Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose

Clemmons, David R.; Moses, Alan C.; Sommer, Andreas; Jacobson, W.; Rogol, Alan D.; Sleevi, M.; Allan, Geoffrey

doi:10.1016/j.ghir.2005.05.002

Cited by 62 publications

(34 citation statements)

References 43 publications

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“…36 Although there are many studies using IGF-I as a therapeutic agent to treat dystrophic muscle wasting in an animal model, the mechanism by which IGF-I protects cells from oxidative stress is still not clear. This study has offered a rational mechanism by which IGF-I prevents muscle from contract-mediated damage in a dystrophic animal model.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

Yang

Hoy

Fuller

et al. 2010

Laboratory Investigation

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Oxidative stress has an important role in the pathogenesis of many muscle diseases. The major contributors to oxidative stress in muscle tissue are reactive oxygen species such as oxygen ions, free radicals, and peroxides. Insulin-like growth factor I (IGF-I) has been shown to increase muscle mass and promote muscle cell proliferation, differentiation, and survival. We, therefore, hypothesized that IGF-I might also be cytoprotective for muscle cells during oxidative stress. Exogenous hydrogen peroxide (H 2 O 2 ) was used to induce oxidative stress/damage in two types of skeletal muscle cells. Apoptotic pathways were assessed after the oxidative damage and the effects of IGF-I on oxidative stress in muscle cells were examined. Different IGF-I sub-pathways were analyzed with measurement of the expression of pro-and antiapoptotic proteins. It was found that H 2 O 2 diminishes muscle cell viability and induces a caspase-independent apoptotic cell death. Pretreatment with IGF-I protects muscle cells from H 2 O 2 -induced cell death and enhances muscle cells survival. This effect appears to result from the promotion of the anti-apoptotic protein, Bcl2. Further investigation shows that protection is via an IGF-I sub-pathway: PI3K/Akt and ERK1/2 MAPK pathways. Protecting muscle cells from oxidative damage presents a potential application in the treatment of the muscle wasting, which appears in many muscle pathologies including Duchenne muscle dystrophy and sarcopenia. Many pathological muscle conditions, such as Duchenne muscle dystrophy (DMD) and sarcopenia, have been found to be associated with an increase in oxidative stress. 1 DMD is a severe progressive X-linked muscle disease with the absence of dystrophin, a protein providing structural integrity on the muscle cell membrane. Owing to the fragility of the DMD muscle membrane, normal muscular contraction in DMD destabilizes the myocyte membrane, causing intracellular accumulation of calcium. This stimulates oxidative metabolism, which generates free radicals and triggers the key pathological processes. 2 Sarcopenia is a condition with degenerative loss of skeletal muscle mass and strength associated with ageing. Mitochondrial (Mt) production of reactive oxygen species (ROS) has been shown to increase in skeletal muscle over the course of ageing, 3 which in turn reduces bioenergetic efficiency and leads to muscle fiber atrophy/loss. 4 Although DMD and sarcopenia have different pathological properties, they share a common syndrome, that is, muscle wasting. Abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle wasting. 5 Oxidative stress results from the activities of the reactive compounds called ROS. ROS are natural by-products in the normal metabolism of oxygen and have important roles in cell signalling. ROS including oxygen ions, free radicals, and peroxides usually have highly reactive properties because of the presence of unpaired valence shell electrons. During physiological homeostasis overall oxidati...

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Section: Discussionmentioning

confidence: 99%

Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

Yang

Hoy

Fuller

et al. 2010

Laboratory Investigation

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“…54 When patients were treated with a combination of IGF-I and IGFBP-3, the side effects were markedly reduced even at higher doses. 55 However, serious side effects, including hypoglycemia, paresthesias, and episodes of Bell's palsy, were still observed in some patients with Type II diabetes. 55 Also, the finding that IGF-I treatment can lead to intracranial hypertension 56 deserves special attention with respect to the use of IGF-I in patients with ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

“…55 However, serious side effects, including hypoglycemia, paresthesias, and episodes of Bell's palsy, were still observed in some patients with Type II diabetes. 55 Also, the finding that IGF-I treatment can lead to intracranial hypertension 56 deserves special attention with respect to the use of IGF-I in patients with ischemic stroke. This side effect and its consequences may not have occurred after ICV administration of IGF-I due to the induction of a hole in the skull and meninges.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor I

Kooijman

Sarre²,

Michotte³

et al. 2009

Stroke

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Background and Purpose-Insulin-like growth factor I (IGF-I) exerts neuroprotective effects in both white and gray matter under different detrimental conditions. The purpose of this review is to collect the evidence whether IGF-I is a candidate neuroprotective drug in patients with acute ischemic stroke. Results-IGF-I was found to be neuroprotective in animal models of focal brain ischemia when given Ն2 hours after the insult. Different routes of administration (eg, cerebroventricular, intravenous, and intranasal) were found to be effective. In addition to inhibition of apoptosis and reduction of the infarct volume, IGF-I also improved neurological outcome.

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“…In a recent study, recombi-nant human IGF (rhIGF)-I/rhIGFBP-3 administration to type 2 diabetics resulted in a 34 -38% decrease in fasting glucose. Despite administering an equimolar amount of both proteins, the ratio of IGF-I to IGFBP-3 increased from 0.25 to 1.04 (12). This study was undertaken to determine the dose of the IGF-I/IGFBP-3 complex necessary to achieve a glucose lowering response, to compare the maximum glucose lowering effect to subjects treated with intensive insulin therapy alone, and to determine the changes that occur in the components of the IGF system in response to IGF-I/IGFBP-3 administration.…”

mentioning

confidence: 99%

“…In type 2 diabetics, this response could be demonstrated whether the subjects were receiving insulin or oral hypoglycemic agents, or both (2,3). Although administration of the complex of IGF-I and IGFBP-3 (the principle serum IGFBP) might be expected to lead to attenuation of IGF-I actions, administration of this complex was efficacious in lowering mean daily glucose and insulin requirements in type 1 diabetics (7), and in lowering fasting blood glucose in patients with type 2 diabetes who were receiving insulin (12). The mechanism by which IGF-I administration acts to lower blood glucose has not been definitively established.…”

mentioning

confidence: 99%

Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes

Clemmons

Sleevi

Allan

et al. 2007

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined. Objectives: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment. Design: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125–2.0 mg/kg·d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets. Results: Fasting glucose was reduced in the groups that received either 1 (32 ± 5% reduction) or 2 mg/kg·d (40 ± 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 ± 4% in the 1 mg/kg group and by 33 ± 5% in the 2 mg/kg group compared with 18 ± 4% in the placebo group. Total serum IGF-I increased between 2.0 ± 0.3- and 5.7 ± 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 ± 4% and 64 ± 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment. Conclusions: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.

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Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose

Cited by 62 publications

References 43 publications

Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

Insulin-Like Growth Factor I

Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes

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