Conversely, Van Cauter et al. If indeed involved, GH therefore seems to act as a permissive factor rather than a prime generator of the dawn phenomenon; as pointed out by Clore, Blackard, and co-workers , , it is credible that increased early morning insulin requirements may predominantly be explained by transient sleep-correlated decrements in glucose appearance and disposal, as well as diminished insulin demands, and a subsequent normalization of these parameters at arousal waning of insulin action from precedent meals may also be involved.
Adding to the lack of clarity in the field, it has been reported that administration of very low GH doses may actually improve insulin sensitivity in GHD subjects This could relate to the fact that when low doses of GH are administered long before metabolic assessment, the direct insulin antagonistic actions of GH have waned and the insulin agonistic effects of IGF-I and increased LBM prevail.
On the whole, it is beyond doubt that GH may contribute significantly to the overall insulin resistance in type 1 diabetes and also acts as an initiator of the vicious circles leading to acute metabolic derangement. It is also likely that GH plays a permissive role in the pathogenesis of the dawn phenomenon. As in other stress states, GH plays a beneficial role in the protection against hypoglycemia. Fasting hypoglycemia is a frequent occurrence in GH-naive children with isolated GH deficiency Moreover, GHD children with symptomatic hypoglycemia exhibit lower elevations in both glucose and insulin during exposure to oral glucose and iv arginine, respectively.
Finally, GHD children are hyperresponsive to insulin, including a delayed recovery from hypoglycemia in response to iv insulin. Based on assessment of glucose turnover rates, fasting hypoglycemia in GHD children is attributable to decreased hepatic glucose production HGP rather than an increase in peripheral glucose uptake It was therefore somewhat unexpected when Beshyah et al.
Johansson et al. In both studies, fasting levels of plasma glucose and insulin were comparable between patients and controls. Similar results have been obtained by Hew et al.
In the latter study, duration of GH deficiency was the single most important predictor of insulin resistance The mechanisms underlying the impairment of insulin sensitivity in long-standing untreated GHDA are unclear, but one plausible candidate is increased FFA flux from visceral fat because visceral adiposity is a hallmark of adult GH deficiency.
In this regard, it is noteworthy that a normal body mass index does not exclude visceral obesity Continued GH infusion was associated with reduced basal rates of glucose oxidation and reciprocal changes in lipid oxidation. Insulin sensitivity was increased relative to control subjects during saline infusion and became reduced during GH infusion to a level comparable to the control group Fig. Fasting plasma levels of glucose and insulin increased after 6 wk of GH but returned toward baseline values after 26 wk.
In an open design, O'Neal et al. Based on frequent sampling of arterialized blood for min after an iv glucose load, several indices of insulin kinetics and sensitivity were calculated. Fasting plasma levels of glucose increased after 1 wk but normalized after 3 months.
This was associated with sustained elevations in fasting insulin levels and unaltered HbA1c levels. In addition, insulin sensitivity decreased significantly in concomitance with a reciprocal rise in FFA levels after 1 wk of GH.
By 3 months, most parameters had returned to pretreatment levels, apart from modest hyperinsulinemia. Of note, the patients at baseline were insulin resistant compared with a healthy, normal-weight reference group In a placebo-controlled study using a similar GH dose in adult-onset GHDA, 4-month GH treatment was associated with sustained insulin resistance calculated from an iv glucose tolerance test Moreover, the so-called disposition index, which is the product of the first phase insulin response and insulin sensitivity, was reduced after GH treatment, indicating that the insulin response was not sufficiently increased to compensate for the reduction in insulin sensitivity This contrasts with O'Neal et al.
A number of studies have assessed insulin sensitivity or glucose tolerance before and after 6 months of GH replacement in a parallel, placebo-controlled design followed by an open phase of additional GH treatment for up to 12 months — An increase in fasting insulin levels was recorded after 6 months in two studies , , which in one case was associated with a small increase in fasting plasma glucose levels Beshyah et al.
