6 Growth hormone disorders and secondary diabetes P A T R I C K S. S H A R P SALEM A. BESHYAH DESMOND G. JOHNSTON
There is, at present, renewed interest in the basic actions of growth hormone (GH), stimulated by the now limitless supplies of the synthetic 22K hormone. This allows detailed examination of the actions of GH without the previous concern that extraneous pituitary contaminants were influencing results. The limitless availability of synthetic GH has also increased its potential for use to treat a variety of clinical conditions other than to increase linear growth in GH-deficient children. These include improvement in nitrogen balance in catabolic states (Ponting et al, 1988), GH replacement for hypopituitary adults (Jorgensen et al, 1989; Salomon et al, 1989), increasing lean body mass in the elderly (Rudman et al, 1990), and even possibly for weight reduction and as a treatment for osteoporosis. Whichever of these indications prove to be of subsequent clinical value, it is apparent that iatrogenic secondary diabetes is going to be a consideration in the future, and greater understanding of the actions of GH on carbohydrate metabolism is necessary, both by examining the effects of GH in normal subjects, and also by re-examining the data in hypopituitarism and acromegaly. EFFECTS OF GH ON CARBOHYDRATE METABOLISM
This has been extensively covered by others, and readers are referred to a number of excellent review articles (Altszuler, 1974; Davidson, 1987; Press, 1988). We shall concentrate in this review on in vivo experiments in man. G H has an early insulin-like effect followed by a later anti-insulin effect. The insulin-like effect has been difficult to demonstrate consistently, and is seen mainly in hypophysectomized animals and in tissues not recently exposed to GH. It does not seem to be mediated by changes in either insulin or glucagon concentrations (Adamson, 1981). It may have limited physiological significance, but nonetheless may take on more importance with the pharmacological use of GH. Hypoglycaemia has been reported after GH administration in GH-deficient children (Frohman et al, 1967; Fineberg and Bailli~re's Clinical Endocrinology and Metabolism-819 Vol. 6, No. 4, October 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1621-7 All rights of reproduction in any form reserved
820
P.s.
SHARP ET AL
Merimee, 1974; Hopwood et al, 1975). Young children may be particularly prone as they have a high hepatic glucose output, but have difficulty increasing this further, as may be required following GH administration (Bier et al, 1977; Haymond et al, 1982). Accordingly, the problem seems to be most common in younger and leaner children. The hypoglycaemia has been reported as being symptomatic in about 15 % of children, and asymptomatic in 27-70%. It should, however, be pointed out that these studies report on results in children treated with pituitary-extracted GH, and there have been as yet no reports of hypoglycaemia with the synthetic 22K peptide. Hypoglycaemia has not been reported in any of the studies of GH treatment in adults, and even in careful studies following parenteral administration in the fasting state, the occurrence of early hypoglycaemia is variable (Adamson, 1981; Metcalfe et al, 1981; Rosenfeld et al, 1982; Moller et al, 1990). In contrast, the anti-insulin effect of GH is beyond dispute, and it is undoubtedly of clinical significance. Early studies of the effects of GH established that GH treatment increased plasma insulin concentrations (Altszuler et al, 1968; Sirek et al, 1979). While physiological studies have suggested that GH may release insulin by a direct action on the pancreas (Bouman and Bosboom, 1965), the principal mechanism has been thought to be by induction of insulin resistance which develops 2-12 hours after exposure to GH (Rizza et al, 1982). As expected, therefore, the principal defects of carbohydrate metabolism demonstrated after GH treatment in normal subjects are a defect of glucose uptake by muscle, and a failure of suppression of hepatic glucose output by the liver in response to insulin (Bratusch-Marrain et al, 1982; Rizza et al, 1982). Forearm studies from Denmark have confirmed that in normal subjects following GH administration, muscle glucose uptake is decreased (Moller et al, 1990). In the post-absorptive state in this Danish study, no difference was seen in hepatic glucose output between GH-treated subjects and normal controls. However, hypopituitary children receiving long-term GH treatment do show an elevation in hepatic glucose output (Bougneres et al, 1985). Insulin binding studies with monocytes in normal subjects suggest that the insulin resistance is due to a post-receptor abnormality (Bratusch-Marrain et al, 1982; Rizza et al, 1982; Rosenfeld et al, 1982). This does not seem to be related to the increase in non-esterified fatty acids induced by GH treatment since the abnormality precedes any measurable increase in lipolysis (Fineberg and Merimee, 1974). Bratusch-Marrain et al (1982) suggested that GH impaired non-oxidative glucose disposal, but no measurements were taken. More recently, studies employing indirect calorimetry (Moiler et al, 1990) have suggested that oxidative glucose disposal is decreased while non-oxidative disposal is, in fact, somewhat increased. Hepatic glycogen stores are increased by GH treatment in the dog (Altszuler et al, 1968). The authors of the dog studies have suggested that consequent glycogenolysis contributes to the increased hepatic glucose output with GH treatment. The extent to which increased gluconeogenesis also contributes has been difficult to ascertain, but it is likely to play a part since gluconeogenic precursor concentrations are not decreased, and in rats, the gluconeogenic capacity of the GH-treated liver is greater than normal (Tolman et al, 1973).
