Effects of insulin and the glucagon‐like peptide 1 receptor agonist liraglutide on the kidney proteome in db/db mice

Leena Liljedahl,Jenny Norlin,Peter James,James N Mcguire

doi:10.14814/phy2.13187

Abstract

Diabetes mellitus (DM) is a worldwide disease that affects 9% of the adult world population and type 2 DM accounts for 90% of those. A common consequence of DM is kidney complications, which could lead to kidney failure. We studied the potential effects of treatment with insulin and the glucagon‐like peptide 1 receptor (GLP‐1R) agonist liraglutide on the diabetic kidney proteome through the use of the db/db mouse model system and mass spectrometry (MS). Multivariate analyses revealed distinct effects of insulin and liraglutide on the db/db kidney proteome, which was seen on the protein levels of, for example, pterin‐4 α‐carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor‐1α (PCBD1), neural precursor cell expressed developmentally down‐regulated‐8 (NEDD8), transcription elongation factor‐B polypeptide‐1 (ELOC) and hepcidin (HEPC). Furthermore, the separation of the insulin, liraglutide and vehicle db/db mouse groups in multivariate analyses was not mainly related to the albumin excretion rate (AER) or the level of glycated hemoglobin A1c (HbA1c%) in the mice. In summary, we show that insulin and liraglutide give rise to separate protein profiles in the db/db mouse kidney.

Highlights

The prevalence of type 2 Diabetes mellitus (DM) is increasing rapidly (World Health Organization, 2014) with the number of people suffering from late complications of diabetes
After 12 weeks of vehicle, insulin or liraglutide dosing, HbA1c(%) (Fig. 1A) was 4.3 (0.2)% in the healthy control mice compared to higher levels in the three db/db mouse groups; db/db vehicle 8.5 (1.6)%, db/db insulin 6.8 (0.5)% and db/db liraglutide 6.9 (2.0)%
At 6 weeks the albumin excretion rate (AER) was significantly increased (P < 0.02) in the db/db vehicle mice (855 [608] lg/24 h, n = 5) compared to the healthy control mice (59 [27] lg/24 h, n = 4) while the mean AER was decreased in the db/db insulin mice (489 [140] lg/24 h, n = 5) and in the db/db liraglutide mice (585 [199] lg/24 h, n = 4) no significant difference was detected involving these mouse groups

Summary

Introduction

The prevalence of type 2 Diabetes mellitus (DM) is increasing rapidly (World Health Organization, 2014) with the number of people suffering from late complications of diabetes. Insulin receptors (IR) and insulin-like growth factor-1 receptors (IGF-1R) are located mainly in the tubules and the glomeruli (Butlen et al 1988; Uhlen et al 2015) while in rodents and primates, GLP1 receptors (GLP-1R) are located in the smooth muscle cells in the vascular walls (Pyke et al 2014; Jensen et al 2015) These receptors mediate important functions in the kidneys, as deletion of the IR in the proximal tubules has been shown to lead to increased hyperglycemia involving gluconeogenesis (Tiwari et al 2013). Transgenic mice with podocyte-specific lack of IR has been shown to develop albuminuria (Welsh et al 2010)

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Conclusion