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Anticuerpos Monoclonales Humanizados , Cetoacidosis Diabética , Enteritis , Púrpura Trombocitopénica Trombótica , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Cetoacidosis Diabética/inducido químicamente , Cetoacidosis Diabética/diagnóstico , Púrpura Trombocitopénica Trombótica/inducido químicamente , Púrpura Trombocitopénica Trombótica/diagnóstico , Enteritis/inducido químicamente , Enteritis/diagnóstico , Enteritis/inmunología , Femenino , Masculino , Persona de Mediana Edad , Antineoplásicos Inmunológicos/efectos adversos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamenteRESUMEN
Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.
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Diabetes Mellitus Tipo 1 , Glutamato Descarboxilasa , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Cadenas HLA-DRB1/genética , Glutamato Descarboxilasa/inmunología , Cadenas beta de HLA-DQ/genética , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Haplotipos , Japón , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Pueblos del Este de AsiaRESUMEN
Background: Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at least two of the following endocrinopathies: autoimmune thyroid disease, type 1 diabetes, and Addison's disease. Cases with the full triad are rare. We present a case of an elderly woman who developed APS-2 with the complete triad shortly after starting anti-programmed cell death 1 (anti-PD1) treatment and review the related literature. Case: A 60-year-old woman, without any personal or family history of autoimmune and endocrine diseases, started the immunotherapy of anti-PD1 (camrelizumab) for squamous cell carcinoma of the urethral meatus. She developed primary hypothyroidism with elevated antibodies to thyroid peroxidase and thyroglobulin after 25 weeks of treatment, and developed primary adrenal insufficiency with adrenal crisis and fulminant type 1 diabetes with ketoacidosis after 45 weeks. Therefore, this patient met the diagnosis of APS-2 and was given multiple hormone replacement including glucocorticoid, levothyroxine and insulin therapy. Continuous improvement was achieved through regular monitoring and titration of the dosage. Conclusions: Different components of APS-2 may appear at different time points after anti-PD1 administration, and can be acute and life-threatening. A good prognosis can be obtained by appropriate replacement with multiple hormones. Insights: With the clinical application of ICPis to APS-2, the complexity of its treatment should be paid enough attention.
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Inhibidores de Puntos de Control Inmunológico , Poliendocrinopatías Autoinmunes , Humanos , Femenino , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/diagnóstico , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/diagnósticoRESUMEN
Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRß) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.
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Cadmio , Diabetes Mellitus Tipo 2 , Hígado , Animales , Femenino , Diabetes Mellitus Tipo 2/inducido químicamente , Ratas , Cadmio/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Tipo 1/inducido químicamente , Ratas Wistar , Páncreas/efectos de los fármacos , Páncreas/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Disruptores Endocrinos/toxicidadAsunto(s)
Diabetes Mellitus Tipo 1 , Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Glucemia , Automonitorización de la Glucosa Sanguínea , Nivolumab/efectos adversosRESUMEN
OBJECTIVE: The purpose of this study is to analyze the changes in inflammatory markers and efficacy in the treatment of senior patients with type 2 diabetes mellitus (T2DM) and community-acquired pneumonia with continuous subcutaneous insulin infusion (CSII). METHODS: A total of 105 senior patients with T2DM and community-acquired pneumonia, were randomly divided into two groups, viz., treatment group and control group-52 patients in the treatment group were treated with CSII, and 53 patients in the control group with multiple daily insulin injections (MDI). The changes in fasting blood glucose, postprandial blood glucose, total number of white blood cells, neutrophils, percentage of neutrophils, lymphocytes, percentage of lymphocytes, C-reactive protein, serum amyloid A, procalcitonin, interleukin-6 indexes, and the improvement in clinical outcome between the two groups were compared on the 5th and the 10th day of treatment. RESULTS: In the treatment group, there were 52 patients with an average age of (73.7 ± 8.5) years, which included 28 males and 24 females. In the control group, there were 53 patients, with 27 males and 26 females, with an average age of (74.8 ± 8.8) years. On the 5th and the 10th day of the treatment, the fasting blood glucose, postprandial blood glucose, total number of white blood cells, neutrophils, percentage of neutrophils, lymphocytes, percentage of lymphocytes, C-reactive protein, serum amyloid A, procalcitonin and interleukin-6 of the treatment group were better than that of the control group (P < 0.05). The use of CSII was associated with a higher probability of a prompt recovery (P < 0.05). CONCLUSION: The administration of CSII in the treatment of senior patients with T2DM and community-acquired pneumonia can effectively control fasting and postprandial blood glucose, significantly reduce the levels of inflammatory markers, and improve infection treatment efficacy.
