The manifestation of growth hormone deficiency depends upon the age of onset of the disorder and can result from either heritable or acquired disease. The effect of excessive secretion of growth hormone is also very dependent on the age of onset and is seen as two distinctive disorders:.
In years past, growth hormone purified from human cadaver pituitaries was used to treat children with severe growth retardation. More recently, the virtually unlimited supply of growth hormone produced using recombinant DNA technology has lead to several other applications to human and animal populations. Human growth hormone is commonly used to treat children of pathologically short stature. There is concern that this practice will be extended to treatment of essentially normal children - so called "enhancement therapy" or growth hormone on demand.
Similarly, growth hormone has been used by some to enhance atheletic performance. Although growth hormone therapy is generally safe, it is not as safe as no therapy and does entail unpredictable health risks. Parents that request growth hormone therapy for children of essentially-normal stature are clearly misguided. The role of growth hormone in normal aging remains poorly understood, but some of the cosmetic symptoms of aging appear to be amenable to growth hormone therapy.
This is an active area of research, and additional information and recommendations about risks and benefits will undoubtedly surface in the near future. Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle.
Since the mice in our study, as well as humans with type 2 diabetes [ 5 , 6 ], responded well to growth hormone therapy despite having hyperglycaemia and impaired glucose tolerance prior to treatment, such an explanation is plausible.
Future studies in this model, using mice with varying degrees of insulin resistance and better assessing the degree of insulin resistance with glucose and insulin clamping, will help address this hypothesis. Unfortunately, a direct comparison of dosages used in this study to those used for humans is not appropriate and can only be considered in terms of relative dosage for several reasons.
There are several species differences as mice were treated instead of humans, bovine growth hormone was used instead of human growth hormone and the system used was not homogenous i. This is one of the reasons why such a broad range of growth hormone levels was used in this study to ensure we reached a dosage that was biologically relevant. Importantly, the recombinant bovine growth hormone used in this study was active, since dose-dependent effects were seen in vivo. However, it appears that the two lowest doses of growth hormone 0.
The two highest doses of growth hormone 0. Thus these data suggest that it is possible to improve body composition, glucose and liver triacylglycerol content with dosages of growth hormone that are below the threshold required to elevate total IGF For obese adult humans treated with growth hormone, Mekala et al. Based on our results and those of Mekala et al. In other words, optimal therapy would be the highest level of growth hormone that does not result in elevation of IGF-1 above levels appropriate for the patient age and sex considered.
It is difficult to determine due to species differences exactly how long treatment should be given to humans with type 2 diabetes. However, since changes in body composition occurred well before the 6-week endpoint in mice, it is likely that the improvements to body composition were responsible for the improvements we observed in glucose metabolism. In the two human studies using growth hormone to treat patients with type 2 diabetes, only 12 weeks of growth hormone therapy was needed to improve body composition, fasting blood glucose, insulin and insulin sensitivity [ 5 , 6 ].
While Ahn et al. They [ 5 ] found that an initial increase in insulin occurred at 4 weeks, followed by a progressive decrease in insulin at 8 and 12 weeks.
Similarly, glucose only decreased minimally at 4 weeks, with steeper declines occurring at 8 and 12 weeks In humans, therefore, it appears that more than 4 weeks were needed and 12 weeks were sufficient to see improvements. Taken together, it seems sufficient time should be given for growth hormone to improve body composition, as improvements in glucose metabolism are likely to be a result of altered body composition.
In summary, these data show that type 2 diabetes can be significantly improved with growth hormone treatment in a mouse model of diet-induced obesity and type 2 diabetes. These results are similar to those shown in humans with type 2 diabetes [ 5 , 6 ]. The use of growth hormone to treat human type 2 diabetes remains highly controversial, despite two clinical trials having shown a positive impact on glucose homeostasis [ 5 , 6 ].
It would therefore be important to develop an animal model, as shown here, to investigate more fully the impact of growth hormone treatment on specific tissues and conditions, such as fatty liver, as well as to better determine the mechanisms by which growth hormone impacts on type 2 diabetes.
While our data do not advocate the use of growth hormone to treat humans with type 2 diabetes, they do provide a model to better evaluate the efficacy and safety of its use and may be used to elucidate the mechanisms involved.
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Clemmons DR Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly. Pituitary — J Clin Invest — Nielsen C, Gormsen LC, Jessen N et al Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade.