GROWTH HORMONE DISORDERS AND SECONDARY DIABETES
821
Many of the studies above have claimed to have employed 'physiological' plasma concentrations of GH, similar to those seen with stress or during sleep. However, it is doubtful if any of these regimens are truly physiological, given the episodic nature of GH secretion--producing short-lived peaks in circulating GH. Perhaps the study which most closely mimics physiological GH secretion is that which employed four daily intramuscular injections given at night (Rosenfeld et al, 1982). Its results, however, were similar to others, showing increased insulin concentrations of 35%. This effect on insulin is not observed following physiological bursts of GH secretion. It is interesting to note that both pituitary-extracted and synthetic GH produced identical results, suggesting that any anti-insulin effect of GH is unrelated to contaminants in the material. It is difficult to identify which of the effects of GH on carbohydrate metabolism are direct effects of GH, and which are mediated by its messenger peptide insulin-like growth factor-1 (IGF-1). IGF-1 is secreted directly by tissues in response to GH stimulation, and it too is now produced by recombinant DNA technology. It might be thought that infusion studies of this peptide would separate the effects of GH from IGF-1. However, the results of such studies have to be interpreted with great caution since IGF-1 is capable of binding not only to its own receptor, but also to the insulin receptor. Thus, infusion of IGF-1 into subjects with Laron dwarfism produced quite marked hypoglycaemia, probably acting via the insulin receptor (Laron et al, 1988). Laron dwarfs are otherwise GH-resistant, due to a defect in the GH receptor. A more recent study, again in a subject with Laron dwarfism to avoid any possible effect of GH, examined the effect of a continuous infusion of IGF-1, aiming to produce serum concentrations of IGF-1 in the high physiological range (Walker et al, 1991). During the period of IGF-1 infusion, fasting glucose was lower than on control days, endogenous insulin was almost totally suppressed and mild postprandial hyperglycaemia was seen. It is difficult to interpret these results. IGF-1 is usually highly protein bound, and despite the serum concentrations being normal, the levels of the free peptide may have been much higher than normal. There would probably have been considerable binding to the insulin receptor, accounting for the lower fasting glucose concentrations. The suppressive effect on insulin, coupled with the relatively mild hypoglycaemic effect of IGF-1 may account for the high post-prandial blood glucose excursions. Further information on the effect of the IGF-1 binding proteins is needed before these studies can be evaluated. HYPOPITUITARISM
From its known effects in normal subjects, the effects of GH deficiency are partially predictable. Unfortunately, studies in man are not comprehensive, but animal studies provide the necessary background. Children with GH deficiency are liable to develop fasting hypoglycaemia, and the tendency is most marked in younger, smaller children. It is more common also if there is
822
P . S . SHARP ET AL
deficiency of other anterior pituitary hormones. Hypoglycaemia is rare in GH-deficient adults, except during prolonged starvation. In young children with fasting hypoglycaemia, hepatic glucose output is decreased by 50% after an overnight fast. Glucose turnover is restored to normal by GH therapy. In older children and adults without hypoglycaemia, hepatic glucose output is normal and turnover is unaffected by GH therapy. These results with G H therapy are somewhat surprising in view of the known hyperglycaemic effects of GH on glucose homeostasis. The effects of GH therapy are, however, complex and include raised IGF-1 concentrations, which may increase glucose disposal, and alterations in body composition, such as increased lean body mass and decreased fat deposition. These changes in body composition also favour glucose disposal. Hypophysectomy causes insulin hypersensitivity in animals, peaking 5-6 weeks after operation (De Bodo and Sinkoff, 1953; De Bodo and Altszuler, 1958). In the hypophysectomized dog, the characteristic pattern of blood glucose after insulin injection is a brief drop, followed by a delayed return to normal compared with the normal dog. The difference in insulin sensitivity was estimated to be 10--20-fold based on the insulin dosage required to produce the same response in normal and hypophysectomized dogs. This response was further characterized in the hypophysectomized dog in which, in response to insulin, muscle glucose uptake was increased, and hepatic glucose output fell more than was observed in animals with an intact pituitary (Wall et al, 1957). Studies in humans, although not so complete, confirm these findings. In lean GH-deficient