Acromegaly

Acromegaly is a condition characterised by oversecretion of growth hormone (GH) from the anterior pituitary gland, most commonly caused by a pituitary tumour. In childhood or adolescence, oversecretion of GH leads to an increase in growth of all bones, resulting in gigantism. If GH oversecretion develops after the epiphyseal plates have fused in the long bones, these cannot grow further; however, continued growth occurs in the bones of the face, hands and feet, resulting in the characteristic features of acromegaly. GH opposes several of the actions of insulin to produce insulin resistance. Overt diabetes mellitus develops in about 20%, and glucose intolerance in about 40%, of patients with acromegaly.

Introduction

Acromegaly is an endocrine disorder caused by oversecretion of Growth Hormone (GH). In more than 98% of cases this happens due to a GH-secreting pituitary adenoma; in the other cases (less than 2%) it is the result of over-secretion of Growth Hormone Releasing Hormone (GHRH) from a hypothalamic lesion or from a carcinoid tumour of the gut or pancreas [1]. Acromegaly is occasionally found in association with hyperparathyroidism and pancreatic islet cell tumours like glucagonoma, insulinoma & gastrinoma as part of Multiple Endocrine Neoplasia syndrome (MEN) Type 1 [2][3].

The correlation between acromegaly and diabetes was noted as early as 1884 by Loeb [4]. Subsequent studies have shown that the incidence of hyperglycaemia and glycosuria in acromegalic patients may vary between 10-40 % [5]. Overt diabetes mellitus (DM) has been reported in 13-30% of acromegalic patients [6], while impaired glucose tolerance was noted amongst 36% acromegalic patients in another series [7]. Recent data from the French Acromegaly Registry reported a 22.3% incidence of DM in acromegalic patients [8]. The average interval between the onset of acromegaly and that of DM was 9.5 years (range 1 - 22 years) [9]; however, simultaneous onset of acromegaly and diabetes mellitus was noted in as many as 46.8% patients in the French Acromegaly Registry [8].

Pathogenesis and clinical profile of diabetes mellitus in acromegaly

Dysglycaemia in acromegaly can be explained by the direct hyperglycaemic effects of excess GH. GH increases insulin resistance (IR), and consequently insulin action is reduced in both hepatic and extrahepatic tissues, with decrease in both the suppression of hepatic glucose production and insulin dependent glucose disposal. However, the exact mechanism of insulin resistance in acromegaly is not very clear. Post receptor defects in insulin action are apparently responsible, because insulin receptor concentrations are unaffected [10][11]. Cross talk between insulin and GH receptors is also responsible for the post receptor defect, and this is supposedly mediated by insulin receptor substrate 1 (IRS 1) and phosphatidylinositol 3-kinase (PI3K) [12]. Amongst the extrahepatic tissues, impairment of insulin mediated activation of glycogen synthase has been noted in skeletal muscles [13][14]. Insulin resistance is also worsened by the lipolytic action of GH generating non-esterified fatty acids (NEFAs) that act on the liver to increase hepatic glucose production and inhibit muscle utilisation of glucose. This leads to compensatory hyperinsulinemia, ultimately leading to a β cell failure, finally leading to full blown diabetes.

Clinically, therefore, diabetes in acromegaly resembles Type 2 Diabetes. Diabetic complications, such as retinopathy, are rare but can be seen occasionally [2]. Diabetic ketoacidosis is a rare but documented complication (15). Age at diagnosis of acromegaly, body mass index (BMI), hypertension & duration of evolution of acromegaly were significant independent risk factors associated with development of diabetes [8]. Presence of hypertension increased the risk of diabetes by 2.5%. Female acromegalic patients have a higher probability of developing DM. The evolution of acromegaly was slower in the diabetic group, compared to the non-diabetic acromegaly. There was no significant difference between GH and IGF1 levels in the two groups [8].

Treatment

The French Registry data reported that of the 23% acromegalic patients with DM, 13 % required oral hypoglycaemic agents (OHA) and or insulin, while the remaining 10% could be managed with diet and lifestyle management alone [8]. In another series of 31 acromegalic patients with overt DM, one third required insulin therapy, whilst the other two-thirds were maintained on diet or OHA alone [2]. Diabetic ketoacidosis (DKA), a very rare occurrence, should be managed using the standard protocol for the management of DKA [15]. Following successful treatment of acromegaly with surgery, irradiation or bromocriptine/cabergoline, glucose tolerance improves and insulin values decrease; glucose intolerance usually resolves but those with a shorter duration of DM and lower levels of GH are more likely to undergo complete resolution [15].

Somatostatin analogs and pegvisomant in acromegaly – effects on glucose tolerance

The only exception to the fact that treatment of acromegaly results in an improvement in glucose intolerance is the use of somatostatin analogues (SSA), where hyperglycaemia might worsen because of suppression of insulin secretion by SSA [16]. However, a recent metaanalysis of use of SSAs in acromegalic patients showed that the use of SSAs in non-diabetic acromegalic patients significantly reduced fasting insulin values, without any effect on fasting plasma glucose and HbA1c [17]. Several studies have compared the effects of the different SSAs on glucose tolerance in acromegalic patients: while some have shown the superiority of Lanreotide SR over Octreotide LAR in glycaemic response [18], others did not find any significant difference between the two SSAs, especially when given over periods more than 5 years [19][20]. Pegvisomant, when added to SSAs, did not significantly alter HbA1c, fasting plasma glucose and HOMA–IR over 12 months of treatment, notwithstanding the fact that there was a significant reduction of IGF-I [21]. Addition of pegvisomant to SSAs was seen to transiently raise liver enzymes 2.3 folds higher in the diabetic subgroup as compared to the non-diabetic subgroup [22]. However, when pegvisomant was substituted for SSAs, there was a significant improvement of mean fasting plasma glucose and HbA1c (more than 1%) along with normalisation of IGF-I [23].

