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Agnieszka Łebkowska Department of Internal Medicine and Metabolic Diseases, Diabetology and Internal Medicine

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Anna Krentowska Department of Internal Medicine and Metabolic Diseases, Diabetology and Internal Medicine

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Agnieszka Adamska Department of Endocrinology, Diabetology and Internal Medicine

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Danuta Lipińska Department of Endocrinology, Diabetology and Internal Medicine

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Beata Piasecka Department of Endocrinology, Diabetology and Internal Medicine

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Otylia Kowal-Bielecka Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland

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Maria Górska Department of Endocrinology, Diabetology and Internal Medicine

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Robert K Semple Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

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Irina Kowalska Department of Internal Medicine and Metabolic Diseases, Diabetology and Internal Medicine

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Summary

Type B insulin resistance syndrome (TBIR) is characterised by the rapid onset of severe insulin resistance due to circulating anti-insulin receptor antibodies (AIRAs). Widespread acanthosis nigricans is normally seen, and co-occurrence with other autoimmune diseases is common. We report a 27-year-old Caucasian man with psoriasis and connective tissue disease who presented with unexplained rapid weight loss, severe acanthosis nigricans, and hyperglycaemia punctuated by fasting hypoglycaemia. Severe insulin resistance was confirmed by hyperinsulinaemic euglycaemic clamping, and immunoprecipitation assay demonstrated AIRAs, confirming TBIR. Treatment with corticosteroids, metformin and hydroxychloroquine allowed withdrawal of insulin therapy, with stabilisation of glycaemia and diminished signs of insulin resistance; however, morning fasting hypoglycaemic episodes persisted. Over three years of follow-up, metabolic control remained satisfactory on a regimen of metformin, hydroxychloroquine and methotrexate; however, psoriatic arthritis developed. This case illustrates TBIR as a rare but severe form of acquired insulin resistance and describes an effective multidisciplinary approach to treatment.

Learning points:

  • We describe an unusual case of type B insulin resistance syndrome (TBIR) in association with mixed connective tissue disease and psoriasis.

  • Clinical evidence of severe insulin resistance was corroborated by euglycaemic hyperinsulinaemic clamp, and anti-insulin receptor autoantibodies were confirmed by immunoprecipitation assay.

  • Treatment with metformin, hydroxychloroquine and methotrexate ameliorated extreme insulin resistance.

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Åke Sjöholm Division of Endocrinology and Diabetology, Department of Internal Medicine, Gävle Hospital, Gävle, Sweden

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Maria João Pereira Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Thomas Nilsson Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Torbjörn Linde Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Petros Katsogiannos Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Jan Saaf Department of Internal Medicine, Västmanland Hospital Köping, Köping, Sweden

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Jan W Eriksson Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Summary

Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia. Described here is a patient who within a few months after the onset of autoimmune type 1 diabetes increased her insulin requirements more than 20-fold; despite this she had considerable difficulty maintaining a plasma glucose value of <40–60 mmol/L (720–1100 mg/dL). On suspicion of TBIRS, the patient was started on tapering dose of glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect. Within days, insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L (126–144 mg/dL). The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays. After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses and immune column treatments with temporarily remarkable effect. Mixed and transient results were seen with rituximab, mycophenolic acid and bortezomib, but the glycemic status remained suboptimal. Lack of compliance and recurrent infections may have contributed to this.

Learning points:

  • Type B insulin resistance syndrome (TBIRS) is a very rare autoimmune disorder with acquired polyclonal autoantibodies against the insulin receptor, resulting in severe and refractory hyperglycemia.

  • We describe here a young patient in whom, a few months after the onset of a regular autoimmune diabetes, insulin requirements in a short time increased more than 20-fold, but despite this, the plasma glucose level could be kept at <40–60 mmol/L only with considerable difficulty. Did this patient have TBIRS?

  • On suspicion of TBIRS, the patient was started on tapering glucocorticoids to overcome the autoimmune insulin receptor blockade, resulting in an immediate and pronounced effect; within days insulin requirements decreased by 80–90% and plasma glucose stabilized around 7–8 mmol/L.