subjects, fasting insulin concentrations are normal. Early studies using the insulin tolerance test as a diagnostic tool demonstrated delayed recovery from insulin-induced hypoglycaemia in adults although the slope of the earlier fall in blood glucose concentration was normal (Landon et al, 1966). Using the intravenous glucose tolerance test (Frohman et al, 1967), it was demonstrated that glucose uptake was diminished in hypopituitary subjects, and the insulin response to glucose was also diminished. On calculating a ratio of insulin secretion to glucose uptake, insulin sensitivity was observed to be increased, and it was restored towards normal with GH treatment. These data suggest that GH deficiency is a state of insulin hyperresponsiveness. Other data are in conflict with this conclusion. GH deficiency is associated with obesity and a decrease in muscle bulk. As in other obese subjects, fasting hyperinsulinaemia is observed in obese GHdeficient patients, who also show an impaired response to exogenous insulin in comparison with subjects with lower fasting insulin levels. Insulin sensitivity in G H deficiency is complex therefore; it is likely to be normal or increased in lean patients; patients are commonly obese however, with low muscle mass, and these subjects may be insulin resistant. Insulin receptor binding studies have produced similar results to those in normal subjects; G H treatment in hypopituitarism induced a post-binding defect in insulin action (Lippe et al, 1981). In response to a glucose challenge, patients may have impairment of glucose tolerance. Thus, a number of investigators have demonstrated
GROWTH HORMONE DISORDERS AND SECONDARY DIABETES
823
impaired glucose tolerance in GH-deficient subjects (Gold et al, 1968; Merimee et al, 1968, 1970; Lippe et al, 1981). This has been associated with a decreased insulin response to oral glucose (and arginine). It is of interest to note that in the last two studies, treatment with GH resulted in increased insulin secretion, bringing concentrations toward the normal range, but the two studies differedas to whether blood glucose concentrations improved as a result. Certainly this is an area which requires clarification, especially as GH treatment is now being considered in elderly subjects who may have a degree of impairment of glucose tolerance before therapy. It is probable that body composition (obesity and muscle mass) is important in glucose tolerance and insulin secretion. Hyperinsulinaemia after oral glucose has been described, although information on the body composition of these GH-deficient patients is not available. Glucose tolerance, insulin secretion and insulin sensitivity before treatment, and the response to GH, may be determined more by body composition and its changes than by the degree or duration of GH deficiency. ACROMEGALY From its known physiological effects, the result of pathological GH excess can be predicted. It has long been known that overt diabetes can be produced in the normal dog with large doses of GH given over 7 days (Young, 1953). This arises from a high hepatic glucose output, decreased glucose uptake by muscle when corrected for the plasma glucose concentration, and insulin resistance as evidenced by increased plasma insulin concentrations in the presence of the above changes (Altszuler et al, 1968). A number of investigators have commented on the use of glucose tolerance tests as an important part of the diagnostic work-up in acromegaly. Difficulties arise in interpreting glucose concentration results due to different protocols, the differing criteria used for the diagnosis of diabetes and problems in compiling sufficiently large series of patients. In a series of 20 patients with acromegaly, studied using an intravenous glucose tolerance test (IVGTT) (Luft et al, 1967), higher glucose and insulin values were seen in the patients judged to have the more active disease. Patients with marked hyperglycaemia, however, had low insulin concentrations. In similar studies in 16 acromegalics (S6nksen et al, 1967), 10 of the patients achieved insulin concentrations more than 2 standard deviations above the normal mean level. Other authors have examined the hyperinsulinaemia of acromegaly in response to an oral glucose load. In a study of nine acromegalic patients selected to have fasting blood glucose concentrations below 6mmol1-1 (Fineberg et al, 1970), a 100 g glucose load produced glucose concentrations of 3.5 mmoll -~ greater than in the control group, and insulin levels some threefold greater. Similar, but not so striking results were obtained using a 50 g glucose load (Elkeles et al, 1969; Trimble et al, 1980). In this study also it was observed that those with overt diabetes had lower insulin values than those with normal glucose tolerance, suggesting that in those progressing to
824