Hwu et al. During prolonged open GH treatment, the impairment of insulin sensitivity and glucose tolerance prevailed , , with the exception of the study by Hwu et al. In a open design including 10 young patients with childhood-onset GHD, 9-month GH replacement in a final daily dose of approximately 0. Christopher et al. Based on measurements of total glucose levels and glucose 6-phosphate content in muscle biopsies, the authors hypothesized that a prime defect in glucose disposal at the level of glucose phosphorylation exists in GHD patients both before and after GH therapy Of note, the insulin disposition index was not reduced after GH treatment for 30 months, which contrasts with the short-term study from the same group Effects of continuation vs.
Lipid oxidation estimated by indirect calorimetry; protein oxidation estimated from urinary urea excretion; insulin sensitivity estimated by a euglycemic clamp in combination with a glucose tracer infusion.
A group of healthy, age- and sex-matched subjects were studied once without treatment. Data from two observational studies lasting 4 and 5 yr reported normalization of glucose tolerance and insulin sensitivity , respectively.
Euglycemic glucose clamps in combination with glucose tracer infusions were performed in 11 GHDA at baseline and subsequently after 6 months and 1, 2, and 7 yr of GH replacement The daily GH dose was gradually lowered from approximately 1 mg to approximately 0.
Fasting blood glucose levels were transiently increased during the first year of treatment, whereas fasting morning levels of insulin and FFA remained completely stable Basal hepatic glucose output remained increased after GH replacement, whereas insulin sensitivity assessed by a glucose clamp decreased significantly during the first year with a nadir at 6 months.
After 7 yr, insulin sensitivity was comparable to baseline levels A subsequent, quasi-controlled study of 10 yr GH replacement in adult-onset patients did not detect changes in fasting levels of glucose, insulin, or C-peptide There is no evidence to suggest that GH replacement therapy is associated with either increased urinary albumin excretion or retinal changes , The impact of discontinuing GH replacement after completion of longitudinal growth on body composition and glucose homeostasis has been addressed in a number of trials — Johannsson et al.
Fasting blood glucose levels were in the normal range and did not change in either group during the 2 yr, whereas the levels of HbA1c and fasting insulin decreased slightly, but significantly, in both patient groups Norrelund et al.
The patients were randomized to either continued GH replacement or placebo for 12 months, followed by 12 months of open-labeled GH therapy in both groups. In the group that continued GH therapy, no significant changes were recorded in insulin sensitivity.
By contrast, placebo treatment was accompanied by increased insulin sensitivity despite a concomitant increase in fat mass Fig. After resumption of GH treatment in that group, fat mass decreased together with insulin sensitivity In an open design, Carroll et al.
Cessation of GH resulted in increased insulin sensitivity, but no significant change was seen during 12 months of GH continuation Effects of discontinuation of GH replacement therapy for 1 yr in GHD patients in the transition phase from childhood to adulthood on total body fat and insulin sensitivity.
The patients were studied at baseline on GH therapy black bar , after 1 yr of placebo treatment gray bar , and subsequently after 1 yr of resumed GH replacement white bar. Total body fat was measured by dual-energy x-ray absorptiometry, and insulin sensitivity was measured by a euglycemic clamp.
The ability of GH replacement to increase LBM is well documented , , whereas relatively few studies have investigated the underlying changes in protein metabolism. In all studies, the turnover rates of leucine remained unchanged, whereas protein synthesis increased at the expense of oxidation.
Shi et al. In two other studies of protein kinetics in the fed state, improved protein balances were observed after 1 and 2 months of GH replacement, respectively , In support of the significance of substrate availability for the protein-conserving effects of GH replacement, Norrelund et al. Hallmarks of adult-onset GH deficiency include visceral obesity, reduced LBM, and impaired physical fitness, which may result from a combination of prolonged GH deficiency, i.
Impairment of glucose tolerance as well as insulin sensitivity after GH substitution is almost unanimously reported Fig. Experimental studies suggest that FFA play a causal role in the development of insulin resistance associated with GH substitution by demonstrating that coadministration of acipimox is able to restore insulin sensitivity Fig.
The explanation why insulin sensitivity and glucose tolerance tend to improve or normalize during more prolonged GH substitution is not proven, but it is probably a combination of a gradual reduction in GH dosage and favorable effects of GH on body composition and physical fitness.
