89.Metformin & Growth Hormone

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89.Metformin & Growth Hormone

 

 

 

CATEGORY: Anabolic Steroids 100 Courses

COURSE NUMBER: 89

FEES: 555/- INR only

CERTIFICATE VALIDITY: Lifetime

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Syllabus

  1. ACKNOWLEDGEMENTS …………………………………………………………………………………………… 3
  2. ABBREVIATIONS …………………………………………………………………………………………………….. 4
  3. ABSTRACT ……………………………………………………………………………………………………………… 5
  4. INTRODUCTION ……………………………………………………………………………………………………… 6

4.1 GROWTH HORMONE DEFICIENCY ………………………………………………………………….. 6

4.2 GROWTH HORMONE TREATMENT …………………………………………………………………. 9

4.2.1 SOMATOTROPIN, INDICATIONS AND CONTRAINDICATIONS ………………………….. 9

4.2.2 DOSAGE AND RELATION TO ADULT HEIGHT ………………………………………………. 10

4.2.3 EFFICACY ……………………………………………………………………………………………….. 12

4.2.4 EFFECTS ON BONE AGE …………………………………………………………………………… 12

4.2.5 EFFECTS ON INSULIN AND METABOLIC PARAMETERS …………………………………. 13

4.2.6 ADVERSE EFFECTS AND SAFETY ………………………………………………………………… 15

4.3 METFORMIN ……………………………………………………………………………………………… 17

4.3.1 CONCEPT AND INDICATIONS ……………………………………………………………………. 17

4.3.2 EFFECTS ON INSULIN RESISTANCE…………………………………………………………….. 17

4.3.3 EFFECTS ON METABOLIC PARAMETERS …………………………………………………….. 18

4.3.4 SAFETY IN CHILDREN ………………………………………………………………………………. 18

4.4 LATEST OUTCOMES ……………………………………………………………………………………. 19

4.4.1 METFORMIN EFFECT ON AROMATASE………………………………………………………. 19

4.4.2 METFORMIN AND ITS RELATION TO HEIGHT ……………………………………………… 20

4.4.3 FRENCH ALERT ON GH USE ……………………………………………………………………… 21

4.4.4 METFORMIN AND GH ……………………………………………………………………………… 21

  1. JUSTIFICATION ……………………………………………………………………………………………………… 22
  2. HYPOTHESES ………………………………………………………………………………………………………… 24

6.1 MAIN HYPOTHESIS …………………………………………………………………………………….. 24

6.2 SECONDARY HYPOTHESES …………………………………………………………………………… 24

  1. OBJECTIVES ………………………………………………………………………………………………………….. 24

7.1 MAIN OBJECTIVE ……………………………………………………………………………………….. 24

7.2 SECONDARY OBJECTIVES …………………………………………………………………………….. 24

  1. METHODOLOGY …………………………………………………………………………………………………… 25

8.1 STUDY DESIGN …………………………………………………………………………………………… 25

8.2 STUDY POPULATION …………………………………………………………………………………… 25

8.3 SAMPLE SELECTION ……………………………………………………………………………………. 26

8.3.1 INCLUSION CRITERIA ………………………………………………………………………………. 27 2

8.3.2 WITHDRAWAL CRITERIA ………………………………………………………………………….. 30

8.4 SAMPLE SIZE ……………………………………………………………………………………………… 30

8.5 ENROLLMENT AND PATIENT SELECTION ……………………………………………………….. 31

8.6 RANDOMISATION ………………………………………………………………………………………. 32

8.7 VARIABLES AND INSTRUMENTATION ……………………………………………………………. 33

  1. INTERVENTION …………………………………………………………………………………………………….. 36

9.1 STUDY TREATMENT ……………………………………………………………………………………. 36

9.1.1 INTERVENTION DRUG ……………………………………………………………………………… 36

9.1.2 METFORMIN DOSAGE …………………………………………………………………………….. 36

9.1.3 TREATMENT DURATION ………………………………………………………………………….. 37

9.1.4 DRUG CHARACTERISTICS …………………………………………………………………………. 37

9.2 TREATMENT MONITORING …………………………………………………………………………. 40

9.3 MASKING ………………………………………………………………………………………………….. 40

9.3.1 PATIENT MASKING: PLACEBO ………………………………………………………………….. 40

9.3.2 INVESTIGATOR MASKING ………………………………………………………………………… 40

9.4 BASAL TREATMENT ……………………………………………………………………………………. 41

9.5 ORGANISATION AND DATA COLLECTION ………………………………………………………. 42

  1. FLOW CHART ……………………………………………………………………………………………………. 45
  2. STATISTICAL ANALYSIS ………………………………………………………………………………………. 46
  3. ETHICAL CONSIDERATIONS ………………………………………………………………………………… 48
  4. LIMITATIONS ……………………………………………………………………………………………………. 49
  5. WORK PLAN ……………………………………………………………………………………………………… 51
  6. TIMELINE …………………………………………………………………………………………………………. 54
  7. BUDGET …………………………………………………………………………………………………………… 55
  8. HEALTH IMPACT OF THE PROJECT ………………………………………………………………………. 58
  9. BIBLIOGRAPHY ………………………………………………………………………………………………….. 59
