Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin--angiotensin--aldosterone system in healthy men

Skov, Jeppe; Dejgaard, A.; Frøkiær, Jørgen; Holst, Jens J.; Jonassen, Thomas E. N.; Rittig, Søren; Christiansen, Jens Sandahl

doi:10.1530/endoabs.32.oc6.3

Cited by 36 publications

(76 citation statements)

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“…Whether the combination may similarly exert additive or synergistic e ects on cardiac function in CKD remains to be determined. In this regard, it is noteworthy that several studies have described a relationship between the DPP-4 substrate, GLP-1 and the RAS [45][46][47]. e cardiac dysfunction in the SNx rats in the present study may not have fully developed, recognizing that this was accompanied by impairment in the passive phase of diastole (EDPVR), whereas neither active relaxation (Tau) nor EDP were signi cantly altered.…”

Section: Discussionmentioning

confidence: 60%

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease

Connelly¹,

Bowskill

Advani

et al. 2014

CIM

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Purpose: Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in people with chronic kidney disease (CKD) for which no evidence-based treatment currently exists. Recently, a group of anti-hyperglycemic agents used in the treatment of Type 2 diabetes, termed incretin-based therapies, have come under scrutiny for their putative glucose-independent effects on cardiac function. In the present study, the actions of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of incretin-based therapy in preventing HFpEF induced by chronic renal impairment were investigated. Methods: Sham-operated and subtotally-nephrectomized rats were randomized to receive the DPP-4 inhibitors, linagliptin or sitagliptin for seven weeks before assessment of cardiac and renal structure and function. Results: Analysis of pressure-volume loops revealed that both linagliptin and sitagliptin prevented the development of cardiac diastolic dysfunction, with cardiac collagen I synthesis also being reduced by DPP-4 inhibition. These attenuating cardiac effects occurred without change in renal function or structure where, in the doses administered, neither linagliptin nor sitagliptin affected GFR decline, proteinuria, renal fibrosis or the increased urinary excretion of biomarkers of renal toxicity. Conclusion: The beneficial cardiac effects of DPP-4 inhibition, in the absence of a concurrent improvement in renal dysfunction, raise the possibility that these agents may confer cardiovascular advantages in the CKD population.

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Section: Discussionmentioning

confidence: 60%

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease

Connelly¹,

Bowskill

Advani

et al. 2014

CIM

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“…Blood pressure increases after acute intravenous infusion of GLP-1 or exendin-4 have been observed in both conscious (13) and anesthetized normotensive rats (3,4,44). In healthy humans, GLP-1 transiently increases HR (41) or both HR and MAP (11). However, in hypertensive animal models (23,26,30), GLP-1 has a blood pressure lowering effect.…”

Section: Discussionmentioning

confidence: 99%

“…However, a recent study (41) in healthy men showed that GLP-1 did not affect GFR or renal plasma flow (RPF) but increased Na ϩ excretion without affecting urine flow.…”

mentioning

confidence: 95%

Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

Jensen

Poulsen

Kissow

et al. 2015

American Journal of Physiology-Renal Physiology

104

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Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats.

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“…Glucagon‐like peptide 1 receptor agonists have been suggested to reduce hyperfiltration in patients with T2DM by beneficially affecting distinct pathophysiological mechanisms underlying this phenomenon. First, several small‐sized mechanistic studies in humans suggested that acute GLP‐1 peptide or GLP‐1RA administration inhibits Na + /H + ‐exchanger isoform‐3 (NHE3) activity in the proximal tubule. This theoretically increases sodium chloride delivery to the macula densa and restores the disrupted TGF response associated with diabetes and obesity, leading to increased R A and subsequent reductions in (single‐nephron) GFR and ERPF.…”

Section: Discussionmentioning

confidence: 99%

“…Third, GLP‐1RAs may reduce hyperfiltration by lowering body weight . Fourth, as acute GLP‐1 peptide and GLP‐1RA administration reduces plasma renin activity, PRC and angiotensin‐II in some (but not all, including current) trials, prolonged GLP‐1RA treatment could ameliorate RAAS‐mediated hyperfiltration in diabetes . Fifth, we hypothesised that short‐acting GLP‐1RA could reduce hyperfiltration by reducing postprandial insulin concentrations (mainly by delaying gastric emptying rate and subsequent intestinal glucose absorption), as insulin per se increases renal filtration by reducing R A …”

Section: Discussionmentioning

confidence: 99%

Postprandial renal haemodynamic effect of lixisenatide vs once‐daily insulin‐glulisine in patients with type 2 diabetes on insulin‐glargine: An 8‐week, randomised, open‐label trial

Tonneijck

Muskiet

Smits

et al. 2017

Diabetes Obesity Metabolism

103

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Funding informationResearch leading to these results has received funding from Sanofi-Aventis. Sanofi-Aventis provided prefilled lixisenatide and insulinglulisine pens for subcutaneous use. Selfmonitoring blood glucose devices were provided by Menarini Diagnostics. Funders had no role in the study design, or the analysis and interpretation of the data, or drafting of the manuscript or the decision to submit this manuscript for publication Aim: To determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus (T2DM) compared with insulin-glulisine (iGlu).Methods: Postprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 μg vs once-daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin-glargine, with or without metformin [mean AE SD age 62 AE 7 years, HbA1c 8.0% AE 0.9%, estimated glomerular filtration rate (GFR) 85 AE 12 mL/min/ 1.73 m 2 , median (IQR) urinary albumin/creatinine ratio 1.5 (0.9-3.0) mg/mmol]. After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez equations. Results: Compared with iGlu, lixisenatide did not affect GFR [+0.1 mL/min/1.73 m 2 (95% CI −9 to 9)], ERPF [−17 mL/min/1.73 m 2 (−61 to 26)], other (intra-)renal haemodynamics or renal damage markers, but increased fractional sodium excretion [+0.25% (0.09-0.41)] and urinary pH [+0.7 (0.3-1.2)]. Plasma renin, angiotensin-II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8% AE 0.1% and 0.6% AE 0.1%, respectively, while postprandial glucose was lower with lixisenatide (P = .002). Compared with iGlu, lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4-14)]. Conclusion: Eight-week lixisenatide treatment does not affect postprandial (intra-)renal haemodynamics compared with iGlu when added to insulin-glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long-acting GLP-1RA, reduces body weight and increases postprandial blood pressure compared with iGlu.Trial registration: ClinicalTrials.gov identifier NCT02276196 K E Y W O R D S diabetes, glomerular filtration rate, glomerular hyperfiltration, glomerular pressure, GLP-1 receptor agonist, glucagon-like peptide-1, insulin-glulisine, lixisenatide, natriuresis, renal function, renal haemodynamics, type 2 diabetes † M. D. is sadly deceased.This article is in memory of Professor Michaela Diamant, whose experience and expertise were crucial for the design of this study.

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Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin--angiotensin--aldosterone system in healthy men

Cited by 36 publications

References 0 publications

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease

Dipeptidyl peptidase-4 inhibition improves left ventricular function in chronic kidney disease

Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

Postprandial renal haemodynamic effect of lixisenatide vs once‐daily insulin‐glulisine in patients with type 2 diabetes on insulin‐glargine: An 8‐week, randomised, open‐label trial

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