Diabetes in chronic liver disease: from old concepts to new evidence.
Picardi A, D'Avola D, Gentilucci UV, Galati G, Fiori E, Spataro S, Afeltra A.
Internal Medicine and Hepatology Laboratory, Center of Interdisciplinary Investigations CIR, University Campus Bio-Medico of Rome, Via E. Longoni 83, I-00155 Rome, Italy. a.***@****
The liver is one of the principal organs involved in glucose metabolism together with skeletal muscle and adipose tissue. A link between diabetes and chronic liver disease (CLD) was first observed in the early half of the last century, but to date several questions remain unsolved. Altered glucose tolerance has been well described in alcoholic CLD, non-alcoholic fatty liver disease, chronic hepatitis C and portal hypertension. Moreover, insulin resistance is assuming an ever-growing importance in CLD; chronic hepatitis C has recently been proposed as a metabolic disease and insulin sensitivity as a predictive factor for liver fibrosis.CLD is also complicated by acquired growth hormone (GH) resistance, characterized by low concentrations of insulin-like growth factor-1 (IGF-1) with respect to normal or elevated GH levels. GH resistance in CLD is determined by several factors, including malnutrition, impaired liver function and reduced expression of hepatic GH receptors. We recently described the possible role of tumour necrosis factor-alpha (TNF-alpha) in blunting the hepatic response to GH in patients with chronic hepatitis C. The role of GH in impaired glucose metabolism is well known, and recent evidence suggests a receptor and/or post-receptor modulation of insulin signalling. Moreover, as in other chronic inflammatory conditions, pro-inflammatory cytokines may directly modulate the signal cascade that follows insulin binding to its receptor in the course of CLD.In this review, the proposed links between impaired glucose tolerance and CLD are analysed, special emphasis being focussed on the most recent findings concerning the interplay of chronic inflammation, GH resistance and insulin resistance. Copyright (c) 2006 John Wiley & Sons, Ltd.
Takahashi Y, Iida K, Takahashi K, Yoshioka S, Fukuoka H, Takeno R, Imanaka M, Nishizawa H, Takahashi M, Seo Y, Hayashi Y, Kondo T, Okimura Y, Kaji H, Kitazawa R, Kitazawa S, Chihara K.
Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. ***@****-u.ac.jp
BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is an emerging progressive hepatic disease and demonstrates steatosis, inflammation, and fibrosis. Insulin resistance is a common feature in the development of NASH. Molecular pathogenesis of NASH consists of 2 steps: triglyceride accumulation in hepatocytes with insulin resistance and an enhanced oxidative stress caused by reactive oxygen species. Interestingly, NASH demonstrates a striking similarity to the pathologic conditions observed in adult growth hormone deficiency (AGHD). AGHD is characterized by decreased lean body mass, increased visceral adiposity, abnormal lipid profile, and insulin resistance. Moreover, liver dysfunctions with hyperlipidemia and nonalcoholic fatty liver disease (NAFLD) are frequently observed in patients with AGHD, and it is accompanied by metabolic syndrome. METHODS: We studied a case diagnosed as NASH with hyperlipidemia in AGHD. The effect of GH-replacement therapy on the patient was analyzed. RESULTS: Six months of GH-replacement therapy in the patient drastically ameliorated NASH and the abnormal lipid profile concomitant with a marked reduction in oxidative stress. CONCLUSIONS: These results suggest that GH plays an essential role in the metabolic and redox regulation in the liver.
Somatomedin-1 (recombinant insulin-like growth factor-1): clinical pharmacology and potential treatment of endocrine and metabolic disorders.Laron Z.
Endocrine and Diabetes Research Unit, Schneider Children's Medical Center of Israel, Beilinson Campus, Petah Tikva, Sackler School of Medicine, Tel Aviv University, Israel.