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diabetes, [3-cell failure precedes the rise in plasma glucose concentrations. In a large series (Wass et al, 1980), the differing criteria for the diagnosis of diabetes were addressed. Using a 50 g glucose load, and applying different published criteria for the interpretation of the test, the percentage judged to have diabetes varied from 13 to 38%. In this study there was a considerable improvement in glucose tolerance after treatment with bromocriptine. Not surprisingly, treatment of acromegaly with a somatostatin analogue, which suppresses concentrations of insulin as well as those of GH, is not associated with such consistent improvement in glucose tolerance (James et al, 1991). Somatostatin analogues also influence gastrointestinal motility and absorption, such that effects on glucose homeostasis are complex and variable. In two further large series of 155 and 256 patients with acromegaly (Jadresic et al, 1982; Nabarro, 1987) the percentage of patients with diabetes was quoted as 27% and 18.8% respectively, figures similar to those of Wass and colleagues (1980). In a study of 23 patients with acromegaly, abnormalities of insulin secretion were reported to persist after treatment of the condition, with normalization of the GH levels and return of glucose concentrations to normal (Roelfsema and Fr61ich, 1985). However, numbers were small, and judgement on this matter should be reserved. There are few studies on the pathogenesis of abnormal glucose tolerance in acromegaly in man. In a study of 10 active acromegalic patients (Foss et al, 1991), forearm glucose uptake after glucose ingestion was lower than in normal controls. Since glucose oxidation rates were similar in acromegalics and controls, the defect was presumed to be an impairment of glucose storage. This finding is at odds with the study of Moller et al (1990), who found that in normal subjects treated with GH, glucose oxidation was decreased. In acromegalics, the impairment of muscle glucose uptake was considered insufficient to account for the raised plasma glucose concentrations, and the major abnormality was thought therefore to be an impairment of suppression of hepatic glucose output. Hepatic glucose output in acromegaly was examined in five acromegalic patients using the hyperinsulinaemic glucose clamp and isotopic dilution methods (Hansen et al, 1986). In this study, whole body glucose disposal was lower in acromegaly than in the control subjects, in response to insulin. However basal hepatic glucose output, and hence basal glucose uptake, was increased. This anomalous finding was ascribed to the mass action of glucose since the acromegalics had slightly higher basal glucose values than the normal controls. This may also have been a factor in previous studies in which glucose turnover was observed to be markedly increased in GHtreated dogs (Young, 1953). Similar high glucose turnover rates were reported in a study of hepatic glucose output in response to glucose infusion (Karlander et al, 1986). These authors also found that hepatic glucose output failed to suppress with glucose infusion. Insulin receptor binding studies in adipose tissue from acromegalic subjects (Bolinder et al, 1986) demonstrated results similar to those found with GH treatment in normal subjects. Insulin binding to adipocytes was decreased, but glucose oxidation and suppression of lipolysis remained defective even when insulin concentrations were raised. The authors
825
GROWTH HORMONE DISORDERS AND SECONDARY DIABETES
suggested that insulin resistance in acromegaly was due to a post-binding defect. Similar conclusions were reached in studies of insulin binding to erythrocytes and monocytes (Hansen et al, 1986). Although these authors found that insulin binding in acromegalics did not differ from that of the normal controls, a post-binding defect was apparent. IATROGENIC DIABETES DUE TO GH ADMINISTRATION Although this is not a major clinical problem at present, it deserves consideration in view of the likely proliferation of indications for GH treatment in adult populations. Studies in adults to date have used daily GH doses of 0.05-0.07 U kg -1 body weight (Table 1). The first published study of GH treatment in hypopituitary adults did not comment on changes in plasma glucose or insulin levels (Jorgensen et al, 1989), but a similar study (Salomon et al, 1989), using the higher dose of GH, reported a trivial rise in fasting plasma glucose. A small rise in fasting plasma insulin was also observed (Table 1). Glucose turnover was not affected significantly. A third study using a higher dose of GH for 6 months demonstrated no effect on fasting glucose, insulin or glycosylated haemoglobin concentrations, nor on the insulin response to a 75 g oral glucose load (Whitehead et al, 1992).
Table 1. Metabolic effects of prolonged GH treatment in hypopituitary adults.
