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.


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].


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].


  • 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


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  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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