[Diabetic ketoacidosis secondary to immunotherapy]. / Cetoacidosis diabética secundaria a inmunoterapia.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treatments. As experience in the use of immunotherapy increases, more is known about its safety profile and immune-mediated adverse effects. Among them is diabetic ketoacidosis (DKA), a rare but serious fatal complication of treatment. In this paper we describe the cases of three patients who presented with episodes of DKA during treatment with ICIs, two of which manifested with fulminant forms, leading to an acute course with initially normal glycosylated hemoglobin values. In addition, we conducted a review of the literature on DKA associated with ICIs in order to highlight the importance of noticing these potentially fatal complications and promptly establishing appropriate therapy.

Los inhibidores de puntos de control inmune (ICIs) son anticuerpos monoclonales cada vez más utilizados en tratamientos oncológicos. A medida que aumenta la experiencia en el uso de inmunoterapia, se conoce cada vez más su perfil de seguridad y los efectos adversos inmunomediados. Entre ellos se encuentra la cetoacidosis diabética (CAD), complicación infrecuente, grave y potencialmente mortal. En este trabajo describimos los casos de tres pacientes que se presentaron con episodios de CAD durante el tratamiento con ICIs, dos de los cuales manifestaron con formas fulminantes, llevando un curso agudo con valores de hemoglobina glicosilada inicialmente normales. Asimismo, realizamos una revisión de la literatura sobre la CAD asociada a ICIs a fines de resaltar la importancia de advertir estas complicaciones potencialmente fatales e instaurar rápidamente la terapéutica apropiada.

Cetoacidosis diabética secundaria a inmunoterapia / Diabetic ketoacidosis secondary to immunotherapy

Resumen Los inhibidores de puntos de control inmune (ICIs) son anticuerpos monoclonales cada vez más utilizados en tratamientos oncológicos. A medida que aumenta la experiencia en el uso de inmunoterapia, se conoce cada vez más su perfil de seguridad y los efectos adversos inmunomediados. Entre ellos se encuentra la cetoaci dosis diabética (CAD), complicación infrecuente, grave y potencialmente mortal. En este trabajo describimos los casos de tres pacientes que se presentaron con episo dios de CAD durante el tratamiento con ICIs, dos de los cuales manifestaron con formas fulminantes, llevando un curso agudo con valores de hemoglobina glicosilada inicialmente normales. Asimismo, realizamos una revi sión de la literatura sobre la CAD asociada a ICIs a fines de resaltar la importancia de advertir estas complica ciones potencialmente fatales e instaurar rápidamente la terapéutica apropiada.

Abstract Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are increasingly used in cancer treat ments. As experience in the use of immunotherapy increases, more is known about its safety profile and immune-mediated adverse effects. Among them is dia betic ketoacidosis (DKA), a rare but serious fatal compli cation of treatment. In this paper we describe the cases of three patients who presented with episodes of DKA during treatment with ICIs, two of which manifested with fulminant forms, leading to an acute course with initially normal glycosylated hemoglobin values. In ad dition, we conducted a review of the literature on DKA associated with ICIs in order to highlight the importance of noticing these potentially fatal complications and promptly establishing appropriate therapy.

The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype.

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Ketosis prone diabetes presenting as fulminant type 1 diabetes.

Patients with ketosis prone diabetes have been reported primarily in Africans and African Americans. At presentation, both insulin secretion and insulin action are impaired in ketosis prone diabetes patients. Fulminant diabetes is a subtype of type 1 diabetes reported mainly in the Asian populations characterized by diabetic ketosis or ketoacidosis occurring soon after the onset of hyperglycemic symptoms with inappropriately low HbA1c (< 8.5%). We report here the first case of a ketosis prone diabetes presenting as fulminant diabetes.

Challenges in diagnosing type 1 diabetes in different populations.

