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Open access

Ellada Sotiridou, Henrike Hoermann, Sommayya Aftab, Antonia Dastamani, Eva Thimm, Louise Doodson, Spyros Batzios, Sebastian Kummer, and Pratik Shah

Summary

Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Learning points

Open access

Jennifer R Snaith, Duncan McLeod, Arthur Richardson, and David Chipps

Summary

Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.

Learning points:

Open access

Deeb Daoud Naccache

Summary

Ten years after the successful withdrawal from heroin abuse, a person with diabetes suffered intractable pain and severe muscular emaciation consistent with the syndrome of diabetic neuropathic cachexia. Anti-neuropathic medications failed neither to alleviate suffering and reverse weight loss, nor to stop muscular emaciation. Vigilant evaluation for weight loss aetiologies revealed no responsible aetiology. Prescribing medical cannabis became mandatory, with the intention to alleviate neuropathic pain, regain muscular mass and strengthen legs, enable standing upright and walking normally. Medical cannabis for pain-relief, and the orexigenic properties of tetrahydrocannabinol (THC) ingredient successfully achieved these goals.

Learning points:

  • Medical cannabis can serve to promptly alleviate severe diabetic neuropathic pain.
  • Past history of heroin abuse was not an absolute contraindication to medical cannabis use.
  • Medical cannabis increased appetite and reversed muscular emaciation.
  • Medical cannabis decreased chronic pain and hence, its catabolic consequences.
Open access

Marcio José Concepción-Zavaleta, Sofía Pilar Ildefonso-Najarro, Esteban Alberto Plasencia-Dueñas, María Alejandra Quispe-Flores, Cristian David Armas-Flórez, and Laura Esther Luna-Victorio

Summary

Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease caused by antibodies against the insulin receptor. It should be considered in patients with dysglycaemia and severe insulin resistance when other more common causes have been ruled out. We report a case of a 72-year-old male with a 4-year history of type 2 diabetes who presented with hypercatabolism, vitiligo, acanthosis nigricans, and hyperglycaemia resistant to massive doses of insulin (up to 1000 U/day). Detection of anti-insulin receptor antibodies confirmed TBIR. The patient received six pulses of methylprednisolone and daily treatment with cyclophosphamide for 6 months. Response to treatment was evident after the fourth pulse of methylprednisolone, as indicated by weight gain, decreased glycosylated haemoglobin and decreased requirement of exogenous insulin that was later discontinued due to episodes of hypoglycaemia. Remission was eventually achieved and the patient is currently asymptomatic, does not require insulin therapy, has normal glycaemia and is awaiting initiation of maintenance therapy with azathioprine. Thus, TBIR remitted without the use of rituximab. This case highlights the importance of diagnosis and treatment in a timely fashion, as well as the significance of clinical features, available laboratory findings and medication. Large controlled studies are required to standardise a therapeutic protocol, particularly in resource-constrained settings where access to rituximab is limited.

Learning points:

  • Type B insulin resistance syndrome is a rare autoimmune disorder that should be considered in patients with dysglycaemia, severe insulin resistance and a concomitant autoimmune disease.
  • Serological confirmation of antibodies against the insulin receptor is not necessary in all cases due to the high associated mortality without timely treatment.
  • Although there is no standardised immunosuppressive treatment, a protocol containing rituximab, cyclophosphamide and steroids has shown a significant reduction in previously reported mortality rates.
  • The present case, reports successful remission in an atypical patient using cyclophosphamide and methylprednisolone, which is an effective therapy in countries in which rituximab is not covered by health insurance.
  • When there is improvement in the hypercatabolic phase, the insulin dose should be reduced and/or discontinued to prevent hypoglycaemia; a mild postprandial hyperglycaemic state should be acceptable.
Open access

Annabelle M Warren, Duncan J Topliss, and Peter Shane Hamblin

Summary

Despite improvements in localisation techniques and surgical advances, some patients with insulinoma will not be cured by surgery or may not be suitable for surgery. Medical management with diazoxide is an option for such cases. This case report details 27 years of successful management of insulinoma using diazoxide. It has been effective and safe, with only minor adverse effects.

Learning points:

  • Long term diazoxide use can be a safe, effective option for insulinoma when it cannot be localised or removed surgically.
  • Common adverse effects include peripheral oedema, hyperuricaemia, and hirsutism.
  • 68Ga-NOTA-exendin-4 PET/CT scan should be considered for insulinoma localisation when other modalities have been unhelpful.
Open access

Yuki Fujita, Daisuke Tanaka, Hisato Tatsuoka, Miho Matsubara, Takanori Hyo, Yoshiyuki Hamamoto, Toshiyuki Komiya, Nobuya Inagaki, Yutaka Seino, and Yuji Yamazaki

Summary

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient’s MODY5.