The observation, however, that placebo-controlled discontinuation of GH substitution for 1 yr improves insulin sensitivity despite accumulation of fat mass underscores that induction of absolute or relative insulin resistance is an inherent attribute of conventional GH substitution. Acipimox blocks lipolysis by inhibition of the hormone sensitive lipase.
A, Serum FFA levels in the basal state and during a euglycemic clamp on each occasion. B, Insulin sensitivity assessed by the euglycemic clamp. Results of meta-analysis of GH effects on cardiovascular risk factors.
Stimulation of lipolysis in concomitance with increased protein synthesis and reduced protein oxidation is also observed when GH is used as replacement therapy. The observation that protein synthesis in the fed state reaches a steady state after prolonged GH replacement is not surprising, but it is noteworthy that the protein-conserving actions seem to prevail in the fed state and become accentuated during fasting where lipid oxidation is concomitantly stimulated.
Hyperinsulinemia, impaired glucose tolerance, and overt diabetes mellitus are common features of active acromegaly , , and it is likely, albeit not formally demonstrated, that these abnormalities contribute to the observed increase in cardiovascular morbidity and mortality , This section will deal mainly with studies focusing on glucose tolerance and insulin sensitivity in acromegaly before and after surgery and medical treatment. Elevated basal HGP, together with hepatic and peripheral resistance to insulin stimulation and increased glucose cycling, was recorded in a study employing infusion of different glucose tracers in the basal state and during an OGTT Hansen et al.
The GIRs during the clamps were significantly lower in the patients at any insulin infusion rate, which was accompanied by elevated HGP at the two lower insulin infusion rates Insulin resistance in skeletal muscle in terms of reduced nonoxidative glucose disposal has also been documented with the forearm technique in combination with indirect calorimetry Moller et al.
In the basal state, plasma levels of insulin and glucose were significantly elevated before surgery and became normalized afterward. This was associated with reduced forearm uptake of glucose and increased hepatic glucose output. The GIR during a subsequent clamp was abnormally low in active acromegaly and became normalized with surgery Fig.
Comparative results were reported in a study involving 23 patients who underwent an OGTT before and after transsphenoidal Kasayama et al. A relationship between biochemical markers of disease activity and glucose homeostasis after surgery is also evident from other studies , Serri et al. A normal postoperative serum IGF-I value, rather than GH status, was more predictive of insulin sensitivity in another study involving 66 patients Substrate metabolism and insulin sensitivity in acromegalic patients before white bar and after successful adenomectomy gray bar and compared with a matched group of healthy subjects hatched bar.
A, Lipid oxidation assessed by indirect calorimetry. B, Glucose uptake across the forearm. C, Endogenous glucose production. D, Insulin sensitivity as assessed by the M value.
Measurements were performed in the basal state Basal and during a euglycemic glucose clamp Clamp. A discussion of treatment algorithms and biochemical definitions of disease activity for acromegaly has been the subject for several consensus statements and is not within the scope of this review , — The use of radiation therapy varies between centers and countries, and data on its impact on glucose metabolism are lacking.
Medical therapy is frequently used in patients with persistent disease after surgery and less frequently as primary treatment. Dopamine agonists such as bromocriptine and cabergoline have been used in the management of acromegaly for many years. Cabergoline appears to be superior to bromocriptine , but disease control is rarely obtained, and data on the impact of dopamine agonists on glucose homeostasis are limited Octreotide, a somatostatin analog with a prolonged half-life relative to native somatostatin, was introduced for the treatment of acromegaly more that 20 yr ago.
Moreover, somatostatin delays gastrointestinal glucose absorption , , reduces the clearance of insulin , and may also improve insulin-stimulated muscle glucose uptake via direct effects The initial formulation of octreotide was administered as sc injections thrice daily, which in most patients resulted in wide circadian fluctuations in serum GH levels with nadir values obtained 2—3 h after each injection, followed by a rebound increase after 4—6 h.
Ho et al. Glucose tolerance did not change significantly although insulin levels tended to be lower after treatment. During a glucose clamp, octreotide treatment was associated with an increase in GIR, which however remained lower compared with healthy subjects ; glucose tracer data indicated that octreotide predominantly acted to suppress HGP during the clamp Koop et al.