Barbour LA, Mizanoor Rahman S, Gurevich I et al Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. J Biol Chem — It signals the liver to break down its starch or glycogen stores and helps to form new glucose units and ketone units from other substances. It also promotes the breakdown of fat in fat cells.
The consequence? Glucagon levels fall. Unfortunately, in individuals with diabetes, the opposite occurs. While eating, their glucagon levels rise, which causes blood sugar levels to rise after the meal. GLP-1 glucagon-like peptide-1 , GIP glucose-dependent insulinotropic polypeptide and amylin are other hormones that also regulate mealtime insulin.
GLP-1 also slows down the rate at which food empties from your stomach, and it acts on the brain to make you feel full and satisfied. People with type 1 diabetes have absent or malfunctioning beta cells so the hormones insulin and amylin are missing and the hormone GLP1 cannot work properly. GH stimulates lipolysis and causes insulin resistance within 1—2 h, and these effects disappear after approximately 8 h 35 , The stimulating effect of GH on IGF-I production and action is a more chronic process, which, as previously discussed, depends on a positive energy balance and ensuing elevations in insulin.
Interestingly, the liver-specific IGF-I gene-deleted mice mentioned previously show normal postnatal growth and development despite low circulating IGF-I levels, which indicates an important role for direct GH effects in target tissues such as adipose tissue, bone, and skeletal muscle, which may involve stimulation of local IGF-I production In support of the importance of GH per se , two very recent studies failed to record any independent effects of GH-induced hyperinsulinemia on whole body and muscle protein metabolism in humans and in a pig model 37 , In the immediate postprandial period, insulin acts alone to promote storage of glucose.
In the remote postabsorptive or fasting state, GH acts alone to promote lipolysis. In the intermediate phase, insulin and GH act in synergy to promote IGF-I production and bioactivity and subsequent protein synthesis. GHR signaling is a separate and prolific research field by itself, as recently reviewed This section will focus on recent data obtained in human models.
The GHR belongs to class I of the hematopoietin superfamily of cytokine receptors, which includes more than 30 members, among others prolactin, erythropoietin, leptin, granulocyte stimulating factor, and several IL e.
GHRs have been identified in many tissues including muscle, fat, liver, heart, kidney, brain, and the pancreas After GH binding, the intracellular domains of the GHR dimer undergo rotation, which is thought to bring together the two intracellular domains, each of which binds one JAK2 molecule.
This in turn induces cross-phosphorylation of tyrosine residues in the kinase domain of each JAK2 molecule, followed by tyrosine phosphorylation of the GHR. GHR signaling in human models in vivo has been reported in a study in healthy young male subjects exposed to an iv GH bolus vs.
In muscle and fat biopsies, significant STAT5b tyrosine phosphorylation was recorded 30—60 min after GH exposure, compared with saline 46 Fig. Evidence of less intense STAT5b activation associated with small spontaneous GH bursts in the saline study was also observed in several subjects. The latter observation is noteworthy in relation to the insulin antagonistic effects of GH.
There is animal and in vitro evidence to suggest that insulin and GH share postreceptor signaling pathways The infusion of GH induced a sustained increase in FFA levels and subsequently insulin resistance as assessed by the euglycemic clamp technique. This finding could be time-dependent because some studies have failed to detect any effects of FFA on proximal insulin signaling The arrows indicate the time points for muscle biopsies. The signaling mechanisms subserving the insulin antagonistic effects of GH in humans, however, remain to be unveiled.
The available data in humans have failed to demonstrate significant effects of GH on either basal or insulin-stimulated PI 3-kinase activity Fig.
Schematic and simplified depiction of alleged GH signaling proteins, which so far have been investigated in human muscle and adipose tissue. The solid lines and boxes indicate pathways that have been shown to be activated by GH; the hatched lines and boxes represent signaling proteins where activation by GH so far has not been documented.
The human in vivo studies were performed in healthy subjects with single biopsies obtained 30—60 min 46 and min 52 after the start of acute GH exposure. It remains to be investigated whether sampling at different time points in relation to acute GH exposure or biopsies obtained in states of chronic excess or deficiency of GH may reveal additional effects on the same signaling pathways.