Diabetes affects today an estimated 366 million people world-wide, including 20 million to 40 million of patients with type 1 diabetes (T1D). While T1D accounts for 5% to 20% of those with diabetes, it is associated with higher morbidity, mortality and health care cost than the more prevalent type 2 diabetes. Patients with T1D require exogenous insulin for survival and should be identified as soon as possible after diagnosis to avoid high morbidity due to a delay in insulin treatment. It is also important to present to the patient correct prognosis that differs by the type of diabetes. From the research point of view, correct classification should help to identify the etiologies and to develop specific prevention for T1D. This review summarizes evidence that may be helpful in diagnosing T1D in various ethnic groups. Challenges in interpretation of results commonly used to determine the type of diabetes are highlighted.

Challenges in Diagnosing Type 1 Diabetes in Different Populations

Diabetes affects today an estimated 366 million people world-wide, including 20 million to 40 million of patients with type 1 diabetes (T1D). While T1D accounts for 5% to 20% of those with diabetes, it is associated with higher morbidity, mortality and health care cost than the more prevalent type 2 diabetes. Patients with T1D require exogenous insulin for survival and should be identified as soon as possible after diagnosis to avoid high morbidity due to a delay in insulin treatment. It is also important to present to the patient correct prognosis that differs by the type of diabetes. From the research point of view, correct classification should help to identify the etiologies and to develop specific prevention for T1D. This review summarizes evidence that may be helpful in diagnosing T1D in various ethnic groups. Challenges in interpretation of results commonly used to determine the type of diabetes are highlighted.

The feature, diagnosis, and treatment of fulminant type 1 diabetes / 中华内分泌代谢杂志

Type 1 diabetes includes two categories:autoimmune (type 1A) and idiopathic (type 1B)diabetes.Fulminant type 1 diabetes is a recently discovered subtype of type 1 diabetes with extremely rapid progression of hyperglycemia and ketoacidosis.The prevalence of fulminant type 1 diabetes among acute-onset type 1 diabetic patients is around 15%-20%.Class Ⅱ HLA genotype and virus infection may contribute to its development.The near-normal HbA_(1C) level despite a very high plasma glucose concentration in patients with ketoacidosis is the clue to diagnosis of fulminant type 1 diabetes.Treatment must be started immediately and aggressively when the diagnosis of fulminant type 1 diabetes is made or strongly suspected.

Clinical analysis of five cases of fulminant type 1 diabetes mellitus / 中华内分泌代谢杂志

The clinical data of 5 cases of fulminant type 1 diabetes mellitus were analyzed retrospectively.This disease was characterized by abrupt onset and severe diabetic ketoacidosis.The mean duration from the appearance of hyperglycemic symptoms to first hospital visit was 3.4 days.The mean plasma glucose level was 47.7 mmol/L,but the mean value of HbA_(1C) level was 6.8% at first visit.The mean fasting serum C-peptide was 40.0 pmol/L,and mean serum postprandial C-peptide was 68.0 pmol/L at onset.β-cell function did not recover after 3-26 months of follow-up.

Prevalence and clinical features of fulminant type 1 diabetes / 中华内分泌代谢杂志

Objective To investigate the prevalence and clinical features of fulminant type 1 diabetes.Methods Using data retrieved from Second Xiangya Hospital of Central South University,all patients diagnosed with type 1 diabetes from Jan.1,2001 to Dec.31,2007 were identified.The patients were divided into fulminant type 1 diabetes (F1D) group,typical type 1 diabetes (T1A) group,and idiopathic type 1 diabetes(T1B) group.Their clinical features were compared.Results Eight patients (9.1%) fulfilled the criteria for fulminant type 1 diabetes among 87 newly diagnosed type 1 diabetes,and the percentage of fulminant type 1 diabetes reached 14.0% among type 1 diabetic patients with age of onset of 18 years or older.Patients of F1D group had a markedly higher plasma glucose concentration compared with patients of T1A group and T1B group(P=0.004).Serum amylase was higher in F1D group than that in T1A group(P = 0.021).Four (50%) patients were GADA positive,among whom 1 patient was Coxsackie B virus (CVB) IgM positive and 1 patient was Herpes Simplex virus 1 (HSV1) IgM positive.Conclusions Fulminant type 1 diabetes accounts for about 10% of the type 1 diabetes in the Chinese individuals with ketosis-or ketoacidosis-onset.Patients with this subset of diabetes had severe metabolic derangement.Viral infection and autoimmunity may be involved in the pathogenesis of fulminant type 1 diabetes.