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Baris Akinci Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA
Division of Endocrinology and Metabolism, Dokuz Eylul University, Izmir, Turkey

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Rasimcan Meral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Diana Rus Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Rita Hench Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Adam H Neidert Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Frank DiPaola Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

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Maria Westerhoff Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

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Simeon I Taylor Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Elif A Oral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.

  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.

  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.

  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.

  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

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Alessandro Rossini Endocrinology and Diabetes Unit, ASST Papa Giovanni XXIII, Bergamo, Italy

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Francesca Perticone Endocrine Unit, Department of Internal Medicine

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Laura Frosio Endocrine Unit, Department of Internal Medicine

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Marco Schiavo Lena Department of Pathology, San Raffaele Hospital, Milan, Italy

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Roberto Lanzi Endocrine Unit, Department of Internal Medicine

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Summary

ACTH-secreting pheochromocytoma is a very rare cause of Cushing’s syndrome, with a high morbidity and mortality risk due to both cortisol and catecholamines excess. We report the case of a 45-year-old female patient with a 3 cm, high-density, left adrenal mass, diagnosed as an ACTH-secreting pheochromocytoma. The biochemical sensitivity of the tumor to somatostatin analogues was tested by a 100 μg s.c. octreotide administration, which led to an ACTH and cortisol reduction of 50 and 25% respectively. In addition to alpha and beta blockers, preoperative approach to laparoscopic adrenalectomy included octreotide, a somatostatin analogue, together with ketoconazole, in order to achieve an adequate pre-surgical control of cortisol release. Histopathological assessment confirmed an ACTH-secreting pheochromocytoma expressing type 2 and 5 somatostatin receptors (SSTR-2 and -5).

Learning points:

  • ACTH-secreting pheochromocytomas represent a rare and severe condition, characterized by high morbidity and mortality risk.

  • Surgical removal of the adrenal mass is the gold standard treatment, but adequate medical therapy is required preoperatively to improve the surgical outcome and to avoid major complications.

  • Somatostatin analogs, in addition to other medications, may represent a useful therapeutic option for the presurgical management of selected patients.

  • In this sense, the octreotide challenge test is a useful tool to predict favorable therapeutic response to the treatment.

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Ken Takeshima First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Hiroyuki Ariyasu First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Tatsuya Ishibashi First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Shintaro Kawai First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Shinsuke Uraki First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Jinsoo Koh Department of Neurology, Wakayama Medical University, Wakayama,, Japan

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Hidefumi Ito Department of Neurology, Wakayama Medical University, Wakayama,, Japan

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Takashi Akamizu First Department of Internal Medicine, Wakayama Medical University, Wakayama,, Japan

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Summary

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disease affecting muscles, the eyes and the endocrine organs. Diabetes mellitus and primary hypogonadism are endocrine manifestations typically seen in patients with DM1. Abnormalities of hypothalamic–pituitary–adrenal (HPA) axis have also been reported in some DM1 patients. We present a case of DM1 with a rare combination of multiple endocrinopathies; diabetes mellitus, a combined form of primary and secondary hypogonadism, and dysfunction of the HPA axis. In the present case, diabetes mellitus was characterized by severe insulin resistance with hyperinsulinemia. Glycemic control improved after modification of insulin sensitizers, such as metformin and pioglitazone. Hypogonadism was treated with testosterone replacement therapy. Notably, body composition analysis revealed increase in muscle mass and decrease in fat mass in our patient. This implies that manifestations of hypogonadism could be hidden by symptoms of myotonic dystrophy. Our patient had no symptoms associated with adrenal deficiency, so adrenal dysfunction was carefully followed up without hydrocortisone replacement therapy. In this report, we highlight the necessity for evaluation and treatment of multiple endocrinopathies in patients with DM1.

Learning points:

  • DM1 patients could be affected by a variety of multiple endocrinopathies.

  • Our patients with DM1 presented rare combinations of multiple endocrinopathies; diabetes mellitus, combined form of primary and secondary hypogonadism and dysfunction of HPA axis.

  • Testosterone treatment of hypogonadism in patients with DM1 could improve body composition.

  • The patients with DM1 should be assessed endocrine functions and treated depending on the degree of each endocrine dysfunction.

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Murray B Gordon Allegheny Neuroendocrinology Center, Departments of Medicine and Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA

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Kellie L Spiller Allegheny Neuroendocrinology Center, Departments of Medicine and Neurosurgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA

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Summary

Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5–223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient’s antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin.

Learning points

  • Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide.

  • Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled.

  • Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus.

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