Bidirectional changes in glucose tolerance between patients were observed, but on average a moderate impairment occurred in conjunction with a reduction in insulin secretion Depot preparations of somatostatin analogs, which are administered every 2—4 wk and provide sustained and stable reductions in circadian GH levels, have been available for more than 10 yr and are now preferred by most clinicians Based on routine assessments, this treatment is traditionally not considered to be associated with major deterioration in glucose homeostasis Measurements of insulin sensitivity by a euglycemic glucose clamp and glucose tolerance were performed by Baldelli et al.
The majority of patients had residual disease after surgery, and a baseline assessment was performed after withdrawal of medical treatment for at least 8 wk. In all patients, basal insulin levels were significantly reduced by the treatment, which also resulted in a delayed and reduced insulin response to the OGTT This was accompanied by a minor but significant increase in HbA1c levels after treatment.
No difference was evident between the effects of the two somatostatin analogs. Fasting plasma glucose levels, HbA1c levels, as well as plasma glucose levels during an OGTT rose during medical treatment irrespective of the effect on GH status. However, insulin sensitivity, as indirectly estimated from glucose and insulin levels in the basal state and during the OGTT increased in patients who achieved acceptable control of GH status with somatostatin analogs It includes a single-amino acid substitution at position , which corresponds to binding site 2 for the GHR, and eight amino acid substitutions within binding site 1, in addition to polyethylene glycol moieties that increase the half-life of the molecule It binds to the GHR in competition with native GH and prevents conformational changes of the preformed GHR dimer, which are critical for signal transduction The beneficial effects of pegvisomant on glucose metabolism seem to involve improvement of glucose tolerance as well as insulin sensitivity , There are also data to indicate that glucose tolerance improves in patients partially resistant to somatostatin analogs if that treatment is combined with pegvisomant , In an interesting pilot study, O'Connell and Clemmons added the administration of IGF-I plus IGFBP-3 to ongoing pegvisomant treatment in five patients with acromegaly, which resulted in a further improvement of insulin sensitivity.
This finding suggests direct insulin-sensitizing effects of IGF-I at least in this experimental setting. Patients with active acromegaly are characterized by increased levels of FFA and other lipid intermediates together with markedly increased lipid oxidation rates This occurs despite compensatory hyperinsulinemia and substantial changes of body composition, including a decreased fat mass , an increased LBM , and increased total and extracellular body water Data on protein metabolism in acromegaly are sparse.
It has recently been reported that acromegalic patients have a high turnover state with increased leucine rate of appearance protein breakdown and a high nonoxidative leucine disposal protein synthesis Another study comparing acromegalic patients with surgically cured patients and healthy controls reported normal basal leucine kinetics, but decreased leucine oxidation during a hyperinsulinemic clamp in untreated acromegaly Again, one has to consider the changes in body composition when interpreting these data.
Active acromegaly is associated with glucose intolerance despite compensatory hyperinsulinemia, and hepatic as well as peripheral insulin resistance, and it is likely that these aberrations contribute to the excess mortality. Medical treatment with slow-release formulations of somatostatin analogs is preferred when surgery fails and in some cases also as primary treatment.
The net effect on glucose metabolism seems to be a moderate impairment of glucose tolerance, which is not fully compensated by the improvement of insulin sensitivity.
Whether this bears any clinical significance remains uncertain. Moreover, pegvisomant treatment seems to improve glucose tolerance as well as insulin sensitivity in most patients. The quotation above is one of several statements by Raben in a seminal review of GH published more than 45 yr ago , Shortly thereafter, the revolutionary development of RIAs disclosed the secretory pattern of multiple hormones including GH and insulin.
In the immediate postprandial period phase I , insulin acts alone to promote storage of glucose and fat. In the intermediate period phase II , insulin and GH act in synergy, possibly to stimulate protein synthesis. It is tempting to add that untoward effects are to be expected when this pattern is perturbed.
Notwithstanding its simplicity, we believe that this model has stood the test of time. The prolific era of molecular biology led to the identification and cloning of GH and its receptor and, not least, GH signaling.