  • The presence of antibodies to the insulin receptor was detected by immunoprecipitation and binding assays.

    After a 4-month remission on low maintenance dose prednisolone, the patient relapsed, which required repeated plasmaphereses with temporarily remarkable effect.

  • TBIRS should be considered in diabetic patients whose glycemia and/or insulin requirements are inexplicably and dramatically increased.

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Aishah Ekhzaimy Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Afshan Masood Obesity Research Center, and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Seham Alzahrani Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Waleed Al-Ghamdi Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Daad Alotaibi Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Muhammad Mujammami Department of Medicine and College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Summary

Central diabetes insipidus (CDI) and several endocrine disorders previously classified as idiopathic are now considered to be of an autoimmune etiology. Dermatomyositis (DM), a rare autoimmune condition characterized by inflammatory myopathy and skin rashes, is also known to affect the gastrointestinal, pulmonary, and rarely the cardiac systems and the joints. The association of CDI and DM is extremely rare. After an extensive literature search and to the best of our knowledge this is the first reported case in literature, we report the case of a 36-year-old male with a history of CDI, who presented to the hospital’s endocrine outpatient clinic for evaluation of a 3-week history of progressive facial rash accompanied by weakness and aching of the muscles.

Learning points:

  • Accurate biochemical diagnosis should always be followed by etiological investigation.

  • This clinical entity usually constitutes a therapeutic challenge, often requiring a multidisciplinary approach for optimal outcome.

  • Dermatomyositis is an important differential diagnosis in patients presenting with proximal muscle weakness.

  • Associated autoimmune conditions should be considered while evaluating patients with dermatomyositis.

  • Dermatomyositis can relapse at any stage, even following a very long period of remission.

  • Maintenance immunosuppressive therapy should be carefully considered in these patients.

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Maria Tomkins Department of Endocrinology and Diabetes, Beaumont Hospital Dublin, Dublin, Ireland

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Roxana Maria Tudor Department of Endocrinology and Diabetes, Beaumont Hospital Dublin, Dublin, Ireland

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Diarmuid Smith Department of Endocrinology and Diabetes, Beaumont Hospital Dublin, Dublin, Ireland

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Amar Agha Department of Endocrinology and Diabetes, Beaumont Hospital Dublin, Dublin, Ireland

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Summary

This case is the first to describe a patient who experienced concomitant agranulocytosis and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis as an adverse effect of propylthiouracil treatment for Graves’ disease. A 42-year-old female with Graves’ disease presented to the emergency department (ED) with a 2-week history of fevers, night sweats, transient lower limb rash, arthralgia, myalgia and fatigue. She had been taking propylthiouracil for 18 months prior to presentation. On admission, agranulocytosis was evident with a neutrophil count of 0.36 × 109/L and immediately propylthiouracil was stopped. There was no evidence of active infection and the patient was treated with broad-spectrum antibodies and one dose of granulocyte colony-stimulation factor, resulting in a satisfactory response. On further investigation, ANCAs were positive with dual positivity for proteinase 3 and myeloperoxidase. There was no evidence of end-organ damage secondary to vasculitis, and the patient’s constitutional symptoms resolved completely on discontinuation of the drug precluding the need for immunosuppressive therapy.

Learning points:

  • Continued vigilance and patient education regarding the risk of antithyroid drug-induced agranulocytosis is vital throughout the course of treatment.

  • ANCA-associated vasculitis is a rare adverse effect of antithyroid drug use.

  • Timely discontinuation of the offending drug is vital in reducing end-organ damage and the need for immunosuppressive therapy in drug-induced ANCA-associated vasculitis.

  • Similarities in the pathogenesis of agranulocytosis and drug-induced ANCA-associated vasculitis may offer insight into an improved understanding of vasculitis and agranulocytosis.

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Shivani Patel Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

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Venessa Chin The Kinghorn Cancer Centre, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Jerry R Greenfield Department of Diabetes and Endocrinology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
St Vincent’s Clinical School, UNSW Sydney, Darlinghurst, New South Wales, Australia

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Summary

Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).

Learning points:

  • Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.

  • Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.

  • Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.

  • Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.