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Infecciones Comunitarias Adquiridas , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Neumonía , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Glucemia/análisis , Glucemia/metabolismo , Proteína C-Reactiva , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/uso terapéutico , Inyecciones Subcutáneas , Insulina/uso terapéutico , Sistemas de Infusión de Insulina , Interleucina-6 , Neumonía/tratamiento farmacológico , Neumonía/inducido químicamente , Polipéptido alfa Relacionado con Calcitonina , Proteína Amiloide A SéricaRESUMEN
BACKGROUND: As a newly approved immune checkpoint inhibitor in China, serplulimab has been widely used in the immunotherapy of tumors. However, the immune-related adverse events of immune checkpoint inhibitors should not be ignored. Although immune checkpoint inhibitor-induced type 1 diabetes mellitus is a rare complication, it may cause diabetic ketoacidosis and endanger the lives of patients. CASE PRESENTATION: This case report describes a 55-year-old male of Han nationality from China diagnosed with small-cell lung cancer with multiple metastases who experienced an adverse event of type 1 diabetes mellitus 68 weeks after receiving serplulimab therapy. The patient presented with typical symptoms of diabetic ketoacidosis, including severe thirst, nausea, vomiting, deep respirations, and stupor. Despite the absence of diabetes-related autoantibodies, the patient had extremely low levels of insulin and C-peptide release. Other potential causes of diabetes were ruled out, confirming the condition as serplulimab-induced immune checkpoint inhibitor-induced type 1 diabetes mellitus. After aggressive treatment to correct diabetic ketoacidosis, the patient's blood glucose levels stabilized and symptoms of diabetes improved significantly, although long-term insulin maintenance therapy was necessary. CONCLUSION: This case highlights a rare, late-onset adverse event of immune checkpoint inhibitor-induced type 1 diabetes mellitus that may be overlooked during treatment with serplulimab. The monitoring of blood glucose levels and early signs and symptoms of diabetes cannot be relaxed at the late stage of treatment, even if patients do not have elevated blood glucose levels before and during the middle stage of treatment.
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Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Masculino , Humanos , Persona de Mediana Edad , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Cetoacidosis Diabética/inducido químicamente , Glucemia , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Insulina , Anticuerpos MonoclonalesRESUMEN
Chronic hyperglycemia-induced neuropathological changes include neuronal apoptosis, astrogliosis, decrease in neurotrophic support, impaired synaptic plasticity, and impaired protein quality control (PQC) system. Vitamin B12 is indispensable for neuronal development and brain function. Several studies reported the neuroprotective effect of B12 supplementation in diabetic patients. However, the underlying molecular basis for the neuroprotective effect of B12 supplementation in diabetes needs to be thoroughly investigated. Two-month-old Sprague-Dawley rats were randomly assigned into three groups: Control (CN), diabetes (D; induced with streptozotocin; STZ), and diabetic rats supplemented with vitamin B12 (DBS; vitamin B12; 50 µg/kg) for four months. At the end of 4 months of experimentation, the brain was dissected to collect the cerebral cortex (CC). The morphology of CC was investigated with H&E and Nissl body staining. Neuronal apoptosis was determined with TUNEL assay. The components of neurotrophic support, astrogliosis, synaptic plasticity, and PQC processes were investigated by immunoblotting and immunostaining methods. H& E, Nissl body, and TUNEL staining revealed that diabetes-induced neuronal apoptosis and degeneration. However, B12 supplementation ameliorated the diabetes-induced neuronal apoptosis. Further, B12 supplementation restored the markers of neurotrophic support (BDNF, NGF, and GDNF), and synaptic plasticity (SYP, and PSD-95) in diabetic rats. Interestingly, B12 supplementation also attenuated astrogliosis, ER stress, and ameliorated autophagy-related proteins in diabetic rats. Overall, these findings suggest that B12 acts as a neuroprotective agent by inhibiting the neuropathological changes in STZ-induced type 1 diabetes. Thus, B12 supplementation could produce beneficial outcomes including neuroprotective effects in diabetic patients.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Fármacos Neuroprotectores , Ratas , Humanos , Animales , Lactante , Vitamina B 12/farmacología , Vitamina B 12/uso terapéutico , Ratas Sprague-Dawley , Estreptozocina/farmacología , Diabetes Mellitus Experimental/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Gliosis , ApoptosisRESUMEN