  10. ANNEX …………………………………………………………………………………………………………….. 63

Metformin & Growth Hormone


OBJECTIVE:
Obese women with polycystic ovary syndrome (PCOS) show a marked growth hormone (GH) hyporesponsiveness to several stimuli. We aimed to evaluate the impact of insulin metabolism on the GH secretion impairment in these subjects in relation to food ingestion.


DESIGN:
Prospective clinical study.


SETTING:
Academic research center.


PATIENT(S):
Nine obese women with PCOS.


INTERVENTION(S):
Metformin (1,500 mg/daily) was administered for three months. The study protocol, which was performed before and after therapy, included hormonal and lipid assays, oral glucose tolerance test (75 g), euglycemic hyperinsulinemic clamp, and growth hormone-releasing hormone (GHRH) test (50 microg/ev), both on fasting and after a standard meal.


MAIN OUTCOME MEASURE(S):
Growth hormone response to GHRH (expressed as the area under the curve) in different experimental conditions.


RESULT(S):
The preprandial GH response to GHRH was not modified by the therapy, whereas a significant increase (P<.05) occurred in the postprandial GH secretion, thus resembling the response of obese normal persons. This change was accompanied by a trend towards improvement, though not statistically significant, of all the evaluated glycoinsulinemic parameters. A significant reduction in cholesterol (P<.01) and androstenedione (P<.05) and an increase in sex hormone-binding globulin (P<.05) were also achieved.


CONCLUSION(S):
These data suggest that metformin is able to affect GH secretion in obese women with PCOS, even with minimal metabolic modifications.


Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP–dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
Metformin (1,1-dimetylbiguanide hydrochloride) is widely used for the treatment of type 2 diabetes (1). It lowers blood glucose levels, decreases levels of triglycerides and free fatty acid (FFA), improves glucose tolerance, and decreases insulin resistance by inhibition of hepatic glucose production (2,3). Metformin also increases glucose uptake and promotes fatty acid oxidation in peripheral tissues (4). AMP-activated protein kinase (AMPK) is stimulated by physiologic stimuli, such as exercise, hypoxia, and oxidative stress, and also by pharmacologic agents, metformin and thiazolidinediones (TZD), that lower blood glucose (5). AMPK is regulated by distinct upstream kinases, including Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β), LKB-1, transforming growth factor-β (TGF-β)–activated kinase-1 (Tak1), and ataxia telangiectasia mutated (ATM), a member of the phosphoinositide 3-kinase–related kinase family of protein kinases (5–7). AMPK functions as a master regulator of glucose and lipid homeostasis via its effects on target genes required for gluconeogenesis, lipogenesis, fatty acid oxidation, and lipolysis in diverse tissues (1,7).


The small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a classical DNA-binding domain but retains a putative ligand-binding domain (8). Widely expressed in tissues, SHP represses the transcriptional activity of several nuclear receptors and/or transcription factors, including hepatocyte nuclear factors-4α (HNF-4α), forkhead box class O1 (FoxO1), and HNF-3β/FoxA2, which play important roles in the regulation of glucose, lipid, and bile acid metabolism (8–10). Our previous studies have demonstrated that elevated gene expression of SHP is induced by pharmacologic agents, including metformin, hepatocyte growth factor (HGF), and sodium arsenite, all of which inhibit hepatic gluconeogenesis by repression of key transcription factors via an AMPK-SHP–dependent pathway (11–13). Moreover, loss of SHP exacerbates insulin resistance, hepatic fibrosis, inflammation, and bile acid homeostasis by increasing glucose intolerance and promoting the expression of profibrogenic or proinflammatory genes and the accumulation of bile acid (14–16).