The receptor belongs to the cytokine family, which implies that many of the signaling pathways of GH are shared by. Major areas for the future would be a closer understanding of how specificity is conveyed at the level of cytokine receptor signaling, including the mechanisms whereby GH promotes its impact on substrate metabolism.
It has recently been documented that exposure to endogenous as well as exogenous GH rapidly translates into GH signaling events in muscle and fat in human subjects. Moreover, with this model it has so far not been possible to replicate data obtained in rodents which indicate that GH causes insulin resistance in muscle by interference with insulin signaling, in particular IRSassociated PI 3-kinase activity.
Whether this discrepancy is based on methodological issues or species-specific differences remains to be investigated, but the human model seems to provide a viable tool for translational research in GH signaling. This could have important implications for understanding not only GH physiology and pathophysiology, but also prevalent clinical conditions associated with insulin resistance.
The manufacture of biosynthetic human GH has been another important breakthrough within the last 20 yr. The abundant supply of the authentic hormone prompted a very large number of therapeutic and experimental trials, in particular in adult hypopituitary patients with GH deficiency. As a result of this, replacement therapy with GH in these patients has been a licensed indication for more than 10 yr, although the penetration of the treatment differs considerably between countries.
Long-standing GHDA is associated with insulin resistance, which probably is related to increased abdominal adiposity, reduced LBM, and impaired aerobic exercise capacity. Replacement therapy, in turn, normalizes body composition and improves physical function. Despite these effects, GH may further impair insulin sensitivity. This is not surprising when considering that daily sc administration of GH is unable to mimic the endogenous pattern resulting from pituitary GH release, which allows insulin to act independently due to postprandial suppression of GH.
With more prolonged GH therapy, the favorable effects on body composition may offset the direct insulin antagonistic effects, in particular if attention is paid to avoid overdosing. Insulin resistance as a side effect to GH administration is no less surprising than the risk of hypoglycemia with insulin therapy.
Studies of a more experimental nature with GH in GHDA have also provided new insight into the mechanisms underlying the metabolic effects such as the close link between the lipolytic effects and the resistance to insulin-induced glucose disposal in muscle, and the important protein-conserving effect of GH during fasting.
Moreover, studies in GHDA have generated novel data on the impact of GH on features such as cardiac function, bone metabolism, lipoprotein metabolism, thyroid hormones, and regional glucocorticoid interconversion, most of which has been beyond the scope of this review.
Due to its anabolic and lipolytic properties, GH has also been administered in different catabolic states such as the frail elderly with sarcopenia and obese patients undergoing caloric restriction. At the present stage, it is important to emphasize that metaanalyses of published data do not justify GH as either an antiaging treatment or as adjunct treatment in obesity So-called rejuvenation of GH secretion in the elderly by means of GH secretagogues has also been evaluated, including a recent long-term trial , , and it does again remain a possibility that some in this age group could benefit from more sophisticated anabolic regimens, e.
GH treatment in HIV-associated wasting has been shown in several randomized controlled trials to increase LBM and body weight and to improve physical endurance and quality of life, and GH is a Food and Drug Administration-approved indication for this condition.
It remains to be further investigated whether GH treatment also may cause a sustainable beneficial effect on HIV-associated lipodystrophy. Elevation of blood glucose levels is a frequent side effect of GH also in these patients. The fatal outcome of trials involving patients with acute critical illness as well as the serious complications of acromegaly underscore more than anything that GH treatment outside of the approved indications should not be based on wishful thinking, but rather be confined to appropriately controlled and rigorously monitored trials.
Having said this, a worthy subject for future research would be to dissect whether the detrimental effects of GH in acute critical illness are due to metabolic aberrations or hitherto unrecognized proinflammatory actions. Medical treatment of acromegaly is another area that has undergone major improvements and also provided further insight into the metabolic effects of GH. Treatment with slow-release formulations of somatostatin analogs is well established and provides symptom relief, disease control, and tumor shrinkage in a large proportion of patients.
It does, however, also cause a mild impairment of glucose tolerance, in many cases owing to the fact that its suppressive effect on insulin secretion is not always fully balanced by the concomitant improvement of insulin sensitivity. The GHR antagonist, pegvisomant, seems to provide a more complete suppression GH bioactivity, which also includes reversal of glucose intolerance and insulin resistance.
