doi:10.2174/138161211798999456

Cited by 34 publications

(29 citation statements)

References 76 publications

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“…There is a pathological crosstalk between the AGE-RAGE system and dipeptidyl peptidase-4 (DPP-4)-incretin axis in the pathogenesis of vascular complications in diabetes (95,96). Glucagonlike peptide-1 directly acts on endothelial cells, mesangila cells and proximal tubular cells via the glucagon-like peptide-1 receptor, and glucagon-like peptide-1 could work as an antiinflammatory and antioxidative agent against AGEs by reducing RAGE expression via activation of cyclic AMP pathways (95,96).…”

Section: Dipeptidyl Peptidase-4 Inhibitors and Incretinsmentioning

confidence: 99%

“…Glucagonlike peptide-1 directly acts on endothelial cells, mesangila cells and proximal tubular cells via the glucagon-like peptide-1 receptor, and glucagon-like peptide-1 could work as an antiinflammatory and antioxidative agent against AGEs by reducing RAGE expression via activation of cyclic AMP pathways (95,96). Moreover, we have recently found that AGE-RAGE-induced oxidative stress generation stimulates the release of DPP-4 from endothelial cells, which could act on endothelial cells in an autocrine manner via the interaction with mannose 6-phosphate insulin-like growth factor II receptor, further potentiating the deleterious effects of AGEs (97).…”

Section: Dipeptidyl Peptidase-4 Inhibitors and Incretinsmentioning

confidence: 99%

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Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

Yamagishi

Nakamura

Suematsu

et al. 2015

Mol Med

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144

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Section: Dipeptidyl Peptidase-4 Inhibitors and Incretinsmentioning

confidence: 99%

Section: Dipeptidyl Peptidase-4 Inhibitors and Incretinsmentioning

confidence: 99%

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

Yamagishi

Nakamura

Suematsu

et al. 2015

Mol Med

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144

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“…11,12 GLP-1 and GIP are target proteins of dipeptidyl peptidase-4 (DPP-4) and rapidly degraded and inactivated by this proteolytic enzyme. 13,14 Since GLP-1 and GIP augment glucose-induced insulin release from pancreatic b-cells, suppress glucagon secretion and slow gastric emptying, 11,12 inhibition of DPP-4 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes.…”

mentioning

confidence: 99%

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Matsui

Nakashima

Nishino

et al. 2015

Laboratory Investigation

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Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy. Sugars, including glucose and fructose, can react nonenzymatically with the amino groups of proteins, lipids and nucleic acids to form reversible Schiff bases, and then Amadori products. 1-3 These early glycation products undergo further complex reactions such as rearrangement, dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives called 'advanced glycation end products (AGEs)'. 1-3 The process of non-enzymatic glycation is also known as Maillard reaction, and formation and accumulation of AGEs in various tissues have progressed at a physiological aging and at an extremely accelerated rate under diabetes. [1][2][3] There is a growing body of evidence that AGEs and their receptor (RAGE) interaction evoke oxidative stress generation and inflammatory and fibrotic reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes. [4][5][6][7][8] Furthermore, RAGEoverexpressing diabetic mice have been shown to exhibit progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene. 9 Diabetic homozygous RAGE null mice displayed diminished albuminuria and glomerulosclerosis and failed to develop significantly increased mesan...

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“…Their benefits in protecting the kidneys have been also reported in recent studies (18)(19)(20)(21)(22)(23)(24). These drugs have attracted extensive interest as promising new alternatives to existing diabetes drugs in patients with diabetes and a reduced renal function.…”

Section: Introductionmentioning

confidence: 83%

Effects of Alogliptin in Chronic Kidney Disease Patients with Type 2 Diabetes

et al. 2014

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Objective Diabetes is a major risk factor for chronic kidney disease (CKD). In this study, we examined the effects of alogliptin on blood glucose control and the renal function in type 2 diabetes CKD patients. Methods We recruited 36 CKD patients with type 2 diabetes. The patients were followed up for six months after adding alogliptin. Blood biochemical, urine test and office BP values were obtained six months before and after the start of treatment. Results The mean HbA1c value was not decreased; however, the 1,5-AG values tended to improve (p= 0.1023). The mean eGFR was unchanged. There were no significant changes in the patients with an eGFR of 60 mL/min/1.73 m 2 or more (25 patients) or in the patients with an eGFR less than 60 mL/min/1.73 m 2 (11 patients). A total of 15 patients were identified to have rapidly declining diabetic nephropathy, with an annual reduction in eGFR of 5 mL/min/1.73 m 2 or more. The slope of the regression line for eGFR (-1.296 before starting treatment with alogliptin) was positive, increasing up to 0.08786. The eGFR values appeared to stop decreasing and positively reversed. The urinary albumin-to-creatinine ratio exhibited a downward trend. The effect on the renal function was independent of the levels of blood sugar, blood pressure and lipids. Conclusion We examined the ability of alogliptin to maintain the renal function in patients with CKD complicated by type 2 diabetes. Our study suggests that alogliptin can be safely administered in patients with CKD. However, although we expected alogliptin to demonstrate renal protective effects, were unable to detect statistically significant differences. One reason for this finding is that there are few registered cases.

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Pleiotropic Effects of Glucagon-like Peptide-1 (GLP-1)-Based Therapies on Vascular Complications in Diabetes

Cited by 34 publications

References 76 publications

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Effects of Alogliptin in Chronic Kidney Disease Patients with Type 2 Diabetes

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