BACKGROUND AND AIMS: Automated insulin delivery (AID) improves glycaemia among people with type 1 diabetes in clinical trials and overseas real-world studies. Whether improvements are sustained beyond 12 months in the real world, and whether they occur in the Australian context, has not yet been established. We aimed to observe, up to 2 years, the effectiveness of initiating first-generation AID for type 1 diabetes management. METHODS: Retrospective, real-world, observational study using medical records, conducted across five sites in Australia. Adults with type 1 diabetes, who had AID initiated between February 2019 and December 2021, were observed for 6-24 months after initiation (until June 2022). Outcomes examined included glucose metrics assessed by glycated haemoglobin (HbA1c ) and continuous glucose monitoring (CGM), safety and therapy continuation. RESULTS: Ninety-four adults were studied (median age 39 years (interquartile range, IQR: 31-51); pre-initiation HbA1c 7.8% (7.2-8.6)). After AID initiation, HbA1c decreased by mean 0.5 percentage points (95% confidence interval (CI): -0.7 to -0.2) at 3 months (P < 0.001); CGM time in range 3.9-10.0 mmol/L increased by 11 percentage points (9-14) at 1 month (P < 0.001); these improvements were maintained up to 24 months (all P < 0.02). Median CGM time below 3.9 mmol/L was <1.5% pre- and post-AID initiation. The subgroup with pre-initiation HbA1c above 8.5% had the greatest HbA1c improvement (-1.4 percentage points (-1.8 to -1.1) at 3 months). Twelve individuals (13%) discontinued AID, predominantly citing difficulties with CGM. During the 150 person-years observed, four diabetes-related emergencies were documented: three severe hypoglycaemic events and one hyperglycaemic event without ketoacidosis. CONCLUSIONS: Early glucose improvements were observed after real-world AID initiation, sustained up to 2 years, without excess adverse events. The greatest benefits were observed among individuals with highest glycaemia before initiation. Future-generation systems with increased user-friendliness may enhance therapy continuation.
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Diabetes Mellitus Tipo 1 , Adulto , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inducido químicamente , Insulina , Glucemia , Automonitorización de la Glucosa Sanguínea , Estudios Retrospectivos , Australia/epidemiología , Hipoglucemiantes , Sistemas de Infusión de InsulinaRESUMEN
Diabetes is a chronic, and metabolic disorder that has gained epidemic proportions in the past few decades creating a threat throughout the globe. It is characterized by increased glucose levels that may be due to immune-mediated disorders (T1DM), insulin resistance or inability to produce sufficient insulin by ß-pancreatic cells (T2DM), gestational, or an increasingly sedentary lifestyle. The progression of the disease is marked by several pathological changes in the body like nephropathy, retinopathy, and various cardiovascular complications. Treatment options for T1DM are majorly focused on insulin replacement therapy. While T2DM is generally treated through oral hypoglycemics that include metformin, sulfonylureas, thiazolidinediones, meglitinides, incretins, SGLT-2 inhibitors, and amylin antagonists. Multidrug therapy is often recommended when patients are found incompliant with the first-line therapy. Despite the considerable therapeutic benefits of these oral hypoglycemics, there lie greater side effects (weight variation, upset stomach, skin rashes, and risk of hepatic disease), and limitations including short half-life, frequent dosing, and differential bioavailability which inspires the researchers to pursue novel drug targets and small molecules having promising clinical efficacy posing minimum side-effects. This review summarizes some of the current emerging novel approaches along with the conventional drug targets to treat type 2 diabetes.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Quimioterapia Combinada , Leprostáticos/uso terapéutico , Insulina , Metformina/uso terapéuticoRESUMEN
OBJECTIVE: Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated. RESEARCH DESIGN AND METHODS: Children (n = 6) aged 5-14 years with stage 2 type 1 diabetes received off-label, low-dose ATG. HbA1c, C-peptide, continuous glucose monitoring, insulin requirements, and side effects were followed for 18-48 months. RESULTS: Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1-2 months after therapy. Eighteen months posttreatment, even disease progressors demonstrated near-normal HbA1c (5.1% [32 mmol/mol], 5.6% [38 mmol/mol], and 5.3% [34 mmol/mol]), time in range (93%, 88%, and 98%), low insulin requirements (0.17, 0.18, and 0.34 units/kg/day), and robust C-peptide 90 min after mixed meal (1.3 ng/dL, 2.3 ng/dL, and 1.4 ng/dL). CONCLUSIONS: These observations support additional prospective studies evaluating ATG in stage 2 type 1 diabetes.