Insulin-like growth factor (IGF-1) is a polypeptide of 70 amino acids. The circulatory form of IGF-1 is synthesised in the liver. The metabolic activity of IGF-1 is regulated by 6 IGF-binding proteins (BPs), the most important being IGFBP-3. IGF-1 acts via its own receptor, which resembles that of insulin. It has been demonstrated that the effects of growth hormone (GH) on protein metabolism, including growth and the effect on nerve tissue versus trophic effects, are mediated by IGF-1, whereas these 2 hormones are antagonistic in their effects on insulin and some aspects of lipid metabolism. This paper reviews present knowledge on the physiological role of IGF-1 and clinical effects of recombinant IGF-1 (somatomedin-1). The biosynthesis of somatomedin-1 in 1986 enabled the initiation of clinical trials. Somatomedin-1 has many potential uses in the clinic. The most important is replacement therapy in primary IGF-1 deficiency, such as Laron syndrome (primary GH resistance or insensitivity) and in patients who have developed antibodies to hGH. In Laron syndrome, which is characterised by dwarfism, somatomedin-1 stimulates growth and increases muscle and bone mass, as well as normalising blood chemistry. In types 1 and 2 (insulin-dependent and non-insulin-dependent) diabetes mellitus, somatomedin-1 increases the sensitivity to insulin and improves glucose utilisation. Experimental studies indicate that IGF-1 has a role in nerve tissue metabolism, and in humans may contribute to healing of injured nerve tissue. Other current clinical trials using the anabolic properties of somatomedin-1 are studying its effect on osteoporosis, catabolic states (burns, post-operation, AIDS) and haematopoietic disorders. Adverse effects of somatomedin-1 appear to be related to overdosage. In conclusion, somatomedin-1 is an important hormone which has a promising role as replacement therapy and appears to have many other potential applications in the clinic.
Am J Gastroenterol. 2007 Dec;102(12):2724-31. Epub 2007 Jul 27.Links
Hepatitis-C patients have reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-alpha.Plöckinger U, Krüger D, Bergk A, Weich V, Wiedenmann B, Berg T.
Interdisziplinäres Stoffwechsel-Centrum, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
OBJECTIVES: In vitro and in vivo data indicate multiple, but contradictory effects of interferon on pituitary hormone secretion. We therefore investigated prospectively basal and stimulated pituitary hormone secretion in 21 patients with chronic hepatitis C virus (HCV) infection before and during antiviral therapy. METHODS: Twenty-one patients received pegylated interferon-alpha plus either ribavirin or levovirin. Baseline and stimulated growth hormone (GH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and thyroid-stimulating hormone (TSH) responses were measured using standard pituitary function tests, before therapy in all and during therapy in 17 out of the 21 patients. RESULTS: Before therapy 17 patients (81%) had severe GH insufficiency and 9 of these had low insulin-like growth factor-1 (IGF-1) concentrations. Basal and stimulated GH concentrations increased significantly during therapy, reducing the number of patients with severe GH insufficiency to four, but IGF-1 remained low. Basal PRL and TSH concentrations were normal before and during therapy, while thyroid-releasing hormone (TRH)-stimulated concentrations increased significantly during therapy. The adrenocorticotropic hormone (ACTH)/cortisol axis, basal and stimulated gonadotropin, and testosterone concentrations were normal throughout. Neither the HCV RNA level nor transaminases correlated with hormone concentrations before or during therapy.
CONCLUSIONS: GH insufficiency is common in patients with chronic HCV infection. While GH secretion improves during antiviral therapy, IGF-1 remains low, indicating persistent GH resistance of hepatocytes. Whether improvement in GH secretion during treatment is due to a direct drug effect or related to the suppression of viral load could not be differentiated, as most patients demonstrated a positive virologic response.
I had asked my MD to check my HGH levels and he didn't think it was needed. I felt like I wasn't healing or aging appropriately. A small injury like falling during a run that used to heal up in a few days now takes more than 6 months and I am drying up quickly. My muscles feel like beef jerky and are so stiff/sore with no rebound. I know I am getting older but I was feeling worse than my 81 year old mother. I will push my doctor next time I go in. Has anyone else had their doctor check them for HGH and has been treated for it?
My IGF1 is low. I am a relapser.stage 3 on biopsy.Can GH replacement therapy help in SVR?