A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse

Landau, Daniel; Segev, Yael; Afargan, Michel; Silbergeld, A.; Katchko, Leonid; Podshyvalov, Andrey; Phillip, Moshe

doi:10.1046/j.1523-1755.2001.060002505.x

Cited by 35 publications

(27 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, as a novel finding we have demonstrated octreotide treatment to be effective in reducing renal and glomerular growth along with a reduction in GH hypersecretion and increased local kidney IGF-I levels. Similar effects were observed just recently in the NOD mouse using a novel somatostatin analogue (Landau et al 2001). This may provide further evidence for a significant role for GH and IGF-I in diabetic renal growth and morphological changes in experimental diabetes in mice as has previously been demonstrated in diabetic rats.…”

Section: Discussionsupporting

confidence: 85%

Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice

Grønbæk¹,

Nielsen²,

Schrijvers³

et al. 2002

Journal of Endocrinology

View full text Add to dashboard Cite

It was recently discovered that the streptozotocin (STZ)-diabetic mouse model is characterised by GH hypersecretion in contrast to the STZ-diabetic rat, the former thus mimicking the changes in GH in human type 1 diabetes. Inhibition of circulating and renal IGF-I by long-acting somatostatin analogues reduces renal and glomerular growth and urinary albumin excretion in diabetic rats.The aim of the present study was to examine renal and glomerular growth in early experimental diabetes in mice along with changes in the GH/IGF-I axis following treatment with the somatostatin analogue octreotide. Balb/C(a) mice were randomised into non-diabetic controls, placebo-treated and octreotide-treated diabetic (50 µg/day) mice and examined 7 and 14 days after induction of diabetes.There was no effect of octreotide treatment on body weight, glycaemic control or food intake. However, octreotide treatment significantly inhibited renal and glomerular growth by the end of the study period when compared with placebo treatment. In addition, octreotide prevented an increase in kidney IGF-I by day 7. GH hypersecretion was observed in the diabetic groups but octreotide treatment reduced GH levels compared with placebo treatment by day 14. No significant differences in serum or kidney IGF-binding protein-3 levels were observed between placebo-and octreotride-treated diabetic mice.In conclusion, this new diabetic mouse model mimicking human type 1 diabetes is characterised by GH hypersecretion and the somatostatin analogue octreotide is able to prevent renal and glomerular growth, probably mediated through changes in circulating GH and local kidney IGF-I levels.

show abstract

Section: Discussionsupporting

confidence: 85%

Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice

Grønbæk¹,

Nielsen²,

Schrijvers³

et al. 2002

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Indeed, we and others have previously shown that the inhibition of GH, either by the use of a GHR antagonist [7] or a somatostatin analogue, has protective renal effects in animals with type I DM [8]. In addition, GH administration to diabetic rats had adverse renal effects, such as worsening albuminuria and increased renal IGFBP1 levels, which, as mentioned, may increase the local trapping of IGF-I [9].…”

Section: Introductionmentioning

confidence: 90%

Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation

Landau

Eshet

Troib

et al. 2009

Endocr

Self Cite

View full text Add to dashboard Cite

Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.

show abstract

“…Lean heterozygous and nondiabetic db/N mice were used as controls. All animals were killed 4 weeks after the onset of diabetes mellitus, as previously described [11]. Body weight was measured twice weekly.…”

Section: Animal Experimentationmentioning

confidence: 99%

“…A subset of experiments was performed using a somatostatin analogue (PTR-313: Peptor, Rehovot, Israel) previously described by us as having protective effects on the kidney in a model of type 1 diabetes mellitus [11]. The agent was provided daily over 4 weeks by s.c. injections (1 mg kg −1 day −1 ) to diabetic animals, with control animals receiving the equivalent amount of saline.…”

Section: Animal Experimentationmentioning

confidence: 99%

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. Materials and methods Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.Results Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulinlike growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulindriven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. Conclusions/interpretation Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.

show abstract

A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse

Cited by 35 publications

References 32 publications

Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice

Inhibitory effects of octreotide on renal and glomerular growth in early experimental diabetes in mice

Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

Contact Info

Product

Resources

About