Outcome GH (placebo) Patient number GH dose (weekly) Duration of therapy (months) Fasting glucose (mmol 1-i)
Denmark (Jorgensen et al, 1989)
London (Salomon et al, 1989)
Belfast (Whitehead et al, 1992)
22
12 (12) 0.35 U kg -a 6 5.1 _+0.2:~ (4.9+0.1) 30 _+ 127 (25 + 16) 0.9 + 0.2:) (0.6_+0.2) --
14
14 U m -2 4 --
Fasting insulin (mU 1-1)
--
Fasting C-peptide (nmol 1-1)
--
Insulin area (75 g OGTI')
--
Glycosylated haemoglobin (%) Fasting cholesterol (mmol I 1)
5.6 _+0.2 (5.1 +0.1) __
Fasting triglyceride (mmol 1-1)
--
5.3 (6.5) 5.1 _+0.3" (5.9 + 0.3) 1.9 -+ 0.4 (1.9_+0.5)
0.5 U kg -1 6 4.2 _+0.2 (4.1_.+0.2) 10 (3-28) (6 [2-12]) -5435 (2996-13610) (4139 [1712-8477]) -5.7 _+0.2 (5.4 _+0.3) 1.2 (0.5-4.6) (0.9 [0.,I---3.51)
The Danish and Belfast studies were crossover studies, the London one was a placebocontrolled prospective study. Values are mean _+SEM or median (range). * p
There is, at present, renewed interest in the basic actions of growth hormone (GH), stimulated by the now limitless supplies of the synthetic 22K hormone. This allows detailed examination of the actions of GH without the previous concern that extraneous pituitary contaminants were influencing results. The limitless availability of synthetic GH has also increased its potential for use to treat a variety of clinical conditions other than to increase linear growth in GH-deficient children. These include improvement in nitrogen balance in catabolic states (Ponting et al, 1988), GH replacement for hypopituitary adults (Jorgensen et al, 1989; Salomon et al, 1989), increasing lean body mass in the elderly (Rudman et al, 1990), and even possibly for weight reduction and as a treatment for osteoporosis. Whichever of these indications prove to be of subsequent clinical value, it is apparent that iatrogenic secondary diabetes is going to be a consideration in the future, and greater understanding of the actions of GH on carbohydrate metabolism is necessary, both by examining the effects of GH in normal subjects, and also by re-examining the data in hypopituitarism and acromegaly. EFFECTS OF GH ON CARBOHYDRATE METABOLISM
This has been extensively covered by others, and readers are referred to a number of excellent review articles (Altszuler, 1974; Davidson, 1987; Press, 1988). We shall concentrate in this review on in vivo experiments in man. G H has an early insulin-like effect followed by a later anti-insulin effect. The insulin-like effect has been difficult to demonstrate consistently, and is seen mainly in hypophysectomized animals and in tissues not recently exposed to GH. It does not seem to be mediated by changes in either insulin or glucagon concentrations (Adamson, 1981). It may have limited physiological significance, but nonetheless may take on more importance with the pharmacological use of GH. Hypoglycaemia has been reported after GH administration in GH-deficient children (Frohman et al, 1967; Fineberg and Bailli~re's Clinical Endocrinology and Metabolism-819 Vol. 6, No. 4, October 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1621-7 All rights of reproduction in any form reserved
820
P.s.
SHARP ET AL
Merimee, 1974; Hopwood et al, 1975). Young children may be particularly prone as they have a high hepatic glucose output, but have difficulty increasing this further, as may be required following GH administration (Bier et al, 1977; Haymond et al, 1982). Accordingly, the problem seems to be most common in younger and leaner children. The hypoglycaemia has been reported as being symptomatic in about 15 % of children, and asymptomatic in 27-70%. It should, however, be pointed out that these studies report on results in children treated with pituitary-extracted GH, and there have been as yet no reports of hypoglycaemia with the synthetic 22K peptide. Hypoglycaemia has not been reported in any of the studies of GH treatment in adults, and even in careful studies following parenteral administration in the fasting state, the occurrence of early hypoglycaemia is variable (Adamson, 1981; Metcalfe et al, 1981; Rosenfeld et al, 1982; Moller et al, 1990). In contrast, the anti-insulin effect of GH is beyond dispute, and it is undoubtedly of clinical significance. Early studies of the effects of GH established that GH treatment increased plasma insulin concentrations (Altszuler et al, 1968; Sirek et al, 1979). While physiological studies have suggested that GH may release insulin by a direct action on the pancreas (Bouman and Bosboom, 1965), the principal mechanism has been thought to be by induction of insulin resistance which develops 2-12 hours after exposure to GH (Rizza et al, 1982). As expected, therefore, the principal defects of carbohydrate metabolism demonstrated after GH treatment in normal subjects are a defect of glucose uptake by muscle, and a failure of suppression of hepatic glucose output by the liver in response to insulin (Bratusch-Marrain et al, 1982; Rizza et al, 1982). Forearm studies from Denmark have confirmed that in normal subjects following GH administration, muscle glucose uptake is decreased (Moller et al, 1990). In the post-absorptive state in this Danish study, no difference was seen in hepatic glucose output between GH-treated subjects and normal controls. However, hypopituitary children receiving long-term GH treatment do show an elevation in hepatic glucose output (Bougneres et al, 1985). Insulin binding studies with monocytes in normal subjects suggest that the insulin resistance is due to a post-receptor abnormality (Bratusch-Marrain et al, 1982; Rizza et al, 1982; Rosenfeld et al, 1982). This does not seem to be related to the increase in non-esterified fatty acids induced by GH treatment since the abnormality precedes any measurable increase in lipolysis (Fineberg and Merimee, 1974). Bratusch-Marrain et al (1982) suggested that GH impaired non-oxidative glucose disposal, but no measurements were taken. More recently, studies employing indirect calorimetry (Moiler et al, 1990) have suggested that oxidative glucose disposal is decreased while non-oxidative disposal is, in fact, somewhat increased. Hepatic glycogen stores are increased by GH treatment in the dog (Altszuler et al, 1968). The authors of the dog studies have suggested that consequent glycogenolysis contributes to the increased hepatic glucose output with GH treatment. The extent to which increased gluconeogenesis also contributes has been difficult to ascertain, but it is likely to play a part since gluconeogenic precursor concentrations are not decreased, and in rats, the gluconeogenic capacity of the GH-treated liver is greater than normal (Tolman et al, 1973).
