Altered Insulin Receptor Signalling and β-Cell Cycle Dynamics in Type 2 Diabetes Mellitus

Abstract

Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells – which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.

Determinants of reversibility of β-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes

“…This concept is further supported by studies showing that preceding exposure to exogenous insulin can enhance glucose-stimulated insulin secretion in healthy individuals (2,19). Coupled with evidence that islet cells express insulin receptors and signaling proteins whose disruption can lead to defective glucose metabolism in animal models (8,16), these data support an important physiological role for insulin signaling in the ␤-cell, which may potentially be relevant to the improvement in ␤-cell function that can be achieved with early short-term IIT.…”

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

“…Third, basal body/ciliary defects should compromise at least one of the known signalling networks involved in (pre-) diabetic phenotypes. Altered IR signalling has been observed in human islets from T2DM patients 53 . Loss of first phase insulin secretion has also been reported for the bIRKO mouse, a T2DM susceptibility model.…”

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

“…Furthermore, islets from these mice, and MIN 6 cells, incubated with high glucose and palmitate for 48 h underwent dephosphorylation of FoxO1 along with its upstream kinase Akt (47). Another study reported reduced insulin receptor and insulin receptor substrate 2 expression in islets from humans with type 2 diabetes, and it noted nuclear retention of FoxO1 in islets of mice with a ␤-cell-specific deletion of insulin receptors (48). Alternatively, FoxO1 activity and its subcellular compartmentation in ␤-cells is regulated by other serine/threonine kinases as well the balance between acetylation and deacetylation (21).…”