Upon binding to its receptor, growth hormone (GH) activates the Janus kinase 2 (JAK2) and the downstream transcription factors signal transducer and activator of transcription 5 (STAT5) (17,18). Via its stimulation of IGF-I, GH stimulates anabolic processes that promote an increase in lean body mass. In conditions where food is not available and glucose levels are low, GH functions as a counter-regulatory hormone to insulin, stimulating the release of FFAs from the adipose tissue and the oxidation of FFA in the liver and peripheral tissues. In these conditions, GH antagonizes the action of insulin on glucose and lipid metabolism in most tissues (19), resulting in insulin resistance but preservation of lean muscle mass (20,21). Our previous findings have shown that loss of STAT5 causes liver fibrosis, hepatosteatosis, and insulin resistance by increasing TGF-β and STAT3 activation, fat mass, and intolerance of glucose and insulin (22,23).


Pyruvate dehydrogenase kinase (PDK) is a key regulator of pyruvate dehydrogenase complex (PDC) activity associated with the regulation of glucose oxidation (24). The PDC is activated by pyruvate dehydrogenase phosphatases through dephosphorylation in the well-nourished state but is inactivated by PDK via phosphorylation in response to fasting or the diabetic condition (25). Indeed, the expression of PDK4 is increased by starvation, diabetes, and insulin-resistance conditions in diverse tissues, whereas refeeding decreases PDK4 gene expression (26,27). Inactivation of PDC by upregulation of PDK4 conserves glucose and three carbon compounds that can be converted to glucose. Conservation of these three carbon compounds that can be recycled back to glucose conserves lean body mass by reducing the need for net glucose synthesis from amino acids (28), which is the same effect that GH exerts when food is sparse. Despite this, the potential importance of the regulation of PDC activity by GH had received little attention before a recent report that GH induces PDK4 expression in adipocytes (29). However, no study has monitored whether the effects of GH on liver metabolism can be explained in part by induction of PDK4. The current study shows this is the case. Likewise, whether the effects of GH on liver metabolism are sensitive to inhibition by metformin has not been investigated. Our findings indicate that the GH-activated STAT5-PDK4 signaling is sensitive to inhibition by a metformin-AMPK-SHP–dependent pathway and therefore may provide a new therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-dependent pathway.


Administration of growth hormone (GH) increases muscle mass in F344 × BN rats, but not in Sprague–Dawley (S-D) rats. S-D rats are insulin-resistant and insulin responsiveness is required for the anabolic actions of GH. We hypothesized that correction of insulin resistance with metformin might also restore anabolic effects of GH. Treatment with GH (0.25 or 1.0 mg/kg twice daily for 9 days) had limited anabolic effects, reducing weight gain by 14%, increasing muscle glycogen content by 40% and increasing exercise capacity by 24%, but failing to increase muscle mass or to reduce fat mass. GH also impaired insulin responsiveness and increased visceral fat TNF content of visceral fat by 77%. Metformin enhanced insulin responsiveness in skeletal muscle, but failed to enhance anabolic effects of GH. Rats aged 14 weeks were treated for 21 days with metformin (320 mg/kg/day) and for the last 9 days, with GH (0.25 mg/kg, twice daily). Metformin caused a 2.3-fold increase in insulin-stimulated muscle glucose transport and a 20% reduction in muscle fatty acid oxidation, indicating increased glucose utilization. However, metformin did not augment GH-induced weight reduction. Metformin decreased visceral fat by 22% and subcutaneous fat by 20%, but no decreases were observed in the GH/metformin group. GH increased muscle glycogen by 40%, but the effect was reversed by metformin. VO2max was increased 24% by GH and 17% by metformin, but was not elevated in the GH/metformin group. GH increased TNF in visceral fat and the effect was augmented by metformin (144% increase). We conclude that metformin enhances some aspects of insulin responsiveness, but does not enhance anabolic responses to GH. The latter may, in part, be explained by the failure of metformin to prevent GH-induced elevation of TNF in visceral fat.

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