GROWTH HORMONE DISORDERS AND SECONDARY DIABETES
821
Many of the studies above have claimed to have employed 'physiological' plasma concentrations of GH, similar to those seen with stress or during sleep. However, it is doubtful if any of these regimens are truly physiological, given the episodic nature of GH secretion--producing short-lived peaks in circulating GH. Perhaps the study which most closely mimics physiological GH secretion is that which employed four daily intramuscular injections given at night (Rosenfeld et al, 1982). Its results, however, were similar to others, showing increased insulin concentrations of 35%. This effect on insulin is not observed following physiological bursts of GH secretion. It is interesting to note that both pituitary-extracted and synthetic GH produced identical results, suggesting that any anti-insulin effect of GH is unrelated to contaminants in the material. It is difficult to identify which of the effects of GH on carbohydrate metabolism are direct effects of GH, and which are mediated by its messenger peptide insulin-like growth factor-1 (IGF-1). IGF-1 is secreted directly by tissues in response to GH stimulation, and it too is now produced by recombinant DNA technology. It might be thought that infusion studies of this peptide would separate the effects of GH from IGF-1. However, the results of such studies have to be interpreted with great caution since IGF-1 is capable of binding not only to its own receptor, but also to the insulin receptor. Thus, infusion of IGF-1 into subjects with Laron dwarfism produced quite marked hypoglycaemia, probably acting via the insulin receptor (Laron et al, 1988). Laron dwarfs are otherwise GH-resistant, due to a defect in the GH receptor. A more recent study, again in a subject with Laron dwarfism to avoid any possible effect of GH, examined the effect of a continuous infusion of IGF-1, aiming to produce serum concentrations of IGF-1 in the high physiological range (Walker et al, 1991). During the period of IGF-1 infusion, fasting glucose was lower than on control days, endogenous insulin was almost totally suppressed and mild postprandial hyperglycaemia was seen. It is difficult to interpret these results. IGF-1 is usually highly protein bound, and despite the serum concentrations being normal, the levels of the free peptide may have been much higher than normal. There would probably have been considerable binding to the insulin receptor, accounting for the lower fasting glucose concentrations. The suppressive effect on insulin, coupled with the relatively mild hypoglycaemic effect of IGF-1 may account for the high post-prandial blood glucose excursions. Further information on the effect of the IGF-1 binding proteins is needed before these studies can be evaluated. HYPOPITUITARISM
From its known effects in normal subjects, the effects of GH deficiency are partially predictable. Unfortunately, studies in man are not comprehensive, but animal studies provide the necessary background. Children with GH deficiency are liable to develop fasting hypoglycaemia, and the tendency is most marked in younger, smaller children. It is more common also if there is
822
P . S . SHARP ET AL
deficiency of other anterior pituitary hormones. Hypoglycaemia is rare in GH-deficient adults, except during prolonged starvation. In young children with fasting hypoglycaemia, hepatic glucose output is decreased by 50% after an overnight fast. Glucose turnover is restored to normal by GH therapy. In older children and adults without hypoglycaemia, hepatic glucose output is normal and turnover is unaffected by GH therapy. These results with G H therapy are somewhat surprising in view of the known hyperglycaemic effects of GH on glucose homeostasis. The effects of GH therapy are, however, complex and include raised IGF-1 concentrations, which may increase glucose disposal, and alterations in body composition, such as increased lean body mass and decreased fat deposition. These changes in body composition also favour glucose disposal. Hypophysectomy causes insulin hypersensitivity in animals, peaking 5-6 weeks after operation (De Bodo and Sinkoff, 1953; De Bodo and Altszuler, 1958). In the hypophysectomized dog, the characteristic pattern of blood glucose after insulin injection is a brief drop, followed by a delayed return to normal compared with the normal dog. The difference in insulin sensitivity was estimated to be 10--20-fold based on the insulin dosage required to produce the same response in normal and hypophysectomized dogs. This response was further characterized in the hypophysectomized dog in which, in response to insulin, muscle glucose uptake was increased, and hepatic glucose output fell more than was observed in animals with an intact pituitary (Wall et al, 1957). Studies in humans, although not so complete, confirm these findings. In lean GH-deficient subjects, fasting insulin concentrations are normal. Early studies using the insulin tolerance test as a diagnostic tool demonstrated delayed recovery from insulin-induced hypoglycaemia in adults although the slope of the earlier fall in blood glucose concentration was normal (Landon et al, 