Indeed, this compound may even induce functional GH deficiency in patients with acromegaly. Data generated so far suggest that cotreatment with somatostatin analogs and pegvisomant may offer a favorable combination of tumor control and peripheral blockade. Moreover, pegvisomant is an interesting experimental tool for studying the metabolic actions of GH in other conditions.
Future vistas of research related to the metabolic effects of GH are multiple, and not all of them have been addressed in this review.
The discovery of ghrelin as an endogenous ligand for the so-called GH secretagogue receptor is one example. This gut-derived peptide is not only a potent stimulator of GH release when administered exogenously, but it also possesses independent effects on substrate metabolism and appetite regulation, which are just beginning to be unveiled.
Moreover, it remains to be assessed to what degree endogenous gut-derived ghrelin drives GH secretion. Another white spot on the map is the role of GH as a fat-burning cytokine in the regulation of adipokines and myokines, which may have implications for the understanding of fundamental conditions such as obesity, cardiovascular disease, and aging processes.
Exciting progress within the research of the regulation and function of the GH-IGF-I axis during life span continues to be made, and surprises are hopefully ahead. But data so far confirm the statement by Bernardo A. Disclosure Summary: N. Gen Comp Endocrinol : 3 — Google Scholar. J Biol Chem : — Diabetologia 49 : — Diabetes 50 Suppl 1 : S25 — S Am J Hum Genet 14 : — Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
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Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess e.
In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact beta-cell function these changes are counterbalanced by hyperinsulinemia--such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality 'Reavens syndrome X'.
GH administration was found to increase glycogenolysis in healthy adults, and inversely, pituitary microsurgery in patients with acromegaly decreased glycogenolysis [ 5 ].
Despite the increased glycogenolysis, significantly increased hepatic glycogen contents were reported in transgenic rats overexpressing the human GH gene, suggesting increased glycogen synthesis by excessive GH [ 6 ]. Enhanced glycogen synthase activity was also reported in those human GH transgenic rats [ 6 ]. Previous studies have shown that GH suppresses glucose uptake in the adipose tissue.
The insulin-dependent cellular response, which includes trafficking of GLUT4 to the plasma membrane, requires the activation of phosphoinositide 3-kinase PI3K , a key mediator of metabolic signaling downstream of the insulin receptor. PI3K signaling is negatively regulated by the p85 regulatory subunit. GH was found to induce up-regulation of p85 in white adipose tissues in mice with excess GH production, and in adipocytes treated with GH in an in vitro study [ 8 ].
These results imply a mechanism involving GH-induced insulin resistance through up-regulation of the p85 regulatory subunit of PI3K. GH stimulates lipolysis via activation of the hormone-sensitive lipase, primarily in the visceral adipose tissue, which results in free fatty acid FFA flux from adipose tissue to circulation [ 1 ]. Previous studies have shown that increased FFA in circulation can induce insulin resistance by inhibition of insulin receptor substrate-1 IRS-1 activity and subsequent failure of PI3K activation in the skeletal muscle and liver [ 1 ].
Acetyl-CoA stimulates two key enzymes for gluconeogenesis pyruvate carboxylase and phosphoenolpyruvate carboxykinase and an enzyme liberates glucosephosphate as glucose from the liver and kidney into circulation glucosephosphatase , resulting in an increase of blood glucose levels [ 9 ].
In contrast to the GH effects on adipose tissue, GH promotes cellular uptake of FFA in skeletal muscle by increasing the activity of lipoprotein lipase [ 10 ]. The re-esterification of triglycerides from FFA results in the accumulation of lipid intermediates such as diacylglycerol and ceramides in skeletal muscle [ 11 ]. Previous studies have revealed that diacylglycerol and ceramide impede insulin signaling pathways.
As in the adipose tissue, up-regulation of the p85 regulatory subunit in skeletal muscle by GH was involved in insulin resistance in mice with excess GH production [ 12 ]. The cross-talk between insulin and GH downstream of receptor activation in the skeletal muscle and adipose tissue provides another alternative potent mechanism mediating GH-induced insulin resistance, which is supported by experiments both in vitro and in animal models.
