Treatment with Recombinant Human Insulin-Like Growth Factor (rhIGF)-I/rhIGF Binding Protein-3 Complex Improves Metabolic Control in Subjects with Severe Insulin Resistance

Regan, Fiona; Williams, Rachel; McDonald, Anna; Umpleby, A. Margot; Acerini, Carlo L.; O’Rahilly, Stephen; Hovorka, Roman; Semple, Robert K.; Dunger, David B.

doi:10.1210/jc.2009-2088

Cited by 51 publications

(34 citation statements)

References 41 publications

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“…Several studies documented rhIGF-1 use in patients with severe IR syndromes (5–7, 20), and anecdotal evidence suggests further unpublished use. Decreases in insulin, but not glucose, were seen in two DS children treated with continuous IV rhIGF-1 for 66 and 62 h, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Weber

Stanescu

Semple

et al. 2014

Journal of Pediatric Endocrinology and Metabolism

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Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor (INSR) gene. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance due to INSR mutation(s). Traditional subcutaneous therapy may be limited by the shortened IGF-1 half-life in these patients. We report the case of a female with molecularly confirmed DS treated with continuous rhIGF-1 therapy via an insulin pump. With treatment, the patient’s hemoglobin A1c decreased from 9.8% to 8.8%, and her weight increased by 0.8 kg. Development of an ovarian tumor complicated her course, but it was unclear whether this was related to rhIGF-1 therapy. Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.

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Section: Discussionmentioning

confidence: 99%

“…In severe IR syndromes, IGFBP-3 levels are decreased and IGF-1 half-life was reported to be 1–3 h (8), vs. 17–20 h in normal individuals (21). An attempt to overcome this problem using a rhIGF-1/rhIGFBP-3 complex demonstrated decreased HbA1c and metabolic parameters, suggesting improved first phase insulin secretory response (20). …”

Section: Discussionmentioning

confidence: 99%

Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Weber

Stanescu

Semple

et al. 2014

Journal of Pediatric Endocrinology and Metabolism

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“…Mecasermin rinfabate is currently in clinical trials for the treatment of other diseases associated with poor growth, including amyotrophic lateral sclerosis (Lou Gehrig’s disease) and myotonic muscular dystrophy 2 . Improved insulin sensitivity in patients with severe insulin resistance was achieved recently by treatment with Mecasermin rinfabate, possibly by promoting improve beta cell function (Regan et al, 2010). …”

Section: Implications Of Igfbp Structural Studies For the Design Of Dmentioning

confidence: 99%

Insulin-Like Growth Factor Binding Proteins: A Structural Perspective

Forbes¹,

McCarthy²,

Norton³

2012

Front. Endocrin.

152

165

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Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development, as well as in disease.

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“…It was reported that abnormally low levels of IGF-1 and IGFBP-3 were found in the serum of diabetic patients compared to controls; IGF-1 and IGFBP-3 levels decreased significantly with age in diabetic patients [13]. Some have suggested that a rescue of IGFBP-3 may prevent the progression of diabetic retinopathy [14]. Previously, we found that IGFBP-3 decreases apoptosis in retinal endothelial cells in high glucose [15]; which was in agreement with other studies demonstrating that IGFBP-3 is neuroprotective, anti-apoptotic, and anti-inflammatory after retinal injury [16].…”

Section: Introductionmentioning

confidence: 99%

Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor

2013

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The goal of this study was to investigate whether insulin-like growth factor binding protein-3 receptor (IGFBP-3 receptor) is required for IGFBP-3 to inhibit retinal endothelial cell (REC) apoptosis. REC were grown in normal glucose (5 mM) or high glucose medium (25 mM) for 3 days. Once cells reached confluence, they were transfected with an endothelial- specific IGFBP-3 plasmid DNA (non-IGF binding; IGFBP-3 NB) at 1 μg/ml for 24 h. Cell proteins were extracted and analyzed for IGFBP-3 receptor expression by Western blotting or use in coimmunoprecipitation or co-localization experiments for detection of IGFBP-3 and IGFBP-3 receptor binding. REC were also transfected with or without IGFBP-3 receptor siRNA before IGFBP-3NB plasmid DNA transfection. Cell lysates were processed for a cell death ELISA, a cleaved caspase 3 ELISA, and Western blotting to measure key pro- and anti-apoptotic markers: Bcl-xL, Bax, Cytochrome C and Akt. The IGFBP-3 receptor is present on REC. Overexpression of IGFBP-3 in REC significantly increased protein levels of IGFBP-3 receptor (p < 0.05). Significant increases in cell death were found in cells transfected with IGFBP-3 receptor siRNA versus not treated samples (p < 0.05). Data suggest that IGFBP-3 inhibits retinal endothelial cell death through activation of an IGFBP-3 receptor in a hyperglycemic environment. This is the first demonstration of the involvement of IGFBP-3 receptor in inhibition of REC cell death. Future studies will investigate the mechanism by which IGFBP-3 receptor may inhibit retinal endothelial cell death.

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Treatment with Recombinant Human Insulin-Like Growth Factor (rhIGF)-I/rhIGF Binding Protein-3 Complex Improves Metabolic Control in Subjects with Severe Insulin Resistance

Abstract: rhIGF-I/rhIGFBP-3 is well tolerated and clinically effective in subjects with SIR.

Cited by 51 publications

References 41 publications

Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Insulin-Like Growth Factor Binding Proteins: A Structural Perspective

Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor

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