In the basal state, i. As previously mentioned, GH secretion in this state occurs in small discrete bursts, whereas many clinical studies have employed prolonged exposure to higher levels of GH. The most striking effect of a single exogenous GH pulse is a marked increase in circulating levels of FFA and ketone bodies 55 , reflecting stimulation of lipolysis and ketogenesis Fig.
The increase in FFA levels is also robust and lasts for 1—8 h 35 , 36 , In addition, palmitate tracer dilution has shown a similar increase in palmitate flux after pulsatile GH exposure 35 , 60 , indicative of increased FFA turnover.
A, Circulating concentrations of GH top , insulin middle , and glucagon bottom. B, Interstitial levels of glycerol in abdominal top and femoral bottom fat assessed by microdialysis.
As regards the source of FFA, microdialysis studies have shown that a GH pulse increases glycerol concentrations—indicative of in situ lipolysis—in both femoral and abdominal adipose tissue, indicating that both regions contribute 56 , 59 Fig. It is not known whether visceral adipose tissue participates, but the finding that long-term GH treatment decreases visceral fat volume supports this It has been observed that interstitial muscle glycerol concentrations increase after a GH bolus 35 , but this could also reflect spillover from the circulating glycerol pool.
The finding of increased intramyocellular triglyceride content after GH exposure 36 argues against mobilization of FFA stored in muscle as the primary event. The secretory pattern of GH plays an important role in the diurnal supply of fuel substrates. An investigation of young healthy subjects reported that the nocturnal GH peaks preceded the early morning rise of FFA by 2 h 62 , a time lag very close to the one found after GH bolus administration, thus providing evidence that GH regulates the circadian oscillations in the release and oxidation of lipids and other fuel substrates.
The idea is corroborated by studies showing that lack of nocturnal GH release compromises the physiological overnight surge of lipid fuels 62 — 65 and studies implying a correlation between nocturnal GH and ketone body concentrations in terms of time and magnitude 65 , There is evidence that the lipolytic response to GH may be blunted in females, older subjects, and abdominally obese subjects 64 , 68 , 69 , whereas Hansen et al.
It remains unresolved whether GH directly impacts hepatic ketogenesis. Some studies suggest so 70 — 72 , but increased hepatic precursor supply of FFA is probably more important. The potential role of GH in the regulation of lipogenesis and adipose tissue growth and differentiation in humans is also controversial, and it appears that major species-specific differences exist Porcine studies suggest that GH may inhibit lipogenesis and fatty acid synthase 74 , thus contributing to loss of fat mass.
It is uncertain whether GH affects lipid deposition in muscle and liver, but one study in healthy subjects has recorded increased intramyocellular lipid disposition after 8-d GH treatment There is no evidence that GH acutely affects triglyceride synthesis rates The lipolytic effects are at least partly mediated via the hormone-sensitive lipase HSL 75 , and in accordance with this administration of acipimox, a nicotinic derivative that blocks the actions of HSL has been shown to suppress the lipolytic effects of GH in humans 76 — In addition, in vitro data suggest that GH directly stimulates FFA oxidation in human fibroblasts 80 , and several studies also demonstrate that GH suppresses the lipoprotein lipase LPL activity in human adipose tissue 81 — 83 Fig.
To what degree this intriguing effect of IGF-I contributes to the lipolytic and insulin-antagonistic effects of GH remains, however, uncertain. Schematic and simplified illustration of studied effects of GH on fat metabolism in adipose tissue and skeletal muscle. For additional information, see text. Thus, the primary effect of GH in the basal state is to promote lipid mobilization and oxidation.
As pointed out by Rabinowitz and Zierler 7 these actions may be viewed as a means of switching substrate metabolism from glucose and protein utilization to lipid oxidation. Similar observations have emerged from studies using discrete GH pulses, i. The rapid initial decrease in muscle glucose uptake may either be a direct effect of GH or secondary to local im augmentation of lipid utilization Rabinowitz et al. It is also noteworthy that GH signaling in muscle and fat tissues is detectable 30 min after a GH pulse Acknowledging that GH decreases glucose oxidation and muscle glucose uptake in the presence of unchanged endogenous glucose production and plasma glucose concentrations implies that GH must promote nonoxidative glucose utilization in some nonmuscle compartment of the body.
Stimulated lipogenesis in adipose tissue or liver is an unlikely candidate because there is no evidence of any such effects and because ongoing lipogenesis would increase the respiratory exchange ratio, whereas the opposite is recorded after GH exposure Alternatively, GH may increase gluconeogenesis and glucose cycling in, e.
