Growth factor control of pancreatic islet regeneration and function

Assmann, Anke; Hinault, Charlotte; Kulkarni, Rohit

doi:10.1111/j.1399-5448.2008.00468.x

Cited by 63 publications

(67 citation statements)

References 258 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The secretory granules contain the enzymes necessary for cleavage of proinsulin to insulin plus C-peptide, i.e. PC-1/ 3, PC2 and CPE [48]. Remarkably, we found that PC-1/3 production was reduced at the mRNA and protein level in islets constitutively producing SOCS2.…”

Section: Discussionmentioning

confidence: 51%

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas. Methods Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.Results Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca 2+ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, inElectronic supplementary material The online version of this article

show abstract

Section: Discussionmentioning

confidence: 51%

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

et al. 2010

View full text Add to dashboard Cite

show abstract

“…22). An increase in circulating proinsulin in the βIRKO mice led us to hypothesize that insulin signaling regulates proinsulin processing.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to insulin's actions in classical insulin-responsive tissues (muscle, liver, and fat), insulin signaling regulates β-cell mass and function (17)(18)(19)(20)(21)(22), as well as transcription of the insulin gene itself (23). We hypothesized that disruption of normal growth factor (insulin) signaling in the β cell has an impact on proinsulin processing and/or adversely affects the function of the ER and, ultimately, the β cell.…”

mentioning

confidence: 99%

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Liew

Assmann

Templin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Insulin resistance, hyperinsulinemia, and hyperproinsulinemia occur early in the pathogenesis of type 2 diabetes (T2D). Elevated levels of proinsulin and proinsulin intermediates are markers of β-cell dysfunction and are strongly associated with development of T2D in humans. However, the mechanism(s) underlying β-cell dysfunction leading to hyperproinsulinemia is poorly understood. Here, we show that disruption of insulin receptor (IR) expression in β cells has a direct impact on the expression of the convertase enzyme carboxypeptidase E (CPE) by inhibition of the eukaryotic translation initiation factor 4 gamma 1 translation initiation complex scaffolding protein that is mediated by the key transcription factors pancreatic and duodenal homeobox 1 and sterol regulatory element-binding protein 1, together leading to poor proinsulin processing. Reexpression of IR or restoring CPE expression each independently reverses the phenotype. Our results reveal the identity of key players that establish a previously unknown link between insulin signaling, translation initiation, and proinsulin processing, and provide previously unidentified mechanistic insight into the development of hyperproinsulinemia in insulinresistant states.ER stress | prohormone | bIRKO | GWAS

show abstract

“…In humans and in rodent models of diabetes and obesity, β-cells compensate for insulin resistance with both increased mass and function (16,17). Recent studies demonstrate the presence and importance of insulin signaling in the β-cell, and insulin and insulinlike growth factor-1 (IGF1) receptors participate in β-cell development and function (1,5). Genetic engineering techniques to knockout or knockdown IRS proteins in the insulin signaling pathway either at the whole body level or in β-cells demonstrate their significance in glucose homeostasis (4,6,18,19).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin and insulin-like growth factor-1 (IGF1) receptors and major insulin receptor substrates, IRS-1 through IRS-4, are present and functional in islets and/or β-cells (1,2). Furthermore, β-cell-specific insulin receptor knockout (βIRKO) mice manifest defective glucosestimulated insulin secretion and progressive glucose intolerance (3), leading to overt diabetes in some animals (1). Likewise, deletion of IRS-1, IRS-2, or Akt2 alters glucose sensing and β-cell growth (4)(5)(6).…”

mentioning

confidence: 99%

Insulin enhances glucose-stimulated insulin secretion in healthy humans

Bouché

López

Fleischman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Islet β-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates β-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of β-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by ≈40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of β-cell secretory response when using these methods during prolonged dynamic testing. beta cell | type 2 diabetes mellitus | insulin resistance | insulin clearance |

show abstract

Growth factor control of pancreatic islet regeneration and function

Cited by 63 publications

References 258 publications

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells

Insulin enhances glucose-stimulated insulin secretion in healthy humans

Contact Info

Product

Resources

About