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Suero Antilinfocítico , Diabetes Mellitus Tipo 1 , Niño , Humanos , Suero Antilinfocítico/uso terapéutico , Glucemia , Automonitorización de la Glucosa Sanguínea , Péptido C , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Hemoglobina Glucada , Hipoglucemiantes , Insulina , Estudios ProspectivosRESUMEN
Objective: Checkpoint inhibitors (CPIs) can trigger complications related to the autoimmune process such as CPI-triggered diabetes mellitus. The typical treatment for CPI-triggered diabetes is insulin, but a detailed therapeutic method has not yet been established. To prevent severe symptoms and mortality of diabetic ketoacidosis in advanced-stage cancer patients, the establishment of effective treatment of CPI-triggered diabetes, other than insulin therapy, is required. Methods: We present a case of a 76-year-old man with CPI-triggered diabetes who was treated with nivolumab and ipilimumab for lung cancer. We also conducted a systematic review of 48 case reports of type 1 diabetes associated with nivolumab and ipilimumab therapy before June 2023. Results: The patient's hyperglycemia was not sufficiently controlled by insulin therapy, and after the remission of ketoacidosis, the addition of a sodium-glucose transporter (SGLT) 2 inhibitor, dapagliflozin, improved glycemic control. Most of the reported nivolumab/ipilimumab-induced type 1 diabetes was treatable with insulin, but very few cases required additional oral anti-diabetic agents to obtain good glucose control. Conclusion: Although SGLT2 inhibitors have been reported to have adverse effects on ketoacidosis, recent studies indicate that the occurrence of ketoacidosis is relatively rare. Considering the pathological mechanism of CPI-triggered diabetes, SGLT2 inhibitors could be an effective choice if they are administered while carefully monitoring the patient's ketoacidosis.
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Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Neoplasias Pulmonares , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Masculino , Humanos , Anciano , Nivolumab/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Ipilimumab/uso terapéutico , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Cetoacidosis Diabética/inducido químicamente , Cetoacidosis Diabética/tratamiento farmacológico , Insulina/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
RATIONALE: With the popularity of ICIs in different oncology treatments, immune-related adverse events have raised concerns, mostly occurring in skin and endocrine gland injury. This disease involves different organ systems and presents with a variety of clinical manifestations. Most patients with immune checkpoint inhibitor-induced type 1 diabetes are reported to have no combination of autoimmune disease. We report a case of Sintilimab-related diabetes mellitus and psoriasis. PATIENT CONCERNS: We report a case of a 65-year-old female with Sintilimab-related diabetes mellitus and psoriasis. DIAGNOSIS: The patient treated with anti-programmed cell death protein 1 (Sintilimab) for 4 cycles. The patient presented with inexplicable bouts of nausea and vomiting, accompanied by chest discomfort and a feeling of breathlessness, prompting their admission to the local hospital. The initial assessment upon admission revealed an abrupt elevation in blood glucose levels, alongside normal ketone levels, lactic acidosis, and hyperuricemia. A comprehensive regimen was provided to regulate glucose levels and address the symptoms, resulting in notable improvement and subsequent discharge. Regrettably, the patient's personal decision to discontinue medication for a single day led to the emergence of acute ketoacidosis, coupled with a recurrence of psoriasis vulgaris. Consequently, readmission became necessary. Based on the patient's medical history and diabetes antibody testing, the diagnosis of immune checkpoint inhibitor induced diabetes mellitus has been confidently established. INTERVENTIONS: The patient ceased treatment with Sintilimab and was initiated on insulin therapy for glycemic control, alongside symptomatic management for psoriasis. Upon stabilization of the condition, long-term administration of exogenous insulin was implemented as a substitute treatment. OUTCOME: Outside of the hospital, insulin therapy effectively maintained stable blood glucose levels, and there were no further episodes of psoriasis flare-ups. LESSON: The clinical manifestations of immune checkpoint inhibitor induced diabetes mellitus are variable, and in this case the patient presented with unique primary symptoms. Therefore, it is crucial to accumulate relevant cases, understand the different clinical presentations and identify the underlying mechanisms of the disease. This will provide further evidence for early therapeutic intervention in similar patients in the future.
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Diabetes Mellitus Tipo 1 , Psoriasis , Femenino , Humanos , Anciano , Glucemia/metabolismo , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Insulina , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/complicacionesRESUMEN
Introduction: Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. Methods: This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Results: Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. Discussion: These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.