Large doses of GH have been reported to decrease net postabsorptive splanchnic glucose output acutely, compatible with increased glucose uptake 89 , and in vitro experiments have shown increased gluconeogenesis from either alanine, or more likely, lactate in canine kidney cortex incubated with GH Besides, Butler et al.
A more recent study of GH treatment in HIV-infected patients showed that gluconeogenesis assessed by mass isotopomer distribution analysis increased, and hepatic de novo lipogenesis decreased after months of treatment It is likely that increased FFA levels contribute to this putative stimulation of gluconeogenesis On the whole, there is circumstantial evidence that GH increases gluconeogenesis, probably lactate-dependently, but there is a need of acute studies using, e.
Data on the acute effects of GH on protein metabolism in the basal state are not very consistent. Fryburg et al. Another study did not detect any effects of acute GH withdrawal on whole body or forearm muscle phenylalanine kinetics in GH-deficient GHD adults GHDA , whereas Fryburg and Barrett reported decreased whole body leucine oxidation, unaltered whole body leucine proteolysis and protein synthesis, and increased muscle protein synthesis after acute GH exposure in healthy humans.
In general, circulating amino acid concentrations do not consistently change after acute GH administration. As regards more prolonged effects, a study assessing the impact of GH on protein metabolism postabsorptively has shown that high doses of GH 0. These observations were confirmed by Yarasheski et al. In addition, it has been reported that 6 wk of high-dose GH treatment to malnourished hemodialysis patients stimulated muscle protein synthesis without any effects on muscle protein degradation Some studies have, however, not been able to find any effects of prolonged GH exposure on whole body protein turnover or albumin synthesis , A study of protein turnover in GHDA has demonstrated reduced rates of protein synthesis and breakdown and subsequent normal net protein loss compared with normal controls , in line with earlier observations of the effect of chronic GH deficiency on protein metabolism It should be noted that most studies assessing the protein metabolic effects of prolonged GH exposure have used relatively high GH doses and invariably have affected insulin, IGF-I, and FFA levels, which together with changes in body composition have independent effects on substrate metabolism, discussed below.
In addition, experiments in hypophysectomized rats show that GH acts on the liver to decrease urea synthesis and, in parallel, increase glutamine release, thereby diminishing hepatorenal clearance of the circulating nitrogen pool In the postabsorptive state, Wolthers et al. This suggests that the anabolic effect of GH on whole body protein metabolism in normal subjects involves both peripheral protein synthesis and degradation as well as a specific reduction of hepatic urea nitrogen synthesis.
On the whole, the acute effects of GH on protein metabolism in the basal state are not straightforward and perhaps of minor biological significance, and studies of the effects of GH on protein metabolism in stress states e. An increase in REE has been observed 5 h after GH infusion compared with saline in normal subjects during a concomitant euglycemic clamp The underlying mechanisms are not fully clarified, but it is noteworthy that IGF-I administration does not to the same extent increase REE , which could relate to its suppressive effect on insulin secretion.
A primary stimulatory effect of GH infusion on key mitochondrial enzymes involved in biological oxidation was recently recorded in muscle biopsies from healthy subjects, although that particular study did not observe an increase in REE An increase in the expression of mRNA for uncoupling protein UCP 3 in skeletal muscle, and fat has been reported after 4-month GH substitution in hypopituitary patients ; the UCPs, which are assumed to be under sympathoadrenal control, act by uncoupling oxidative phosphorylation resulting in heat production without ATP generation.
GH increases resting cardiac output and blood flow in several organs, including skeletal muscle and kidneys , , all of which are likely to elevate REE.
As outlined above GH secretion is amplified during fasting, exercise, and stress, and these catabolic conditions may be regarded as the natural domains for GH, in which the body benefits from the impact of GH on substrate metabolism.
These conditions are all characterized by progressive fuel depletion, because of either reduced supply or increased demand.
Houssay, 28 ]. Classic observations by Cahill have suggested that a normally proportioned kg man stores — g glycogen cal , 6—7 kg mobilizable muscle protein 25, cal , and 10—15 kg triacylglycerol in adipose tissue , cal. With sustained fasting, the degree of glucose oxidation becomes rate limiting for protein degradation because amino acids are major substrates for gluconeogenesis.
