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Marina Yukina Department of Therapeutic Endocrinology, Endocrinology Research Centre (ERC), Moscow, Russia

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Nurana Nuralieva Department of Therapeutic Endocrinology, Endocrinology Research Centre (ERC), Moscow, Russia

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Maksim Solovyev Department of Therapeutic Endocrinology, Endocrinology Research Centre (ERC), Moscow, Russia

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Ekaterina Troshina Department of Therapeutic Endocrinology, Endocrinology Research Centre (ERC), Moscow, Russia
Russian Academy of Sciences, Endocrinology Service, Department of Therapeutic Endocrinology, Endocrinology Research Centre (ERC), Moscow, Russia

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Evgeny Vasilyev Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre (ERC), Moscow, Russia

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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.

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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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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.

Open access
D Cappellani Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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C Sardella Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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M C Campopiano Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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A Falorni Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, University of Perugia, Perugia, Italy

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P Marchetti Division of Metabolism and Cell Transplantation, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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E Macchia Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Summary

Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS.

Learning points:

  • Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid.

  • Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available.

  • The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

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Takashi Matsuo Internal Medicine, Nobeoka city Medical Association Hospital, Nobeoka, Japan

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Yoshihiko Ushiroda Internal Medicine, Nobeoka city Medical Association Hospital, Nobeoka, Japan

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Summary

A 32-year-old woman presented with 3days of epigastric pain and was admitted to our hospital (day 3 of disease). We diagnosed acute pancreatitis based on epigastric abdominal pain, hyperamylasemia, and an inflammatory reaction of withdrawn blood, pancreatic enlargement, and so on. Her condition improved with treatment; however, on day 8, she had decreased level of consciousness. Laboratory results led to a diagnosis of fulminant type 1 diabetes mellitus (FT1DM) with concomitant diabetic ketoacidosis. Insulin therapy improved her blood glucose levels as well as her symptoms. Fatty liver with liver dysfunction was observed on day 14, which improved by day 24. Blood levels of free fatty acids (FFAs) increased rapidly from 440μEq/L (normal range: 140–850μEq/L) on day 4 to 2097μEq/L on days 7–8 (onset of FT1DM) and subsequently decreased to 246μEq/L at the onset of fatty liver. The rapid decrease in insulin at the onset of FT1DM likely freed fatty acids derived from triglycerides in peripheral adipocytes into the bloodstream. Insulin therapy rapidly transferred FFAs from the periphery to the liver. In addition, insulin promotes the de novo synthesis of triglycerides in the liver, using newly acquired FFAs as substrates. At the same time, inhibitory effects of insulin on VLDL secretion outside of the liver promote the accumulation of triglycerides in the liver, leading to fatty liver. We describe the process by which liver dysfunction and severe fatty liver occurs after the onset of FT1DM, from the perspective of disturbed fatty acid metabolism.

Learning points

  • FT1DM is rare but should be considered in patients with pancreatitis and a decreased level of consciousness.

  • Fatty liver should be considered in patients with FT1DM when liver dysfunction is observed.

  • Insulin is involved in mechanisms that promote fatty liver formation.

  • Pathophysiological changes in fatty acid metabolism may provide clues on lipid metabolism in the early phases of FT1DM.

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E Rapti Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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S Karras Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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M Grammatiki Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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A Mousiolis Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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X Tsekmekidou Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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E Potolidis Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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P Zebekakis Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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M Daniilidis 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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K Kotsa Diabetes Center of 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

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Summary

Latent autoimmune diabetes in adults (LADA) is a relatively new type of diabetes with a clinical phenotype of type 2 diabetes (T2D) and an immunological milieu characterized by high titers of islet autoantibodies, resembling the immunological profile of type 1 diabetes (T1D). Herein, we report a case of a young male, diagnosed with LADA based on both clinical presentation and positive anti-glutamic acid decarboxylase antibodies (GAD-abs), which were normalized after combined treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4) (sitagliptin) and cholecalciferol.

Learning points

  • Anti-glutamic acid decarboxylase antibodies (GAD-abs) titers in young patients being previously diagnosed as type 2 diabetes (T2D) may help establish the diagnosis of latent autoimmune diabetes in adults (LADA).

  • Sitagliptin administration in patients with LADA might prolong the insulin-free period.

  • Vitamin D administration in patients with LADA might have a protective effect on the progression of the disease.

Open access
Junji Kawashima Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

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Hideaki Naoe Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

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Yutaka Sasaki Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

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Eiichi Araki Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

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Summary

Anti-tumor necrosis factor (TNF)-α therapy is established as a new standard for the treatment of various autoimmune inflammatory diseases. We report the first case showing subacute thyroiditis-like symptoms with an amyloid goiter after anti-TNF-α therapy. A 56-year-old man with Crohn's disease presented with fever and a diffuse, tender goiter. To control the diarrhea, anti-TNF therapy (infliximab) was administered 4 weeks before the thyroid symptoms emerged. The patient reported a swollen neck with tenderness on the right side and fever 4 days after the second infliximab injection. An elevated serum C-reactive protein (CRP) and serum thyroid hormone level with suppressed serum thyrotropin were observed. The thyroid-stimulating antibody was not elevated. An ultrasonograph of the thyroid revealed an enlarged goiter with posterior echogenicity attenuation and a low echoic region that was tender. The thyroid uptake value on technetium-99m scintigraphy was near the lower limit of the normal range. The patient was initially diagnosed with thyrotoxicosis resulting from subacute thyroiditis. Administration of oral prednisolone improved the fever, thyroid pain, and thyroid function, but his thyroid remained swollen. The patient developed diarrhea after prednisolone withdrawal; therefore, adalimumab, another TNF inhibitor, was administered. After three injections, his abdominal symptoms were alleviated, but the thyroid pain and fever recurred. Elevated serum CRP levels in the absence of thyroid dysfunction were observed. The patient's symptoms resolved after prednisolone retreatment, but an elastic, firm goiter persisted. A fine-needle biopsy revealed amyloid deposition in the thyroid.

