Case report
QJM
IGF2-induced hypoglycemia unresponsive to everolimus
T.I.M. KOREVAAR1, F. RAGAZZONI1, A. WEAVER2, N. KARAVITAKI1 and A.B. GROSSMAN1
From the 1 Oxford Centre for Diabetes, Endocrinology and Metabolism and 2 Department of Clinical Oncology, Churchill Hospital, University of Oxford, Headington, Oxford, UK
Address correspondence to Prof. Ashley B. Grossman, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Headington, Oxford OX3 7LE, UK. email: ashley.grossman@ocdem.ox.ac.uk
Large tumours, usually of mesodermal origin, can cause severe and often intractable hypoglycaemia in the presence of undetectable levels of insulin. This phenomenon, referred to as non-islet-cell tumour hypoglycaemia (NICTH), is now generally thought to be due to secretion by the tumour of insulin-like growth factor-2 (IGF-2). Various inter- actions of IGF-2 with different receptors have been described,1 but most of the biological actions of IGF-2 are thought to be mediated via the IGF-1 re- ceptor (IGF-1R), the binding of which results in differentiation, malignant transformation and the regulation of cell-cell adhesion. Interaction with the IGF-2 receptor (IGF2-R) promotes endocytosis and degradation of extra-cellular IGF-2 and may play a role in the transport of lysosomal enzymes, but is unlikely to be pathologically important. However, IGF-2 has also been shown to have high affinity bind- ing with the insulin receptor; binding to the A isoform predominantly leads to mitogenic effects, but it also has (low) affinity with the B isoform that is principally concerned with its metabolic effects, including hypo- glycaemia. Usually, IGF-2 is extensively bound to its binding-protein BP-3, and thus very little has access to the extravascular space. In NICTH the secretory product is principally the precursor pro-IGF-2, which is unable to bind BP-3 and thus can access extra-vascular receptors such as the insulin receptor isoforms. Thus, it has been thought that the hypogly- caemia in this condition relates to IGF-2 occupation of the insulin receptor. Downstream signalling form the insulin receptor involves the mammalian target of rapamycin (mTOR) pathway, and several recent case
reports have suggested that blockade of the mTOR pathway with everolimus can effectively treat the severe hypoglycaemia associated with malignant insulinomas. We encountered a patient with an adre- nocortical carcinoma secreting IGF-2 who developed intractable hypoglycaemia, but treatment with ever- olimus was unable to control the metabolic upset to any extent. We suggest that mTOR inhibitors used for malignant insulinomas act to change the secretion or production of insulin per se, and are unlikely to be effective at attenuating the effects of other activators of the insulin receptor.
A 41-year-old female patient initially presented to her GP in November 2008 with right-sided loin pain, sweating, light-headedness and palpitations for the previous 1-2 months. She noticed that her symptoms were relieved by food. Her past medical history consisted of pyelonephritis several years before, but nil else. On examination she had evi- dence of a right abdominal mass; she was not clin- ically Cushingoid. Ultrasound of the abdomen revealed a large mass adjacent to her right kidney. She was referred to our hospital for biopsy but while awaiting this she presented the following month as an emergency with severe hypoglycaemia. Investigations on that admission are shown in Table 1; in essence, they confirmed significant hypoglycaemia in the face of undetectable levels of insulin and an inappropriate IGF-1/IGF-2 ratio highly suggestive of an IGF-2-secreting tumour.2,3 The hypoglycaemia was then stabilized on 10% dextrose infusion and 8 mg dexamethasone. Subsequently, as shown in Figure 1, CT scanning revealed a heterogeneously
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| Blood test | Outcome | Reference range |
|---|---|---|
| Normetadrenaline | 0.81 umol/24 h | 0.00-3.45 |
| Metadrenaline | 0.41 umol/24 h | 0.00-1.40 |
| 3-Methoxytyramine | 0.40 umol/24 h | 0.00-2.55 |
| 09.00 h Cortisol | 386 nmol/l | 180-620 |
| Androstenedione | >35 nmol/l | 3-8 |
| DHEASA | 15.1 mol/l | 1.9-9.4 |
| Testosterone4 | 3.5 nmol/l | 0.5-2.6 |
| IGF-2:IGF-1 ratio4 | 30.4 | <10 |
| IGF-1+ | 3.4 nmol/l | 13-50 |
| IGF-2 | 103.2 nmol/l | |
| IGFBP-3+ | 1.3 mg/l | 1.7-5.2 |
| Glucose+ | 1.4 mmol/l | 3.0-5.5 |
| Insulin+ | 2.0 pmol/l | 17-77 |
| C-peptide+ | <0.02 nmol/l | 0.27-1.28 |
DHEAS, Dehydroepiandrosterone; IGF, insulin-like growth factor; IGFBP-3, IGF binding protein-3.
enhancing 14 x 4.5 x 11 cm right adrenal mass that was radiographically highly suggestive of an adrenal carcinoma and liver metastases. CT of the chest revealed multiple lung metastases. A right adrenalect- omy and right nephrectomy were performed, with the histopathology confirming an adrenocortical carcinoma.