Despite numerous in vitro studies and animal models supporting this hypothesis, human studies have failed to demonstrate direct inhibitory effects of GH on insulin signaling pathways in skeletal muscle or fat [ 15 ]. Hyperinsulinism after GH administration or in excess GH conditions have been explained by beta-cell compensation for insulin resistance; however, a recent study found that GH directly promotes beta-cell proliferation and glucose-stimulated insulin secretion [ 16 ]. The receptors for IGF-1 and insulin are highly homologous in structure and biological function.
Binding of the ligands results in autophosphorylation of the intracellular kinase domains and subsequent activation of downstream signaling cascades, which regulate gene transcription involved in substrate metabolism, cell growth and differentiation.
IGF-1 and insulin strongly activate their respective receptors, but can also bind and weakly activate each other's receptors [ 18 ]. IGF-1 had caused a hypoglycemic effect in previous in vivo studies through stimulation of glucose uptake and gluconeogenesis, possibly either via activation of IGF-1 or via insulin receptors [ 19 ].
For example, administration of recombinant human IGF-1 to insulin receptor deficient mice induced insulin-mimetic effects, including both an increase in glucose uptake of skeletal muscle and a decrease in hepatic gluconeogenesis, through IGF-1 receptor activation. Consistent with this, IGF-1 infusion improved serum glucose levels in individuals with diabetes mellitus [ 20 ].
The clinical presentations of GH-deficient adults are characterized by increased visceral adiposity, insulin resistance, dyslipidemia and hyperglycemia, which contributes to increased risk of cardiovascular morbidity and mortality [ 2 ]. Because IGF-1 has anti-inflammatory properties and is important for glucose uptake from peripheral tissues, metabolic disturbances in GH-deficient adults can be explained by the IGF-1 deficit [ 1 ].
A deprivation of GH-induced lipolysis and subsequent increased visceral adiposity are also involved in increased circulating FFAs and insulin resistance in these patients [ 2 ]. Most of the metabolic disturbances, including visceral adiposity, sarcopenia, hypertension, and dyslipidemia were reported to be relieved after GH treatment [ 1 ].
However, a number of studies suggested that there are possible negative impacts on glucose homeostasis such as impaired glucose tolerance as well as insulin sensitivity in patients with GH deficiency after GH administration.
Notably, the interpretation of human studies regarding GH treatment and associated changes of glucose metabolism is intricate, because dosage and duration of GH as well as age, body mass index BMI , and family history of diabetes in study participants can influence the study results.
The original dosage of GH treatment used in GH deficient adults were body weight-adjusted high dosing derived from the dosage used in GH deficient children, however this practice has changed to individualized dosing with lower doses to avoid adverse events of overtreatment since early s. GH treatment in high doses was effective for the reduction of total and visceral fat mass [ 21 , 22 ].
However, long-term GH replacement in high doses decreased insulin sensitivity and aggravated insulin resistance, which can be explained by the anti-insulin effects of GH.
Despite increased insulin resistance, hemoglobin A 1c HbA 1c levels remained unchanged in both short-term and long-term treatment Table 1. Effects of recombinant human GH treatment on glucose metabolism in adults with GH deficiency. Low-dose GH administration in GH-deficient adults has been reported to be effective in improving body composition, albeit to a lesser degree than high-dose GH [ 23 , 24 ]. Most of these studies reported unchanged insulin resistance and insulin sensitivity after long-term treatment with low-dose GH.
Two studies conducted by the same investigators [ 25 , 26 ] showed an improvement of insulin sensitivity in GH-deficient patients with obesity after a short-term treatment with a fixed low-dose GH 0. Most studies with low-dose GH treatment reported no significant changes in HbA 1c levels, although a few studies showed a mild decrease in HbA 1c within normal range in GH deficient adults [ 24 ]. One study investigated the effect of GH on fasting glucose levels and HbA 1c in GH-deficient patients with pre-existing diabetes mellitus, and it revealed a mild elevation of fasting glucose without statistical significance and no aggravation of HbA 1c values [ 23 ].
Recent studies assessed the risk of development of diabetes mellitus after low-dose GH treatment Table 2. Because GH-deficient adults are at increased risk of impaired glucose tolerance compared to the general population, it is sufficient to compare the incidence of diabetes in GH treated patients with that of untreated patients. Currently, only one study with relatively short duration 2.