Learning points:

  • Genetic diagnosis of MODY is relevant for appropriate treatment.
  • Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5.
  • Scanning the non-coding regions is important for not missing a mutation in HNF1B.
Open access

Agnieszka Łebkowska, Anna Krentowska, Agnieszka Adamska, Danuta Lipińska, Beata Piasecka, Otylia Kowal-Bielecka, Maria Górska, Robert K Semple, and Irina Kowalska

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.
Open access

Silvia M Becerra-Bayona, Víctor Alfonso Solarte-David, Claudia L Sossa, Ligia C Mateus, Martha Villamil, Jorge Pereira, and Martha L Arango-Rodríguez

Summary

Diabetic foot ulcer morbidity and mortality are dramatically increasing worldwide, reinforcing the urgency to propose more effective interventions to treat such a devastating condition. Previously, using a diabetic mouse model, we demonstrated that administration of bone marrow mesenchymal stem cells derivatives is more effective than the use of bone marrow mesenchymal stem cells alone. Here, we used the aforementioned treatments on three patients with grade 2 diabetic foot ulcers and assessed their beneficial effects, relative to the conventional approach. In the present study, two doses of cell derivatives, one dose of mesenchymal stem cells or one dose of vehicle (saline solution with 5% of human albumin), were intradermally injected around wounds. Wound healing process and changes on re-epithelialization were macroscopically evaluated until complete closure of the ulcers. All ulcers were simultaneously treated with conventional treatment (PolyMen® dressing). Patients treated with either cell derivatives or mesenchymal stem cells achieved higher percentages of wound closure in shorter times, relative to the patient treated with the conventional treatment. The cell derivative and mesenchymal stem cells approaches resulted in complete wound closure and enhanced skin regeneration at some point between days 35 and 42, although no differences between these two treatments were observed. Moreover, wounds treated with the conventional treatment healed after 161 days. Intradermal administration of cell derivatives improved wound healing to a similar extent as mesenchymal stem cells. Thus, our results suggest that mesenchymal stem cell derivatives may serve as a novel and potential therapeutic approach to treat diabetic foot ulcers.

Learning points:

  • In diabetic mouse models, the administration of mesenchymal stem cells derivatives have been demonstrated to be more effective than the use of marrow mesenchymal stem cells alone.
  • Mesenchymal stem cells have been explored as an attractive therapeutic option to treat non-healing ulcers.
  • Mesenchymal stem cells derivatives accelerate the re-epithelialization on diabetic foot ulcers.
Open access

Marina Yukina, Nurana Nuralieva, Maksim Solovyev, Ekaterina Troshina, and Evgeny Vasilyev

Summary

Insulin autoimmune syndrome (Hirata’s disease) is a disorder caused by development of autoantibodies to insulin and manifested by hypoglycaemic syndrome. The overwhelming majority of physicians do not include it in the differential diagnosis of hypoglycaemic states because of a misconception of an extremely low prevalence of this condition. This results in unnecessary drug therapy and unjustified surgical interventions in patients that otherwise would be successfully treated conservatively. This disease is strongly associated with certain alleles of the HLA gene. In most cases, this condition develops in predisposed individuals taking drugs containing sulfhydryl groups. Formation of autoantibodies to insulin may be observed in patients with other autoimmune disorders, as well as in those with multiple myeloma or monoclonal gammopathy of undetermined significance. This paper presents the first Russian case report of insulin autoimmune syndrome in an adult patient.

Learning points:

  • Insulin autoimmune syndrome, Hirata’s disease, anti-insulin antibodies, and hypoglycaemia.
Open access

Kazuhisa Kusuki, Saya Suzuki, and Yuzo Mizuno

Summary

A 72-year-old man with no history of diabetes was referred to our department due to hyperglycemia during pembrolizumab treatment for non-small-cell lung carcinoma. His blood glucose level was 209 mg/dL, but he was not in a state of ketosis or ketoacidosis. Serum C-peptide levels persisted at first, but gradually decreased, and 18 days later, he was admitted to our hospital with diabetic ketoacidosis (DKA). The patient was diagnosed with fulminant type 1 diabetes (FT1D) induced by pembrolizumab. According to the literature, the insulin secretion capacity of a patient with type 1 diabetes (T1D) induced by anti-programmed cell death-1 (anti-PD-1) antibody is depleted in approximately 2 to 3 weeks, which is longer than that of typical FT1D. Patients with hyperglycemia and C-peptide persistence should be considered for hospitalization or frequent outpatient visits with insulin treatment because these could indicate the onset of life-threatening FT1D induced by anti-PD-1 antibodies. Based on the clinical course of this patient and the literature, we suggest monitoring anti-PD-1 antibody-related T1D.

Learning points:

  • Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are increasingly used as anticancer drugs. Anti-PD-1 antibodies can cause immune-related adverse events, including T1D.
  • FT1D, a novel subtype of T1D, is characterized by the abrupt onset of hyperglycemia with ketoacidosis, a relatively low glycated hemoglobin level and depletion of C-peptide level at onset.
  • In patients being treated with anti-PD-1 antibody, hyperglycemia with C-peptide level persistence should be monitored through regular blood tests. Because of C-peptide persistence and mild hyperglycemia, it is possible to miss a diagnosis of life-threatening FT1D induced by anti-PD-1 antibody.
  • In particular, in patients who have no history of diabetes, hyperglycemia without DKA is likely to be the very beginning of anti-PD-1 antibody-induced T1D. Therefore, such patients must be considered for either hospitalization or frequent outpatient visits with insulin injections and self-monitoring of blood glucose.