Post-operatively, the patient was started on mito- tane therapy, 1 g tds, together with hydrocortisone replacement, but over the next 3 months the re- sidual tumour progressed with new-onset liver metastases and retroperitoneal/para-arotic lymph- adenopathy. Her mitotane levels were found to be
non-therapeutic and the daily dose was increased to 4 g daily, and then over the next 3 months to 7 g daily. Between the beginning of August 2009 and January 2010 the patient received 6 cycles of etopo- side, doxorubicin and cisplatin combination chemo- therapy. Initially her tumour showed evidence of regression, but 2 months later the disease was found to be progressive. Attempts at targeted therapy were uniformly ineffective.
With regards to her hypoglycaemia, post- operatively this regressed until June 2009 when the hypoglycemic episodes returned requiring mul- tiple recurrent hospital admissions. For ~1 year the patient was treated with dexamethasone, hydrocor- tisone and growth hormone 8 mg daily.4-6 Initially, the quantity and severity of the hypoglycaemic epi- sodes improved but after several months they returned; by July 2011 the patient required continu- ous infusion of glucose to maintain normogly- caemia. The dexamethasone was replaced with prednisolone 30 mg daily, and octreotide 100 mcg tds sc was added,7,8 but the hypoglycaemia per- sisted. The patient had thus proven to be resistant to high doses of glucocorticoids, growth hormone and octreotide.
Everolimus is an oral inhibitor of the mTOR kinase that is involved in the cellular response to nutrients and growth factor signalling. Insulin-receptor stimu- lation is a major upstream effector of mTOR which, in response to glucose, increases protein synthesis to modulate anabolic processes. Recently, hypogly- caemia secondary to insulinomas refractory to con- ventional therapy has been reported to respond to treatment with everolimus with resumption of normoglycaemia and frequently a loss of the need
for continuous glucose infusion.9-11 In a previously diabetic patient, hyperglycemia even recurred after treatment with everolimus, necessitating insulin treatment.9 One explanation for this effect was con- sidered to be blockade of the downstream signalling from insulin through the mTOR pathway. We rea- soned that if IGF-2 operated through the same mechanism then everolimus should be effective in restoring normoglycaemia in our patient. We there- fore commenced her on oral everolimus 10 mg daily. However, after 2 weeks everolimus had no impact on the hypoglycaemia whatsoever, and after transfer to hospice care she succumbed to her disease.
This is the first report regarding mTOR inhibition in a patient presenting with NICTH. In such patients the proportions of pro-IGF-2 to native IGF-2 are altered, and these can be measured by thin- layer chromatography, as we have previously described.12 However, an alternative technique is to measure the ratio of IGF-2 and IGF-1,2,3 a level >10 being indicative of NICTH; in our patient the ratio was 30.4. While being treated with everolimus our patient did not exhibit any glycaemic improve- ment. This suggests that either IGF-2 does not cause hypoglycaemia by activation of the insulin receptor, or that the mode of action of everolimus in this situ- ation is not downstream of the insulin receptor. It is possible that the IGF1-R and insulin receptor A or B may form receptor hybrids when co-expressed on the same cell;13 high expression of these hybrid re- ceptors has been found in different types of can- cer,14 but the significance of IGF-2 binding to these receptors is unknown. More likely, mTOR in- hibition blocks mechanisms involved in insulin re- lease rather than its action and a decrease in insulin levels of 14-64% has been shown in one study of patients treated with everolimus.1º Moreover, beta- cell insulin-receptors mediate insulin-stimulated in- sulin production that may be disrupted by mTOR inhibition.15,16 Furthermore, another mTOR inhibi- tor, tacrolimus, was shown to partially close the ATP-sensitive potassium channel in pancreatic beta-cells, which would lead to an initial insulin release but reduce subsequent responses through this pathway.17 The latter is of particular interest seeing as, in insulinomas, everolimus was reported to work within a time frame of 14 days.10
The combined hypoglycemia treatment of steroids and growth hormone temporarily worked and im- proved our patient’s quality of life and she was able to stay at home longer and could continue lim- ited work. After failure of this regimen to stabilize blood glucose levels we remain unable to offer a medical solution for severe hypoglycemic episodes in patients with severe/progressive NICTH. It may be
that treatment with an IGF1-R antagonist, such as figitumumab,18 may offer more hope for the future.
Funding
Everolimus was supplied on a compassionate single- patient basis by Novartis. No funding was received by an author concerning the support of this study.
Conflict of interest: None declared.
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