Therefore, maintenance of metabolic homeostasis becomes increasingly dependent on mobilization and utilization of FFA and ketone bodies 92 , — , and GH plays a central role in this process. During fasting, GH is the only anabolic hormone to increase, whereas insulin and IGF-I levels decrease, and levels of catabolic hormones such as glucagons, epinephrine, and cortisol increase Many studies using high-dose GH administration have shown that GH reduces serum urea concentrations and urea excretion 29 , 30 , , including conditions of dietary restriction or a hyponitrogenous diet The increase in whole-body protein loss secondary to GH deprivation was accounted for by a net reduction in protein synthesis.
Furthermore, a significant decrease in branched-chain amino acid levels, consistent with decreased proteolysis, was seen during fasting with GH substitution , Effects of continued vs.
M-value is the amount of glucose infused during a euglycemic clamp performed during the last 2. Studies in obese subjects have generated similar results. Obesity is associated with suppressed levels of circulating GH compared with normal-weight subjects In the treatment of obesity with caloric restriction, protein loss presents a major therapeutic obstacle, and the concurrence of increased lipolysis and protein conservation observed during GH administration could make adjunct GH therapy a rational approach.
The metabolic response to GH during prolonged fasting in obese subjects was first studied more than 30 yr ago by Felig et al. It has also been shown that GH treatment in combination with a hypocaloric diet in 20 obese subjects resulted in a significantly more positive nitrogen balance, although the effect faded after 4—5 wk of GH treatment , Finally, it has been reported that GH administration preserves LBM and protein stores and leads to a relative decrease of phenylalanine-to-tyrosine degradation in obese women during well-defined hypocaloric regimens for 4 wk Another central feature of GH during fasting is stimulation of lipolysis, although this effect may be partially masked by insulin.
These defects are to a large degree restored when intralipid is infused to raise FFA levels. As would be predicted, GH-induced lipolysis during fasting also leads to insulin resistance On the other hand, Sakharova et al. In conclusion, fasting unmasks the marked ability of GH to preserve protein.
This is to a large extent due to a similar increase in muscle protein breakdown and appears to depend on the protein sparing effects of FFA and other lipid fuels. The concept of a central role of lipolysis and lipid intermediates is supported by a number of classic studies reporting protein conserving actions of FFA and ketone bodies — The role of GH and IGF-I in exercise and sport has been extensively reviewed recently , , and this review will not cover the potential effects of GH to improve athletic performance.
Only a few studies have addressed the acute physiological role of GH during exercise. When the normal physiological GH surge is mimicked in GHD subjects during 45 min at moderate intensity exercise, FFA fluxes during and after exercise increase, whereas glucose and amino acid metabolism are unaltered There is also a significant correlation between the peak GH response to exercise and subsequent indices of lipolysis Notably, recent studies in human subjects have recorded increased mitochondrial oxidative capacity and expression of mRNAs that encode mitochondrial proteins after GH exposure alone and in combination with exercise , The possible metabolic significance of repeated or prolonged GH bursts during repetitive exercise or during more prolonged and exhaustive exercise is largely unknown.
Administration of very high doses of GH for 4 wk to trained athletes reduced leucine oxidation and increased leucine protein synthesis and FFA levels and lipolysis in the basal state and in the periexercise period , Other studies have shown that GH treatment increases lipolysis and FFA availability before and during exercise, but not necessarily FFA oxidation during exercise , Studies in GHD subjects have also shown that withdrawal of GH for 3 months reduces glycerol and FFA palmitate release and utilization during exercise Thus, the major metabolic effect of GH during moderate exercise appears to be stimulation of lipolysis, whereas protein and glucose metabolism remain unaffected.
When GH is administered in high doses for a long time, lipolysis prevails and protein oxidation decreases. In the acute phase of severe critical illness, GH secretion is amplified, whereas protracted less severe critical illness suppresses GH release , Knowledge about the role of GH under these different circumstances is very limited.
A number of protocols have assessed the effects of adjuvant GH therapy during a variety of acute and chronic disease states, and in general these studies show that GH induces an acromegaly-like state characterized by 1 increased lipolysis and elevated FFA levels; 2 insulin resistance with elevated endogenous glucose production and decreased peripheral muscle glucose uptake; 3 protein preservation due to decreased oxidation; 4 elevated levels of IGF-I and insulin; and 5 increased LBM and decreased fat mass — When GH is administered to patients with HIV, an increase in muscle protein synthesis is observed, whereas muscle protein synthesis is decreased in patients with HIV-associated wasting, and this condition is an FDA-approved indication for GH treatment It is of particular interest that GH reduces visceral and sc fat mass, whereas intermuscular fat deposition increases , although the mechanisms remain elusive.