Summary

  • Overt diabetes develops in about 20% of patients with acromegaly and glucose intolerance in about 40%.
  • Body mass index appears to be the major predictor of worsening glycaemic control.
  • Glycaemic control is best achieved by treating the underlying state of growth hormone (GH) excess.
  • Glucose tolerance and diabetes generally improve following treatment of underlying disease.
  • There are conflicting data regarding the effects of somatostatin analogues (SSA) on glucose homeostasis.
  • SSAs may reduce insulin resistance, but they also might impair insulin secretion.
  • Reduced fasting glucose levels and glycosylated haemoglobin are reported following treatment with pegvisomant.
  • If diabetes persists after treatment, hyperglycaemia should be managed according to standard treatment guidelines for patients with type 2 diabetes.
  • Oral secretagogues and/or insulin sensitizers theoretically offer the greatest potential for glycaemic control based on the pathophysiology of diabetes in acromegaly.
  • Insulin should be started if oral agents are unsuccessful in controlling blood glucose.

[a] La Sapienza

References

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  2. ^ Nabarro JDN. Acromegaly. Clin Endocrinol.1987; 26: 481-512.

  3. ^ Jadresic A, Banks LM, Child DF et al. The acromegaly syndrome: the relation between clinical features, growth hormone values and radiological characteristics of pituitary tumours. Q J Med 1982; 51: 189-204

  4. ^ Loeb M. Ein Erklarungsversuch der verschiedenartigen Temperaturver-haltnisse bei der tuberculosen Basilarmeningitis. Deutsches Arch f. klin Med. 1884; 34:443

  5. ^ Darragh JH, Shaw WM. Acromegaly and Diabetes. Canad MAJ 1954; 64:146-150

  6. ^ Wass JAH, Cudworth AG Bottazzo GF et al. An assessment of glucose intolerance in acromegaly and its response to medical treatment. Clin Endocrinol 1980; 12:53-59

  7. ^ Ezzat S, Forster MJ, Berghtold P et al. Acromegaly: clinical and biochemical features in 500 patients. Medicine 1994; 73:233-240

  8. ^ Fieffe S, Morange I, et al. Diabetes in Acromegaly: prevalence, risk factors and evolution: data from French Acromegaly Registry. Eur J Endocrinol 2011; 164: 877-884

  9. ^ Coggeshall C, Root HF. Acromegaly and diabetes mellitus. Endocrinology 1940; 26:1-25

  10. ^ Rizza RA, Mandarino LJ, Gerich JE. Effects of growth hormone on insulin action in men: mechanisms of insulin resistance, impaired suppression of glucose production and impaired stimulation of glucose utilisation. Diabetes 1982; 31:663-669.

  11. ^ Rosenfeld RG, Wilson DM, Dollar LA et al. Both human growth hormone and recombinant DNA derived human growth hormone cause insulin resistance at a post receptor site. JCEM 1982; 54: 1033-1038

  12. ^ Dominicini FP, Argentino DP et al. Influence of the cross talk between Growth Hormone and Insulin signalling on the modulation of insulin sensitivity. Growth Hormone and IGF Research 2005; 15:324-336

  13. ^ Fowelin J, Attavall Svon Schenck H et al. Characterisation of insulin antagonistic effects of growth hormone in Man. Diabetologia 1991; 34:500-506.

  14. ^ Bak JF, Moller N, Schmitz O. Effects of growth hormone on fuel utilisation and muscle glycogen synthase activity in normal humans. Am J Physiol 1991; E736-E742

  15. ^ Simmons LR & Markovic TP. Clinical Diabetes 2012; 30:170-172

  16. ^ Ho KK, Jenkins AB, Furler SM, Borkman M et al. Impact of octreotide, a long acting somatostatin analogue on glucose tolerance and insulin sensitivity in acromegaly. Clin Endocrinol 1992; 36:271-279

  17. ^ Maziotti G, Floriani I et al. Effects of Somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. JCEM 2009; 94:1500-1508

  18. ^ Ronchi C, Epaminonda P, Cappiello V et al. Effects of two different somatostatin analogs on glucose tolerance in acromegaly: Journ Endocrinol Invest 2002; 25:502-507

  19. ^ Colao A, Auriemma RS et al. Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin like growth factor-1 levels, tumor shrinkage and cardiovascular disease. JCEM 2009; 94:3746-3756

  20. ^ Colao A, Auriemma RS et al. Glucose tolerance and somatostatin analog in acromegaly: a 12 month study. JCEM 2009; 94:2907-2914

  21. ^ Marinis LD, Bianchi A et al: Long term effects of pegvisomant when combined with somatostatin analogs (SSA) in glucose homeostasis in patients with active acromegaly partially resistant to SSA. Pituitary 2007; 10: 227-232

  22. ^ Neggers SJCMM, de Herder WW et al. Combined treatment for acromegaly with somatostatin analogs and pegvisomant: long term safety of upto 4.5 years (median 2.2 years) of follow up in 86 patients. Euro J Endocrinol 2009; 160:529-533

  23. ^ Barkan AL, Burman P, Trainer P, Drake WM, Clemmons D et al. Glucose homeostasis and safety in patients with acromegaly converted from long acting octreotide to Pegvisomant. JCEM 2005; 90:5684-5691

Footnotes

  1. ^ This artcile supersedes an earlier version of this entry, prepared by the following students at La Sapienza - Bertoccini Laura, Cianotti Silvia, Cursano Maria Concetta, Danza Aurora ILaria.

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