Chronic supplementation of beta-hydroxy-beta methylbutyrate (HMB) increases the activity of the GH/IGF-I axis and induces hyperinsulinemia in rats

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes, São Paulo/SP, Brazil.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society (Impact Factor: 1.41). 04/2011; 21(2):57-62. DOI: 10.1016/j.ghir.2010.12.006
Source: PubMed


Beta-hydroxy-beta-methylbutyrate (HMβ) is a metabolite of leucine widely used for improving sports performance. Although HMβ is recognized to promote anabolic or anti-catabolic effects on protein metabolism, the impact of its long-term use on skeletal muscle and/or genes that control the skeletal protein balance is not fully known. This study aimed to investigate whether chronic HMβ treatment affects the activity of GH/IGF-I axis and skeletal muscle IGF-I and myostatin mRNA expression.
Rats were treated with HMβ (320mg/kg BW) or vehicle, by gavage, for 4 weeks, and killed by decapitation. Blood was collected for evaluation of serum insulin, glucose and IGF-I concentrations. Samples of pituitary, liver, extensor digitorum longus (EDL) and soleus muscles were collected for total RNA or protein extraction to evaluate the expression of pituitary growth hormone (GH) gene (mRNA and protein), hepatic insulin-like growth factor I (IGF-I) mRNA, skeletal muscle IGF-I and myostatin mRNA by Northern blotting/real time-PCR, or Western blotting.
Chronic HMβ treatment increased the content of pituitary GH mRNA and GH, hepatic IGF-I mRNA and serum IGF-I concentration. No changes were detected on skeletal muscle IGF-I and myostatin mRNA expression. However, the HMβ-treated rats although normoglycemic, exhibited hyperinsulinemia.
The data presented herein extend the body of evidence on the potential role of HMβ-treatment in stimulating GH/IGF-I axis activity. In spite of this effect, HMβ supplementation also induces an apparent insulin resistance state which might limit the beneficial aspects of the former results, at least in rats under normal nutritional status and health conditions.

