Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

Uchida, Tsuyoshi; Nakamura, Takehiro; Hashimoto, Naoko; Matsuda, Tomokazu; Kotani, Ko; Sakaue, Hiroshi; Kido, Yoshiaki; Hayashi, Yoshitake; Nakayama, Keiichi I.; White, Morris F.; Kasuga, Masato

doi:10.1038/nm1187

Cited by 200 publications

(201 citation statements)

References 43 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…In vitro studies suggest that hepatic GH resistance may develop in response to chronic hyperinsulinaemia [17]. The result of these changes may be a decrease in circulating IGF1 and IGF1 action, which may by itself be a mechanism for decreased beta cell survival in long-term type 2 diabetes mellitus [18,19]. Free serum IGF1 levels (which depend on levels of the significant IGF binding proteins) were not measured in our study.…”

Section: Discussionmentioning

confidence: 55%

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

Section: Discussionmentioning

confidence: 55%

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

show abstract

“…In contrast, global deletion of p27 kip1 enhances beta cell proliferation, as also observed in genetic mouse models of insulin resistance (e.g. IRS2 KO, db/db) [59]. Beta cell hyperplasia is also observed in humans with a focal loss of heterozygosity of p57 kip2 , who suffer from hyperinsulinism of infancy [60].…”

Section: Adulthoodmentioning

confidence: 78%

“…This suggests that mature beta cells are sensitive to perturbations in cell cycle control, and this is probably due to differential involvement of cell cycle regulators compared with most other cell types as exemplified by models lacking CDK6 [56] and/or redundant expression of cyclin D2 [57,58]. Furthermore, overexpression of the inhibitor p27 kip1 [59] in beta cells impairs proliferation, resulting in reduced beta cell mass. In contrast, global deletion of p27 kip1 enhances beta cell proliferation, as also observed in genetic mouse models of insulin resistance (e.g.…”

Section: Adulthoodmentioning

confidence: 99%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

View full text Add to dashboard Cite

Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

show abstract

“…Also, several studies using animal models of diabetes showed the importance of downregulation or loss of p27 in b-cells for accelerating replication of b-cells and thereby expansion of b-cell mass for correcting diabetes. [36][37][38] We have found robust interaction of p27 with GSK-3 in human islets and rodent b-cells (Fig. 2).…”

confidence: 79%

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Stein¹,

Milewski²,

Hara³

et al. 2011

Islets

View full text Add to dashboard Cite

Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

Cited by 200 publications

References 43 publications

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

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

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

GSK-3 inactivation or depletion promotes β-cell replication via down regulation of the CDK inhibitor, p27 (Kip1)

Contact Info

Product

Resources

About