1966). Using the intravenous glucose tolerance test (Frohman et al, 1967), it was demonstrated that glucose uptake was diminished in hypopituitary subjects, and the insulin response to glucose was also diminished. On calculating a ratio of insulin secretion to glucose uptake, insulin sensitivity was observed to be increased, and it was restored towards normal with GH treatment. These data suggest that GH deficiency is a state of insulin hyperresponsiveness. Other data are in conflict with this conclusion. GH deficiency is associated with obesity and a decrease in muscle bulk. As in other obese subjects, fasting hyperinsulinaemia is observed in obese GHdeficient patients, who also show an impaired response to exogenous insulin in comparison with subjects with lower fasting insulin levels. Insulin sensitivity in G H deficiency is complex therefore; it is likely to be normal or increased in lean patients; patients are commonly obese however, with low muscle mass, and these subjects may be insulin resistant. Insulin receptor binding studies have produced similar results to those in normal subjects; G H treatment in hypopituitarism induced a post-binding defect in insulin action (Lippe et al, 1981). In response to a glucose challenge, patients may have impairment of glucose tolerance. Thus, a number of investigators have demonstrated
GROWTH HORMONE DISORDERS AND SECONDARY DIABETES
823
impaired glucose tolerance in GH-deficient subjects (Gold et al, 1968; Merimee et al, 1968, 1970; Lippe et al, 1981). This has been associated with a decreased insulin response to oral glucose (and arginine). It is of interest to note that in the last two studies, treatment with GH resulted in increased insulin secretion, bringing concentrations toward the normal range, but the two studies differedas to whether blood glucose concentrations improved as a result. Certainly this is an area which requires clarification, especially as GH treatment is now being considered in elderly subjects who may have a degree of impairment of glucose tolerance before therapy. It is probable that body composition (obesity and muscle mass) is important in glucose tolerance and insulin secretion. Hyperinsulinaemia after oral glucose has been described, although information on the body composition of these GH-deficient patients is not available. Glucose tolerance, insulin secretion and insulin sensitivity before treatment, and the response to GH, may be determined more by body composition and its changes than by the degree or duration of GH deficiency. ACROMEGALY From its known physiological effects, the result of pathological GH excess can be predicted. It has long been known that overt diabetes can be produced in the normal dog with large doses of GH given over 7 days (Young, 1953). This arises from a high hepatic glucose output, decreased glucose uptake by muscle when corrected for the plasma glucose concentration, and insulin resistance as evidenced by increased plasma insulin concentrations in the presence of the above changes (Altszuler et al, 1968). A number of investigators have commented on the use of glucose tolerance tests as an important part of the diagnostic work-up in acromegaly. Difficulties arise in interpreting glucose concentration results due to different protocols, the differing criteria used for the diagnosis of diabetes and problems in compiling sufficiently large series of patients. In a series of 20 patients with acromegaly, studied using an intravenous glucose tolerance test (IVGTT) (Luft et al, 1967), higher glucose and insulin values were seen in the patients judged to have the more active disease. Patients with marked hyperglycaemia, however, had low insulin concentrations. In similar studies in 16 acromegalics (S6nksen et al, 1967), 10 of the patients achieved insulin concentrations more than 2 standard deviations above the normal mean level. Other authors have examined the hyperinsulinaemia of acromegaly in response to an oral glucose load. In a study of nine acromegalic patients selected to have fasting blood glucose concentrations below 6mmol1-1 (Fineberg et al, 1970), a 100 g glucose load produced glucose concentrations of 3.5 mmoll -~ greater than in the control group, and insulin levels some threefold greater. Similar, but not so striking results were obtained using a 50 g glucose load (Elkeles et al, 1969; Trimble et al, 1980). In this study also it was observed that those with overt diabetes had lower insulin values than those with normal glucose tolerance, suggesting that in those progressing to
824
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SHARP ET AL
