The increased insulin sensitivity in growth hormone‐deficient adults is reduced by growth hormone replacement therapy

Riedl, Valentin; Ludvik,; Pacini,; Clodi,; Kotzmann,; Wagner, Verena; Kautzky‐Willer,; Präger,; Luger,

doi:10.1046/j.1365-2362.2000.00695.x

Cited by 25 publications

(22 citation statements)

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“…However, evidence has accumulated suggesting that changes of systemic insulin sensitivity may be secondary to alterations in body composition (increase in visceral adiposity and decrease in lean mass) and not due to GHD per se (14,30). This is supported by studies showing AOGHD patients can have reduced (5) or normal (12) insulin levels and can even show improved insulin sensitivity compared with BMI-matched controls (28). In the current study, the pituitary defect was induced after sexual maturation and was selective for GH (10,22).…”

Section: Discussionmentioning

confidence: 99%

“…A wide spectrum of insulin sensitivity in AOGHD patients may be in part due to the length, severity, multiplicity, and etiology of pituitary deficiencies, leading to variable effects on body composition (1,9,14,30). In fact, insulin sensitivity was shown to be improved in AOGHD subjects compared with age-, sex-, and body mass index (BMI)-matched controls (28). Also, subjects with congenital isolated GHD resulting from an inactivating mutation in the growth hormone-releasing hormone (GHRH) receptor are more insulin sensitive compared with their unaffected relatives despite increased visceral adiposity and glucose intolerance (27,32).…”

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confidence: 99%

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Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

Córdoba-Chacón

Gahete

McGuinness

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Cordoba-Chacon J, Gahete MD, McGuinness OP, Kineman RD. Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice. Am J Physiol Endocrinol Metab 307: E928 -E934, 2014. First published September 30, 2014; doi:10.1152/ajpendo.00420.2014.-A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotropespecific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulinmediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency. growth hormone; hepatic glucose production; triglycerides; glucose disposal; hyperinsulinemic-euglycemic clamps HUMANS WITH LONG-TERM adult-onset growth hormone deficiency (AOGHD) have been reported to have impaired glucose tolerance (5, 27, 32), systemic insulin resistance, and increased hepatic glucose production [HGP;(12,16,24)], with a higher prevalence of diabetes (1). However, the direct impact of growth hormone deficiency (GHD) on insulin-mediated glucose homeostasis is not clear cut. AOGHD patients can show reduced (5), normal (12), or elevated (8) insulin levels. A wide spectrum of insulin sensitivity in AOGHD patients may be in part due to the length, severity, multiplicity, and etiology of pituitary deficiencies, leading to variable effects on body composition (1,9,14,30). In fact, insulin sensitivity was shown to be improved in AOGHD subjects compared with age-, sex-, and body mass index (BMI)-matched controls (28). Also, subjects with congenital isolated GHD resulting from an inactivating mutation in the growth hormone-releasing hormone (GHRH) receptor are more insulin sensitive compared with their unaffected relatives despite increased visceral adiposity and glucose intolerance (27,32). Glucose intolerance, with improved systemic insulin sensitivity [as measured by insulin tolerance tests (ITT)], is also observed in mouse models with GHD (7) and growth hormone (GH) resistance (11,13). Notably, the opposite metabolic phenotype (improved glucose tolerance with normal/reduced insulin sensitivity) is observed in mice with elevated heterologous (6) or endogenous (10) GH levels.The disconnect between systemic insulin sensitivity and glucose tolerance observed in mouse model systems and humans with isolated changes in GH production and signaling (6,7,10,...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

Córdoba-Chacón

Gahete

McGuinness

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Reports of diabetes mellitus and increased fasting blood glucose concentrations have been noted following initiation of GH therapy in children (10). A study in eight adults with GHD evaluated the effects of GH replacement on insulin sensitivity (26). In this investigation, serum fasting blood glucose and cholesterol concentrations, blood pressure, and body weight were unchanged after 18 months of GH replacement.…”

Section: Adverse Effects Of Gh Replacement Therapymentioning

confidence: 99%

“…This decrease in insulin sensitivity corresponded with an increase in basal and total insulin secretion during the study period. The investigators concluded that patients with a family history of diabetes mellitus or compromised b-cell function should be closely monitored for a worsening of glycaemic control during GH therapy (26).…”

Section: Adverse Effects Of Gh Replacement Therapymentioning

confidence: 99%

Long-term experience with GH replacement therapy: efficacy and safety

Monson¹

2003

European Journal of Endocrinology

108

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Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries.Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors. These beneficial effects are maintained for at least 2 years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance.Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density. Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions.GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 months of therapy and sustained during long-term follow-up.Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.

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“…Both acromegaly and GH treatment are described to induce insulin resistance (11,30). After treatment for acromegaly, the characteristic of insulin insensitive state for active acromegaly obviously does not recover, suggesting either a persistently increased pancreatic islet b-cell mass and/or peripheral insulin resistance (30,36,37). This might have primed patients with previous acromegaly for a steeper increase in HbA1c levels during GH treatment than patients with previous NFPA.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Effect of long-term GH replacement therapy on cardiovascular outcomes in GH-deficient patients previously treated for acromegaly: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults

Bunderen

Varsseveld

Heymans

et al. 2014

European Journal of Endocrinology

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Objective: The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA). Design: A nationwide surveillance study. Methods: Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated. Results: GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002-0.06, PZ0.04). The risk for developing cardiovascular diseases was not different between the groups. Conclusions: The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity.

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The increased insulin sensitivity in growth hormone‐deficient adults is reduced by growth hormone replacement therapy

Cited by 25 publications

References 55 publications

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

Long-term experience with GH replacement therapy: efficacy and safety

Effect of long-term GH replacement therapy on cardiovascular outcomes in GH-deficient patients previously treated for acromegaly: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults

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