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    • "While several studies have observed an upregulation of certain target proteins in the mTOR pathway [17] [18], less is known about upstream components of the insulin-like growth factor-1 (IGF-1) dependent pathway [19]. Gerlinger- Romero and colleagues [19] observed increased growth hormone (GH) and hepatic IGF-1 expression, which corresponded to increased serum concentrations as a result of four weeks of HMB administration in male rats, suggesting that the effects of HMB may be mediated via IGF-1 activation of the mTOR cascade. While chronic HMB-Ca supplementation "
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    ABSTRACT: Objective. To examine the endocrine response to a bout of heavy resistance exercise following acute β-hydroxy-β-methylbutyrate free acid (HMB-FA) ingestion. Design. Twenty resistance trained men were randomized and consumed either 1 g of HMB-FA (BetaTor) or placebo (PL) 30 min prior to performing an acute heavy resistance exercise protocol. Blood was obtained before (PRE), immediately after (IP), and 30 min after exercise (30P). Circulating concentrations of testosterone, growth hormone (GH), insulin-like growth factor (IGF-1), and insulin were assayed. Data were analyzed with a repeated measures ANOVA and area under the curve (AUC) was analyzed by the trapezoidal rule. Results. The resistance exercise protocol resulted in significant elevations from PRE in testosterone , GH , and insulin at IP, with GH and insulin remaining elevated at 30P. A significant interaction was noted between groups in the plasma GH response at IP, which was significantly higher following HMB-FA compared to PL . AUC analysis revealed an elevated GH and IGF-1 response in the HMB-FA group compared to PL. Conclusion. HMB-FA prior to resistance exercise augments the GH response to high volume resistance exercise compared to PL. These findings provide further support for the potential anabolic benefits associated with HMB supplementation.
    International Journal of Endocrinology 03/2015; 2015:1-7. DOI:10.1155/2015/856708 · 1.95 Impact Factor
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    • "Previous studies of our laboratory have suggested an association of HMB supplementation with insulin resistance state in healthy sedentary rats. It was detected in this condition an increased activity of the GH/IGF-I axis (Gerlinger-Romero et al. 2011), which is known to impair the insulin sensitivity (Smith et al. 1997, Cho et al. 2006). "
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    ABSTRACT: AimInvestigate, in healthy sedentary rats, the potential mechanisms involved on the effects of beta hydroxy beta methylbutyrate (HMB) supplementation upon the glycemic homeostasis, by evaluating the insulin sensitivity in liver, skeletal muscle, and white adipose tissue.Methods Rats were supplemented with either beta hydroxy beta methylbutyrate (320 mg kg−1 BW) or saline by gavage for 4 weeks. After the experimental period, the animals were subjected to the glucose tolerance test (GTT) and plasma non-esterified fatty acids (NEFA) concentration measurements. The soleus skeletal muscle, liver and white adipose tissue were removed for molecular (western blotting and RT-PCR) and histological analysis.Results: The beta hydroxy beta methylbutyrate supplemented rats presented: 1) higher ratio between the area under the curve (AUC) of insulinemia and glycemia during glucose tolerance test; 2) impairment of insulin sensitivity on liver and soleus skeletal muscle after insulin overload; 3) reduction of glucose transporter 4 (GLUT 4) total and plasma membrane content on soleus; 4) increased hormone sensitive lipase (HSL) mRNA and protein expression on white adipose tissue and plasma non-esterified fatty acids (NEFA) levels and 5) reduction of fibre cross-sectional area of soleus muscle.Conclusion The data altogether indicate that beta hydroxy beta methylbutyrate supplementation impairs insulin sensitivity in healthy sedentary rats, which, in the long-term, could lead to an increased risk of developing type 2 diabetes.This article is protected by copyright. All rights reserved.
    Acta Physiologica 06/2014; 212(1). DOI:10.1111/apha.12336 · 4.38 Impact Factor
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    • "However, such hypothesis still remains to be tested in HMB-supplemented rats or volunteers. Despite the absence of glucose tolerance data, it is important to highlight that healthy human subjects (Rathmacher et al. 2004) or rats (Nunes et al. 2008; Gerlinger-Romero et al. 2011; Pimentel et al. 2011) seem to present fasting glycemia between normal ranges after HMB supplementa- tion. We demonstrated that rats receiving HMB concomitant to DEX had higher glucose AUC values during the ipGTT compared with rats receiving only DEX. "
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    ABSTRACT: Glucocorticoid (GC) excess alters glucose homeostasis and promotes modifications in murinometric and anthropometric parameters in rodents and humans, respectively. β-hydroxy-β-methylbutyrate (HMB), a leucine metabolite, has been proposed as a nutritional strategy for preventing muscle wasting, but few data regarding its effects on glucose homeostasis are available. Here, we analyzed whether the effects of GC excess on glucose homeostasis may be attenuated or exacerbated by the concomitant ingestion of HMB. Adult Wistar rats (90-days-old) were assigned to four groups: (1) vehicle treated (Ctl), (2) dexamethasone (DEX) treated (Dex), (3) HMB treated (Hmb), and (4) DEX plus HMB treated (DexHmb). Dex groups received DEX (1 mg·kg body weight (BW)(-1), intraperitoneal) for 5 consecutive days. HMB groups ingested HMB (320 mg·kg BW(-1), oral gavage) for the same 5 days. HMB ingestion did not attenuate the effects of DEX on food intake and body weight loss, changes in masses of several organs, insulin resistance, and glucose intolerance (p > 0.05). In fact, in DexHmb rats, there was increased fasting glycemia and exacerbated glucose intolerance with the main effect attributed to DEX treatment (p < 0.05). HMB exerted no attenuating effect on plasma triacylglycerol levels from DexHmb rats, but it seems to attenuate the lipolysis induced by β-adrenergic stimulation (20 μmol·L(-1) isoproterenol) in fragments of retroperitoneal adipose tissue from DexHmb rats. Therefore, HMB does not attenuate the diabetogenic characteristics of GC excess. In fact, the data suggest that HMB may exacerbate GC-induced glucose intolerance.
    Applied Physiology Nutrition and Metabolism 11/2013; 38(11):1137-46. DOI:10.1139/apnm-2012-0456 · 2.34 Impact Factor
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