IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

Carroll, Paul; Christ, Emanuel; Umpleby, A. Margot; Gowrie, I; Jackson, Nicola; Bowes, S. B.; Hovorka, Roman; Croos, P; Ph, Sönksen; Russell-Jones, DL

doi:10.2337/diabetes.49.5.789

Cited by 45 publications

(28 citation statements)

References 44 publications

(42 reference statements)

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“…The mechanism of insulin resistance in subjects with NASH may be related to levels of insulin-like growth factor, an independent affector of insulin sensitivity. [42][43][44][45] Free insulin-like growth factor levels were lower in patients with NASH than in either obese or lean controls in these experiments, although the differences did not reach statistical significance. The higher levels of nonessential fatty acids, ␤-hydroxybutyrate, and glycerol that were observed in this study in patients with NASH when compared with lean controls, despite higher circulating insulin levels, also point to insulin resistance.…”

Section: Discussionmentioning

confidence: 65%

Apolipoprotein synthesis in nonalcoholic steatohepatitis

et al. 2002

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The pathophysiology of hepatic steatosis, a prerequisite of nonalcoholic fatty liver disease, is poorly understood. Because very-low-density lipoprotein (VLDL) formation is the chief route of hepatic lipid export, we hypothesized that the synthesis of apoB-100, a rate-determining step in hepatic VLDL formation, may be altered in patients with nonalcoholic steatohepatitis (NASH). This study evaluated the relative synthesis rates of apolipoprotein B-100 (apoB-100) in patients with NASH and in lean and body mass index (BMI)-matched (obese) controls without NASH. A primed continuous infusion of L-[1-13 C] leucine was used to measure the absolute synthesis rates (ASR) of apoB-100 and fibrinogen in 7 patients with NASH and compared them with 7 lean and 7 obese (BMI-matched) controls without NASH. The ASRs of fibrinogen and albumin also were measured. The mean ASR of apoB-100 in patients with NASH was lower (31.5 ؎ 3.4 mg/kg/d) than that of obese (115.2 ؎ 7.2 mg/kg/d, P < .001) and lean controls (82.4 ؎ 4.1 mg/kg/d, P ‫؍‬ .002). In contrast, the mean ASR of fibrinogen was greater in subjects with NASH than in both control groups. These data indicate that NASH is associated with markedly altered hepatic synthesis of apoB-100. The finding that albumin synthesis was not similarly decreased in patients with NASH shows that the attenuation of apoB-100 synthesis is not on the basis of globally impaired hepatic protein synthesis. In conclusion, because apoB-100 synthesis is a rate-determining step in hepatocyte lipid export, decreased synthesis of this protein may be an important factor in the development of hepatic steatosis, a prerequisite for NASH. (HEPATOLOGY 2002;35:898-904.) N on-alcoholic steatohepatitis (NASH; part of the spectrum of nonalcoholic fatty liver disease) is characterized by macrovesicular steatosis, nuclear glycogenation, lobular and portal inflammation, and, occasionally, Mallory's hyaline, in the absence of excessive alcohol ingestion. 1 NASH is most frequently associated with obesity 2-9 and type 2 diabetes mellitus. 3,[7][8][9] Despite the high prevalence and the increasingly recognized morbidity associated with NASH, little is known about the pathophysiology of this condition. The liver is central to the regulation of fat metabolism, and the net accumulation of fat within hepatocytes, a prerequisite for steatosis and steatohepatitis, could potentially result from alterations in the uptake, synthesis, degradation, or secretory pathways of hepatic lipid metabolism.Apolipoprotein B-100 (apoB-100) is a large protein (512 kd) involved in the transport of triglycerides and cholesterol from the liver to peripheral tissues. Lipids are chiefly exported from the liver in the form of very-lowdensity lipoproteins (VLDL), a complex of protein (apoB-100), lipids (triglycerides or cholesteryl esters), and phospholipids. Although the mechanisms regulating the synthesis of apoB-100 are incompletely understood, the production of apoB-100 messenger RNA (mRNA) has been shown to be altered by insulin and unaffected by...

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Section: Discussionmentioning

confidence: 65%

Apolipoprotein synthesis in nonalcoholic steatohepatitis

et al. 2002

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“…Recombinant IGF-I has been produced on a large scale and has been in clinical trials for a variety of pathological conditions including growth failure, 34 type I 35 and type II diabetes. 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.…”

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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“…Somente a administração direta da insulina no sistema-porta pode restaurar essas anormalidades. Entretanto, observações que a correção dos níveis de IGF-1 com IGF-1 humano recombinante (rhIGF-1) diminui o GH, melhora a sensibilidade à insulina e reduz a necessidade insulínica para a euglicemia, estimularam o interesse no potencial do rhIGF-1 como terapia adjuvante à insulina nos indivíduos DM1 (40).…”

Section: Igf-1unclassified

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1

Gabbay

2008

Arq Bras Endocrinol Metab

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RESuMOdesde o diabetes control and complications trial (dcct), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. o objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. outros modos de ação [pirenzepina, fator de crescimento insulina-símile (igF-1) e peptídeo semelhante ao glucagon 1 (glP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5% a 1% na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina. ABStRActAdjunctive therapies to Glycaemic control of type 1 Diabetes Mellitus. since diabetes control and complications trial (dcct), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. the objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor i and glucagon-like peptide-1). Many of these agents have been found to be effective in shortterm studies with decreases in HbA1c of 0.5-1%, lowering postprandial blood glucose levels and decreasing daily insulin doses.

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IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

Cited by 45 publications

References 44 publications

Apolipoprotein synthesis in nonalcoholic steatohepatitis

Apolipoprotein synthesis in nonalcoholic steatohepatitis

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

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1

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