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; Dunger, David

doi:10.1210/edrv.31.2.9978

Cited by 12 publications

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“…Alternatively, it is possible that TAAD may protect against the development of diabetes. TAAD is associated with increased circulating concentrations of insulin‐like growth factor 1, an endocrine peptide with potent antidiabetic effects . Further experimental evidence will be required to determine the plausibility of these various pathophysiologic explanations for our findings.…”

Section: Discussionmentioning

confidence: 87%

Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Prakash

Pedroza

Khalil

et al. 2012

JAHA

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Section: Discussionmentioning

confidence: 87%

Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Prakash

Pedroza

Khalil

et al. 2012

JAHA

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“…However, it is important to note that IGF-1 is approved for human use for growth disorders in children and the combination of IGF-1 complexed to its main circulating binding protein, IGFBP-3, may have advantages versus direct IGF-1 delivery. 55…”

Section: Discussionmentioning

confidence: 99%

Smooth Muscle Cell–Specific Insulin-Like Growth Factor-1 Overexpression in Apoe ^−/− Mice Does Not Alter Atherosclerotic Plaque Burden but Increases Features of Plaque Stability

Shai

Sukhanov

Higashi

et al. 2010

ATVB

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Objective-Growth factors may play a permissive role in atherosclerosis initiation and progression, in part via their promotion of vascular smooth muscle cell (VSMC) accumulation in plaques. However, unstable human plaques often have a relative paucity of VSMC, which has been suggested to contribute to plaque rupture and erosion and to clinical events. Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that is a mitogen for VSMC, but when infused into Apoe Ϫ/Ϫ mice it paradoxically reduces atherosclerosis burden. Methods and Results-To determine the effect of stimulation of VSMC growth on atherosclerotic plaque development and to understand mechanisms of IGF-1's atheroprotective effect, we assessed atherosclerotic plaques in mice overexpressing IGF-1 in smooth muscle cells (SMC) under the control of the ␣-smooth muscle actin promoter, after backcrossing to the Apoe Ϫ/Ϫ background (SMP8/Apoe Ϫ/Ϫ ). Compared with Apoe Ϫ/Ϫ mice, these SMP8/Apoe Ϫ/Ϫ mice developed a comparable plaque burden after 12 weeks on a Western diet, suggesting that the ability of increased circulating IGF-1 to reduce plaque burden was mediated in large part via non-SMC target cells. However, advanced plaques in SMP8/Apoe Ϫ/Ϫ mice displayed several features of plaque stability, including increased fibrous cap area, ␣-smooth muscle actin-positive SMC and collagen content, and reduced necrotic cores. Traditionally, the role of growth factors in atherosclerosis has been thought to be permissive and to promote neointima formation. 6 -8 Insulin-like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that exerts pleiotropic effects on cells involved in atherogenesis. 9 Notably, it has mitogenic and antiapoptotic actions on endothelial cells and VSMC and stimulates VSMC migration. 10 Consistent with the role of IGF-1 as a VSMC mitogen, most [11][12][13][14] but not all 15 studies using inhibitors have demonstrated that reduced VSMC IGF-1 signaling correlates with decreased neointimal responses to mechanical arterial injury. Furthermore, targeted overexpression of IGF-1 in SMC increases neointimal formation. 16 However, although mechanical arterial injury models provide much information about the restenotic process, they have significant limitations when addressing mechanisms of atherogenesis, and the role of VSMC IGF-1 in the latter process remains unclear. Conclusion-TheseWe have previously shown that oxidized low-density lipoprotein downregulates IGF-1 and IGF-1 receptor expression in VSMC 17,18 and that expression of IGF-1 and IGF-1 receptor is reduced in areas of advanced human plaque staining positive for oxidized low-density lipoprotein. 19 These findings suggest that decreased IGF-1 activity could contribute to the atherosclerotic process and notably to depletion of VSMC in advanced unstable plaque. Similar findings have been reported in cultured plaque-derived VSMC. 20 We recently reported that infusion of recombinant human IGF-1 into Apoe-deficient mice on a Western diet for ...

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“…Indeed, because being unresponsive to insulin treatment, these patients may benefit from rhIGF-1 treatment, which has been shown to 'shortcut' the insulin signalling pathway blockade. Subcutaneous rhIGF-1 administration in selected patients with a type A phenotype of severe insulin resistance and diabetes mellitus enhances insulin sensitivity, as shown by the decrease in endogenous insulin levels, normalizing the response to intravenous insulin and reducing plasma glucose, as well as HbA 1c (glycated haemoglobin) [305,306]. A comparison of two rhIGF-1 dose regimens in severely insulin-resistant insulin-treated patients has shown that a short protocol with a high dose of rhIGF-1 (80 μg/kg of body weight, twice a day) was more effective in lowering fasting plasma glucose and serum insulin levels [307].…”

Section: Insulin Resistance and Diabetesmentioning

confidence: 99%

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

et al. 2011

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IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti-thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti-thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine.

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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

Cited by 12 publications

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Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Smooth Muscle Cell–Specific Insulin-Like Growth Factor-1 Overexpression in Apoe ^−/− Mice Does Not Alter Atherosclerotic Plaque Burden but Increases Features of Plaque Stability

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

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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

Cited by 12 publications

References 0 publications

Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Diabetes and Reduced Risk for Thoracic Aortic Aneurysms and Dissections: A Nationwide Case‐Control Study

Smooth Muscle Cell–Specific Insulin-Like Growth Factor-1 Overexpression in Apoe −/− Mice Does Not Alter Atherosclerotic Plaque Burden but Increases Features of Plaque Stability

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

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Smooth Muscle Cell–Specific Insulin-Like Growth Factor-1 Overexpression in Apoe ^−/− Mice Does Not Alter Atherosclerotic Plaque Burden but Increases Features of Plaque Stability