A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes

Robertson, Katie; Lu, Yue; Jesus, Kristine De; Li, Bing; Su, Qing; Lund, Patricia; Liu, Junli

doi:10.1152/ajpendo.00606.2007

Cited by 40 publications

(47 citation statements)

References 64 publications

(88 reference statements)

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“…However, a lower number of apoptotic beta cells was detected in transgenic than in wild-type islets (Fig. 1c), as observed previously [7,8,31]. In addition, at 10 days after STZ treatment the beta cell mass in wild-type and transgenic pancreas was evaluated and a similar decrease (about 30%) observed when compared with non-STZ-treated mice (wild-type 1.12±0.2 mg; transgenic 1.2±0.1 mg; STZwild-type 0.87±0.2 mg; STZ-transgenic 0.85±0.1).…”

Section: Resultssupporting

confidence: 88%

IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice

et al. 2008

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Aims/hypothesis Recovery from diabetes requires restoration of beta cell mass. Igf1 expression in beta cells of transgenic mice regenerates the endocrine pancreas during type 1 diabetes. However, the IGF-I-mediated mechanism(s) restoring beta cell mass are not fully understood. Here, we examined the contribution of pre-existing beta cell proliferation and transdifferentiation of progenitor cells from bone marrow in IGF-I-induced islet regeneration. Methods Streptozotocin (STZ)-treated Igf1-expressing transgenic mice transplanted with green fluorescent protein (GFP)-expressing bone marrow cells were used. Bone marrow cell transdifferentiation and beta cell replication were measured by GFP/insulin and by the antigen identified by monoclonal antibody Ki67/insulin immunostaining of pancreatic sections respectively. Key cell cycle proteins were measured by western blot, quantitative RT-PCR and immunohistochemistry. Results Despite elevated IGF-I production, recruitment and differentiation of bone marrow cells to beta cells was not increased either in healthy or STZ-treated transgenic mice. In contrast, after STZ treatment, IGF-I overproduction decreased beta cell apoptosis and increased beta cell replication by modulating key cell cycle proteins. Decreased nuclear levels of cyclin-dependent kinase inhibitor 1B (p27) and increased nuclear localisation of cyclin-dependent kinase (CDK)-4 were consistent with increased beta cell proliferation. However, islet expression of cyclin D1 increased only after STZ treatment. In contrast, higher levels of cyclin-dependent kinase inhibitor 1A (p21) were detected in islets from non-STZtreated transgenic mice. Conclusions/interpretation These findings indicate that IGF-I modulates cell cycle proteins and increases replication of pre-existing beta cells after damage. Therefore, our study suggests that local production of IGF-I may be a safe approach to regenerate endocrine pancreas to reverse diabetes.

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Section: Resultssupporting

confidence: 88%

IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice

et al. 2008

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“…GH stimulates IGF1 secretion and decreases insulin sensitivity (22). In transgenic mice, overexpressing IGF1, hypoglycemia, and resistance to diabetes were found (23). However, mice overexpressing GH have high-IGF1, insulin resistance, and increased likelihood of developing diabetes (24).…”

Section: Discussionmentioning

confidence: 99%

Prediction of incident diabetes mellitus by baseline IGF1 levels

Schneider

Friedrich

Klotsche

et al. 2011

European Journal of Endocrinology

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Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low-or high-IGF1 are at risk of diabetes. We hypothesized that both low-and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study. Design: An analysis of two prospective cohort studies, the DETECT study and SHIP. Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up. Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (PO0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age-and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07-1.94) and 1.55 (95% CI 1.06-2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline. Conclusions: Subjects with low-or high-IGF1 level are at increased risk of developing diabetes.

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“…Although, to date, most of the supporting evidence for this concept has been derived from animal (mainly rodent) studies, the results of the present investigation suggest that similar regulatory and/or trophic influences, exerted by the ductal epithelia, may be crucial for appropriate and sustained human beta cell function. Soluble mediators such as IGF-1 and -2 and the epidermal growth factor (EGF) family have been implicated in beta cell survival and replication [38][39][40][41], and ductal epithelial cells may provide an additional source of these regulatory hormones in the post-isolation environment [41]. Additionally, components of the ECM are vital for appropriate pancreatic development, and several integrin receptors and their associated ligands, including laminin, fibronectin and collagen I, are produced in ductal cells [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

et al. 2009

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Aims/hypothesis Loss of the trophic support provided by surrounding non-endocrine pancreatic cell populations underlies the decline in beta cell mass and insulin secretory function observed in human islets following isolation and culture. This study sought to determine whether restoration of regulatory influences mediated by ductal epithelial cells promotes sustained beta cell function in vitro. Methods Human islets were isolated according to existing protocols. Ductal epithelial cells were harvested from the exocrine tissue remaining after islet isolation, expanded in monolayer culture and characterised using fluorescence immunocytochemistry. The two cell types were co-cultured under conventional static culture conditions or within a rotational cell culture system. The effect of co-culture on islet structural integrity, beta cell mass and insulin secretory capacity was observed for 10 days following isolation. Results Human islets maintained under conventional culture conditions exhibited a characteristic loss in structural integrity and functional viability as indicated by a diminution of glucose responsiveness. By contrast, co-culture of islets with ductal epithelial cells led to preserved islet morphology and sustained beta cell function, most evident in co-cultures held within the rotational cell culture system, which showed a significantly (p<0.05) greater insulin secretory response to elevated glucose compared with control islets. Similarly, insulin/protein ratio data suggested that the presence of ductal epithelial cells is beneficial for the maintenance of beta cell mass. Conclusions/interpretation The data indicate a supportive role for ductal epithelial cells in islet viability. Further characterisation of the regulatory influences may lead to novel strategies to improve long-term beta cell function both in vitro and following islet transplantation.

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A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes

Abstract: Liu J-L. A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes.

Cited by 40 publications

References 64 publications

IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice

IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice

Prediction of incident diabetes mellitus by baseline IGF1 levels

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

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