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Antineoplásicos Inmunológicos , Enfermedades Autoinmunes , Diabetes Mellitus Tipo 1 , Neoplasias , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inducido químicamente , Estudios Retrospectivos , Estudios Prospectivos , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Enfermedades Autoinmunes/complicacionesRESUMEN
Oxidative stress and abnormal glucose metabolism are the important physiological mechanisms in the occurrence and development of diabetes. Antioxidant peptides have been reported to attenuate diabetes complications by regulating levels of oxidative stress, but few studies have focused on peptides from marine bone collagen. In this study, we prepared the peptides with a molecular weight of less than 1 kD (HNCP) by enzymolysis and ultrafiltration derived from Harpadon nehereus bone collagen. Furthermore, the effects of HNCP on blood glucose, blood lipid, liver structure and function, oxidative stress, and glucose metabolism were studied using HE staining, kit detection, and Western blotting experiment in streptozocin-induced type 1 diabetes mice. After the 240 mg/kg HNCP treatment, the levels of blood glucose, triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in streptozotocin-induced diabetes mice decreased by 32.8%, 42.2%, and 43.2%, respectively, while the levels of serum insulin and hepatic glycogen increased by 142.0% and 96.4%, respectively. The antioxidant enzymes levels and liver function in the diabetic mice were markedly improved after HNCP intervention. In addition, the levels of nuclear factor E2-related factor 2 (Nrf2), glucokinase (GK), and phosphorylation of glycogen synthase kinase-3 (p-GSK3ß) in the liver were markedly up-regulated after HNCP treatment, but the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase1 (PEPCK1) were down-regulated. In conclusion, HNCP could attenuate oxidative stress, reduce blood glucose, and improve glycolipid metabolism in streptozocin-induced type 1 diabetes mice.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Animales , Ratones , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/química , Estreptozocina , Glucemia , Antioxidantes/química , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Experimental/metabolismo , Estrés Oxidativo , Hígado , Glucosa/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Péptidos/metabolismoRESUMEN
A woman in her mid-60s presented to the hospital due to a history of nausea, vomiting, shortness of breath, dyspnoea on exertion and polyuria. She was receiving medical therapy for advanced non-small cell lung cancer and recently initiated immune checkpoint inhibitor (ICI) immunotherapy. Investigations revealed lab results consistent with diabetic ketoacidosis (DKA), elevated cardiac biomarkers, multiple cardiac arrhythmias and reduced ejection fraction on transthoracic echocardiogram. Cardiac catheterisation showed non-obstructive coronary arteries.The patient was diagnosed with an ICI-associated myocarditis and type I diabetes due to recent initiation of the ICI durvalumab. She was treated with the institutional DKA protocol and received corticosteroid therapy for drug toxicity according to guidelines. She was discharged with marked improvement in symptoms. The patient had good recovery after discharge with further investigations showing improvement in her cardiac ejection fraction on cardiac MRI. She remains on medical therapy with an insulin regimen for diabetes management.
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Carcinoma de Pulmón de Células no Pequeñas , Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Neoplasias Pulmonares , Miocarditis , Femenino , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Miocarditis/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Cetoacidosis Diabética/complicacionesRESUMEN
Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of drug eruption that causes multiorgan disorders after the administration of certain drugs such as anticonvulsants. Herein, we report the case of a 66-year-old man with DiHS/DRESS complicated by fulminant type 1 diabetes (FT1D), shock, and cardiac involvement who was treated conservatively without systemic corticosteroid administration. He had taken carbamazepine for trigeminal neuralgia for 7 weeks until he noticed eruptions on his trunk. Two days after admission, he developed diabetic ketoacidosis, resulting in hypovolemic shock. The patient was diagnosed with FT1D, and insulin was administered. Additionally, the patient had a fever over 38°C, elevated white blood cells (>20 000/µL), liver dysfunction, atypical lymphocytes, and lymphadenopathy, but no evidence of viral reactivation. The lymphocyte transformation test for carbamazepine was positive, and human leukocyte antigen typing revealed the A31:01 haplotype, a risk factor for carbamazepine-induced cutaneous adverse drug reactions. Collectively, a diagnosis of atypical DiHS and a definitive case of DRESS was made. Moreover, myocardial dysfunction wall motion was observed. A close examination revealed mild coronary artery stenosis, leading to a diagnosis of type 2 myocardial infarction due to relative ischemia. The patient was carefully monitored without systemic corticosteroid administration because both clinical findings and laboratory data peaked on the same day. The patient's eruption and general condition improved, and he was discharged 4 weeks later. While most cases of DiHS/DRESS with cardiac involvement present with myocarditis, the possibility of ischemic heart disease should be considered in patients with cardiac involvement under shock.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Síndrome de Hipersensibilidad a Medicamentos , Eosinofilia , Infarto del Miocardio , Anciano , Humanos , Masculino , Corticoesteroides , Carbamazepina/efectos adversos , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 2/complicaciones , Síndrome de Hipersensibilidad a Medicamentos/complicaciones , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Eosinofilia/tratamiento farmacológicoRESUMEN
Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D2 receptors.