diabetes, [3-cell failure precedes the rise in plasma glucose concentrations. In a large series (Wass et al, 1980), the differing criteria for the diagnosis of diabetes were addressed. Using a 50 g glucose load, and applying different published criteria for the interpretation of the test, the percentage judged to have diabetes varied from 13 to 38%. In this study there was a considerable improvement in glucose tolerance after treatment with bromocriptine. Not surprisingly, treatment of acromegaly with a somatostatin analogue, which suppresses concentrations of insulin as well as those of GH, is not associated with such consistent improvement in glucose tolerance (James et al, 1991). Somatostatin analogues also influence gastrointestinal motility and absorption, such that effects on glucose homeostasis are complex and variable. In two further large series of 155 and 256 patients with acromegaly (Jadresic et al, 1982; Nabarro, 1987) the percentage of patients with diabetes was quoted as 27% and 18.8% respectively, figures similar to those of Wass and colleagues (1980). In a study of 23 patients with acromegaly, abnormalities of insulin secretion were reported to persist after treatment of the condition, with normalization of the GH levels and return of glucose concentrations to normal (Roelfsema and Fr61ich, 1985). However, numbers were small, and judgement on this matter should be reserved. There are few studies on the pathogenesis of abnormal glucose tolerance in acromegaly in man. In a study of 10 active acromegalic patients (Foss et al, 1991), forearm glucose uptake after glucose ingestion was lower than in normal controls. Since glucose oxidation rates were similar in acromegalics and controls, the defect was presumed to be an impairment of glucose storage. This finding is at odds with the study of Moller et al (1990), who found that in normal subjects treated with GH, glucose oxidation was decreased. In acromegalics, the impairment of muscle glucose uptake was considered insufficient to account for the raised plasma glucose concentrations, and the major abnormality was thought therefore to be an impairment of suppression of hepatic glucose output. Hepatic glucose output in acromegaly was examined in five acromegalic patients using the hyperinsulinaemic glucose clamp and isotopic dilution methods (Hansen et al, 1986). In this study, whole body glucose disposal was lower in acromegaly than in the control subjects, in response to insulin. However basal hepatic glucose output, and hence basal glucose uptake, was increased. This anomalous finding was ascribed to the mass action of glucose since the acromegalics had slightly higher basal glucose values than the normal controls. This may also have been a factor in previous studies in which glucose turnover was observed to be markedly increased in GHtreated dogs (Young, 1953). Similar high glucose turnover rates were reported in a study of hepatic glucose output in response to glucose infusion (Karlander et al, 1986). These authors also found that hepatic glucose output failed to suppress with glucose infusion. Insulin receptor binding studies in adipose tissue from acromegalic subjects (Bolinder et al, 1986) demonstrated results similar to those found with GH treatment in normal subjects. Insulin binding to adipocytes was decreased, but glucose oxidation and suppression of lipolysis remained defective even when insulin concentrations were raised. The authors
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suggested that insulin resistance in acromegaly was due to a post-binding defect. Similar conclusions were reached in studies of insulin binding to erythrocytes and monocytes (Hansen et al, 1986). Although these authors found that insulin binding in acromegalics did not differ from that of the normal controls, a post-binding defect was apparent. IATROGENIC DIABETES DUE TO GH ADMINISTRATION Although this is not a major clinical problem at present, it deserves consideration in view of the likely proliferation of indications for GH treatment in adult populations. Studies in adults to date have used daily GH doses of 0.05-0.07 U kg -1 body weight (Table 1). The first published study of GH treatment in hypopituitary adults did not comment on changes in plasma glucose or insulin levels (Jorgensen et al, 1989), but a similar study (Salomon et al, 1989), using the higher dose of GH, reported a trivial rise in fasting plasma glucose. A small rise in fasting plasma insulin was also observed (Table 1). Glucose turnover was not affected significantly. A third study using a higher dose of GH for 6 months demonstrated no effect on fasting glucose, insulin or glycosylated haemoglobin concentrations, nor on the insulin response to a 75 g oral glucose load (Whitehead et al, 1992).
Table 1. Metabolic effects of prolonged GH treatment in hypopituitary adults.
Outcome GH (placebo) Patient number GH dose (weekly) Duration of therapy (months) Fasting glucose (mmol 1-i)
Denmark (Jorgensen et al, 1989)
London (Salomon et al, 1989)
Belfast (Whitehead et al, 1992)
22
12 (12) 0.35 U kg -a 6 5.1 _+0.2:~ (4.9+0.1) 30 _+ 127 (25 + 16) 0.9 + 0.2:) (0.6_+0.2) --
14
14 U m -2 4 --
Fasting insulin (mU 1-1)
--
Fasting C-peptide (nmol 1-1)
--
Insulin area (75 g OGTI')
--
Glycosylated haemoglobin (%) Fasting cholesterol (mmol I 1)
5.6 _+0.2 (5.1 +0.1) __
Fasting triglyceride (mmol 1-1)
--
5.3 (6.5) 5.1 _+0.3" (5.9 + 0.3) 1.9 -+ 0.4 (1.9_+0.5)
0.5 U kg -1 6 4.2 _+0.2 (4.1_.+0.2) 10 (3-28) (6 [2-12]) -5435 (2996-13610) (4139 [1712-8477]) -5.7 _+0.2 (5.4 _+0.3) 1.2 (0.5-4.6) (0.9 [0.,I---3.51)
The Danish and Belfast studies were crossover studies, the London one was a placebocontrolled prospective study. Values are mean _+SEM or median (range). * p