Learning points

  • Many cases with thyroid dysfunction accompanied by amyloid goiter have been reported.

  • There are cases that develop amyloid goiter with subacute thyroiditis-like symptoms after anti-TNF therapy.

  • When the thyroid remains swollen after improvement of thyrotoxicosis following treatment with prednisolone, it should be assessed to differentiate between an amyloid goiter and common subacute thyroiditis.

Open access
Shinya Makino Department of Internal Medicine, Osaka Gyomeikan Hospital, 5-4-8 Nishikujo, Konohana-ku, Osaka, 554-0012, Japan

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Takeshi Uchihashi Department of Internal Medicine, Osaka Gyomeikan Hospital, 5-4-8 Nishikujo, Konohana-ku, Osaka, 554-0012, Japan

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Yasuo Kataoka Department of Internal Medicine, Osaka Gyomeikan Hospital, 5-4-8 Nishikujo, Konohana-ku, Osaka, 554-0012, Japan

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Masayoshi Fujiwara Department of Internal Medicine, Osaka Gyomeikan Hospital, 5-4-8 Nishikujo, Konohana-ku, Osaka, 554-0012, Japan

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Summary

Recovery from alopecia is rare in autoimmune polyglandular syndrome (APS). A 41-year-old male was admitted to our hospital with hyperglycemia. He developed alopecia areata (AA) 5 months before admission and developed thirst, polyuria, and anorexia in 2 weeks. His plasma glucose level upon admission was 912 mg/dl (50.63 mmol/l) and HbA1c was 13.7%. Although urinary and plasma C-peptide levels showed that insulin secretion was not depleted, anti-insulinoma-associated antigen 2 antibody was present. In addition, measurement of thyroid autoantibodies revealed the presence of Hashimoto's thyroiditis. These findings suggested a diagnosis of APS type 3. The patient has showed signs of improvement with the continuation of insulin therapy. During the successful control of diabetes, he had total hair regrowth within 2–3 months. Human leukocyte antigen typing showed that DRB1*1501-DQB1*0602 and DQB1*0301 were present. Similar cases should be accumulated to clarify the association of APS type 3 with recovery from AA.

Learning points

  • Alopecia in diabetic patients is a suspicious manifestation of autoimmune type 1 diabetes.

  • Patients with autoimmune type 1 diabetes specifically manifesting alopecia should be further examined for diagnosis of APS.

  • Insulin-mediated metabolic improvement may be a factor, but not the sole factor, determining a favorable outcome of alopecia in patients with autoimmune type 1 diabetes.

Open access
Marcos M Lima-Martínez Departamento de Ciencias Fisiológicas, Universidad de Oriente, Ciudad Bolívar, Venezuela
Unidad de Endocrinología, Diabetes, Metabolismo y Nutrición, Anexo A. Centro Médico Orinoco, Avenida Siegart, Ciudad Bolívar 8001, Venezuela

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Ernesto Guerra-Alcalá Departamento de Medicina, Hospital Vargas, Caracas, Venezuela

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Miguel Contreras Centro Médico El Valle, Porlamar, Venezuela

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José Nastasi Servicio de Genética Médica, Universidad de Oriente, Ciudad Bolívar, Venezuela

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Janelle A Noble Children's Hospital Oakland Research Institute, Oakland, California, USA

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Constantin Polychronakos Departments of Paediatrics and Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada

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Summary

Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by the autoimmune destruction of pancreatic β-cells. This paper describes the case of a 19-year-old male patient who presented with glutamic acid decarboxylase (GAD) antibody positive and diabetic ketoacidosis, which mandated intensive insulin treatment. Once the ketoacidosis was controlled, an oral dose of 100 mg of sitagliptin was administered once a day. Ketoacidosis was managed by insulin and insulin daily requirement began to dwindle after one month, until its complete withdrawal at 8 weeks, when partial remission was reached. The patient has now remained on sitagliptin treatment alone for a year, without requiring insulin. The benefit observed with this medication is possibly associated with its immunological effects. Inhibition of dipeptidyl peptidase 4 in animal models deregulates the Th1 immune response, increases secretion of Th2 cytokines, activates CD4+CD25+FoxP3+ regulatory T-cells, and prevents IL17 production.

Learning points

  • The use of insulin-dose-adjusted HbA1c constitutes the best way to define partial remission in T1DM patients.

  • The use of sitagliptin in T1DM patients could help to decrease daily requirement of insulin by delaying β-cell loss and improving endogenous insulin production.

  • The determination of antibodies against insulin, islet cells, and GAD permits differentiation of T1DM patients from those with atypical or ketosis-prone diabetes.

Open access