Other studies compared the incidence of diabetes between GH treated patients and the normal general population, and most of them revealed no significant increase in the incidence of diabetes after 2—10 years of GH treatment Table 2.
One study demonstrated 2—6 times higher incidence of diabetes mellitus than expected in the normal general population [ 28 ]. It is noteworthy that increased age and BMI, female sex, and duration of GH, but not the dose of GH, were associated with increased risk of diabetes mellitus in this study [ 28 ]. To date, relatively few studies have been conducted examining the change of glucose metabolism after GH treatment in the pediatric population. A limited number of euglycemic clamp studies reported decreased insulin sensitivity in GH-deficient children after short-term GH treatment [ 29 , 30 ].
Effects of recombinant human GH treatment on glucose metabolism in children and adolescents with GH deficiency. Because increased insulin resistance and impaired insulin sensitivity are linked to the risk of glucose intolerance and diabetes mellitus, concerns have been raised regarding the possible development of diabetes mellitus during or after GH treatment in the long-term Table 4.
With the advent of National Cooperative Growth Study research [ 31 ], large pharmacoepidemiological studies have demonstrated that the incidences of type 2 diabetes mellitus increased more than 6 times in children under GH treatment compared with the general population, especially in patients with predisposing risk factors for diabetes, such as obesity, family history of diabetes, Turner syndrome, Prader-Will syndrome, or glucocorticoid treatment [ 32 , 33 ].
The development of diabetes mellitus was not associated with the dose or duration of GH treatment, and the incidence of type 1 diabetes mellitus during GH treatment was comparable with that of the general population in all three studies [ 31 - 33 ].
In comparison, a recent French population-based study reported that the prevalence of diabetes mellitus in GH-treated children was similar to the general population when patients reached early adulthood [ 34 ].
Of note, this study included patients with isolated GH deficiency, idiopathic short stature, or short children born small-for-gestational age, excluding patients with high risk of mortality and morbidity, such as patients with cancer, chronic renal failure, multiple pituitary hormone deficiency, Turner syndrome or Prader-Willi syndrome [ 34 ].
Effects of recombinant human GH treatment on the development of DM in children and adolescents. GH therapy antagonizes insulin's action on peripheral tissues, such as the skeletal muscle, liver, and adipose tissue, thereby increases glucose production from the skeletal muscle and liver and decreases glucose uptake from adipose tissue.
Insulin production is increased to compensate the increased circulating glucose after GH administration. GH-induced lipolysis in the visceral adipose tissue and subsequent increased circulating FFA also interferes with insulin signaling pathways, and chronic exposure to high FFA may exert direct toxicity in beta-cells.
Meanwhile, IGF-1 has insulin-mimetic actions in the skeletal muscle and liver, and increased circulating IGF-1 after GH administration may have beneficial effects on glucose homeostasis and insulin resistance.
A number of human studies have suggested that GH administration in GH deficient adults may reduce visceral adiposity and improve cardio-metabolic disturbance.
However, some studies raised concerns over increased insulin resistance and impaired fasting glucose during GH treatment, especially in patients with obesity and elderly patients. Studies in children and adolescents also suggested that GH administration may induce insulin resistance in short-term treatment, but its long-term consequences have not been fully determined yet.
International cohort studies indicate that GH therapy may increase the incidence of type 2 diabetes mellitus in children and adolescents with predisposing risk factors, therefore it is prudent to monitor possible negative consequences on glucose metabolism during and after GH administration. Large-scale longitudinal cohort studies are required to examine the long-term influence of GH therapy on cardiovascular outcomes in GH-deficient children with or without continuation of GH after cessation of skeletal growth.
Conflict of interest: No potential conflict of interest relevant to this article was reported. National Center for Biotechnology Information , U. Ann Pediatr Endocrinol Metab. Published online Sep Author information Article notes Copyright and License information Disclaimer. Received Aug 31; Accepted Sep This article has been cited by other articles in PMC. Abstract Growth hormone GH is important for promotion of somatic growth and the regulation of substrate metabolism.
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