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Masato Kotani Center for Diabetes, Endocrinology and Metabolism
Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan
Asahina Shinryoujo, Fujieda, Shizuoka, Japan

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Naohisa Tamura Center for Diabetes, Endocrinology and Metabolism
Research Support Center, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan

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Tatsuhide Inoue Center for Diabetes, Endocrinology and Metabolism

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Issei Tanaka Center for Diabetes, Endocrinology and Metabolism

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Summary

Type B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings.

Learning points:

  • Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors.

  • This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents.

  • Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.

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Isabella Lupi Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Alessandro Brancatella Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Mirco Cosottini Neuroradiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

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Nicola Viola Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Giulia Lanzolla Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Daniele Sgrò Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Giulia Di Dalmazi Section of Endocrinology, Department of Medicine and Aging Sciences, Ce.S.I-Me.T., “G.D’Annunzio” University of Chieti-Pescara, Chieti, Italy

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Francesco Latrofa Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Patrizio Caturegli Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore Maryland, USA

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Claudio Marcocci Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Summary

Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.

Learning points:

  • PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.

  • Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.

  • Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.

  • PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases

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Jose León Mengíbar Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Ismael Capel Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Teresa Bonfill Medical Oncology Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Isabel Mazarico Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Laia Casamitjana Espuña Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Assumpta Caixàs Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Mercedes Rigla Endocrinology and Nutrition Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain

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Summary

Durvalumab, a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules, is increasingly used in advanced neoplasias. Durvalumab use is associated with increased immune-related adverse events. We report a case of a 55-year-old man who presented to our emergency room with hyperglycaemia after receiving durvalumab for urothelial high-grade non-muscle-invasive bladder cancer. On presentation, he had polyuria, polyphagia, nausea and vomiting, and laboratory test revealed diabetic ketoacidosis (DKA). Other than durvalumab, no precipitating factors were identified. Pre-durvalumab blood glucose was normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. Simultaneously, he presented a thyroid hormone pattern that evolved in 10 weeks from subclinical hyperthyroidism (initially attributed to iodinated contrast used in a previous computerised tomography) to overt hyperthyroidism and then to severe primary hypothyroidism (TSH: 34.40 µU/mL, free thyroxine (FT4): <0.23 ng/dL and free tri-iodothyronine (FT3): 0.57 pg/mL). Replacement therapy with levothyroxine was initiated. Finally, he was tested positive for anti-glutamic acid decarboxylase (GAD65), anti-thyroglobulin (Tg) and antithyroid peroxidase (TPO) antibodies (Abs) and diagnosed with type 1 diabetes mellitus (DM) and silent thyroiditis caused by durvalumab. When durvalumab was stopped, he maintained the treatment of multiple daily insulin doses and levothyroxine. Clinicians need to be alerted about the development of endocrinopathies, such as DM, DKA and primary hypothyroidism in the patients receiving durvalumab.

Learning points:

  • Patients treated with anti-PD-L1 should be screened for the most common immune-related adverse events (irAEs).

  • Glucose levels and thyroid function should be monitored before and during the treatment.

  • Durvalumab is mainly associated with thyroid and endocrine pancreas dysfunction.

  • In the patients with significant autoimmune background, risk–benefit balance of antineoplastic immunotherapy should be accurately assessed.

Open access
Aoife Garrahy Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin 7, Ireland

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Matilde Bettina Mijares Zamuner Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin 7, Ireland

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Maria M Byrne Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin 7, Ireland

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Summary

Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA.

Learning points:

  • We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY.

  • It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA.

  • This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.

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A Veltroni ENETS Center of Excellence, Department of Medicine, University of Verona, Verona, Italy

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G Zambon ENETS Center of Excellence, Department of Medicine, University of Verona, Verona, Italy

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S Cingarlini ENETS Center of Excellence, Department of Oncology, University of Verona, Verona, Italy

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M V Davì ENETS Center of Excellence, Department of Medicine, University of Verona, Verona, Italy

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Summary

Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions.

Learning points:

  • IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients.

  • It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery.

  • It should be suspected in the presence of very high serum insulin levels (100–10  000  μU/mL) associated with high C-peptide levels.

  • There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

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