When assessing all the studies using GH therapy in catabolic illness, it should be noted that the metabolic outcome depends heavily on the timing between GH administration and the subsequent metabolic investigations. Insulin resistance, lipotoxicity, and glucose toxicity raise particular concerns as regards both acute mortality and long-term cardiovascular disease.
The detrimental outcome was associated with significant elevations in blood glucose levels despite more than a doubling of insulin administration in the GH-treated group. Whether the dramatic increase in mortality related to insulin resistance and metabolic disarray, as suggested by the subsequent studies by van den Berghe et al. A large number of small and often uncontrolled studies have confirmed the ability of GH to conserve protein and LBM during catabolic illness.
A large multicenter trial with GH treatment in adult patients with chronic renal insufficiency, with reduced mortality as a primary end point, is currently in progress.
The fatal outcome of GH administration in patients with severe and acute critical illness emphasizes that any future studies with GH in catabolic patients must be very carefully targeted and rigorously monitored. Acute and chronic GH exposure induces insulin resistance in terms of increased endogenous glucose production and decreased peripheral glucose disposal in muscle , These effects appear to be largely secondary to stimulation of lipolysis and subsequent glucose-fatty acid substrate competition 76 , 79 , The existence of the glucose-fatty acid cycle was proposed in by Randle et al.
This substrate competition hypothesis was later expanded by Shulman and colleagues , who —rather than an increase—showed a decrease in intracellular glucose and glucosephosphate after FFA exposure and suggested that accumulation of lipid metabolites e.
Not all studies have supported this concept, and there is no evidence in humans that the insulin antagonistic actions of GH involve inhibition of the PI 3-kinase pathway Furthermore, it is also likely that GH possesses FFA-independent actions to induce insulin sensitivity because acute GH exposure generates insulin resistance before elevations of FFA in the circulation At the same time, serum IGF-I levels are reduced in poorly controlled patients , which may be caused by a combination of a negative nitrogen balance and low portal insulin levels , It is, in turn, likely that the low IGF-I levels cause or contribute to the increased GH secretion via classic feedback mechanisms.
Hypoglycemia remains an inevitable counterpart to treatment of diabetes, and intact GH secretion is important in combating hypoglycemia , This is particularly so in patients with autonomic failure and inadequate glucagon and epinephrine responses to hypoglycemia In patients with appropriately controlled diabetes, GH may be considered as a physiological modulator of metabolic homeostasis These findings, which are very similar to observations in normal man, suggest that in well-insulinized diabetic subjects, modest amounts of GH may serve as a beneficial metabolic regulator working to preserve carbohydrate and protein at the cost of lipid consumption.
In further support of this, low-dose GH replacement therapy for 6 months in hypopituitary patients with type 1 diabetes decreases asymptomatic hypoglycemic attacks in the presence of increased normalized insulin dosage requirements and unaltered glycemic control It is, however, equally well documented that GH hypersecretion worsens metabolic control in type 1 diabetes Whether circulating free IGF-I levels in the physiological range also improves insulin action or sensitivity via GH-independent mechanisms remains uncertain.
The effects of GH on insulin sensitivity in healthy subjects have been assessed in some detail. Reports from the early s repeatedly demonstrated that continuous infusion of 1.
A subsequent study using smaller doses of GH and insulin showed that: 1 GH impairs hepatic and peripheral insulin sensitivity after approximately 2 h; 2 the impairment of peripheral insulin sensitivity largely resides in muscle; and 3 GH has the potency to offset the antilipolytic properties of light hyperinsulinemia There is also evidence to suggest that GH diminishes both insulin- and glucose-dependent glucose disposal Fowelin et al.
It has been reported that GH exposure blunts the activity of glycogen synthase in striated muscle In the course of diabetic ketoacidosis, circulating GH concentrations are inappropriately elevated , which worsens the pronounced insulin resistance of this state and may aggravate the life-threatening ketosis This challenge has received support from a study failing to detect any effect of nocturnal GH surges on morning insulin sensitivity 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
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