Cetoacidosis diabética como debut de diabetes mellitus inmunomediada en paciente en tratamiento con inhibidores de checkpoint / Diabetic ketoacidosis as debut of immune-mediated diabetes mellitus in a patient in treatment with immune checkpoint inhibitors

Los inhibidores de checkpoint (ICP) son anticuerpos usados en inmunoterapia contra el cáncer. Uno de sus blancos de acción es el receptor de muerte celular programada-1 (PD-1), el cual es importante para mantener la tolerancia inmunitaria. Sin embargo, este mecanismo se asocia a riesgo de eventos adversos relacionados a la inmunidad que pueden afectar a múltiples órganos incluyendo el sistema endocrino. Se describe el caso inhabitual de un paciente que a los 18 meses de terapia con ICP debutó con cetoacidosis diabética (CAD).

Immune checkpoint inhibitors consist in antibodies used in immunotherapy against cancer. One of their targets is the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, this mechanism is associated with a risk for immune-related adverse events potentially affecting multiple organs, including the endocrine system. We describe the unusual case of a patient who, after 18 months of treatment with an immune checkpoint inhibitor, debuted with diabetic ketoacidosis

Adverse events associated with immune checkpoint inhibitors: a new era in autoimmune diabetes.

PURPOSE OF REVIEW: To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. RECENT FINDINGS: A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. SUMMARY: Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.

Uncommon Association Between Diabetic Ketoacidosis, Thyrotoxicosis, Cutaneous Abscess and Acute Pericarditis in an Immunocompetent Patient: A Single Case Report and Literature Review.

INTRODUCTION: The typical factors precipitating diabetic ketoacidosis (DKA) include infections (30%), cessation of antidiabetic medication (20%), and a new diagnosis of diabetes (25%). The etiology remains unknown in 25% of cases. Less frequent causes cited in the literature include severe thyrotoxicosis and, infrequently, pericarditis. Few publications have described the role of human T lymphotropic virus type 1 (HTLV-1) in endocrine and metabolic disorders. Based on a clinical case associated with several endocrine and metabolic disorders, we suggest a potential role for HTLV-1, an endemic virus in the Amazonian area, and review the literature concerning the role of this virus in thyroiditis, pericarditis and diabetes mellitus. CASE REPORT: A fifty-year-old Surinamese woman without any medical history was admitted for diabetic ketoacidosis. No specific anti-pancreatic autoimmunity was observed, and the C-peptide level was low, indicating atypical type-1 diabetes mellitus. DKA was associated with thyrotoxicosis in the context of thyroiditis and complicated by nonbacterial pericarditis and a Staphylococcus aureus subcutaneous abscess. The patient was infected with HTLV-1. CONCLUSION: To our knowledge, this uncommon association is described for the first time. Few studies have analyzed the implications of HTLV-1 infection in thyroiditis and diabetes mellitus. We did not find any reports describing the association of pericarditis with HTLV-1 infection. Additional studies are necessary to understand the role of HTLV-1 in endocrine and cardiac disorders.

Anti-PD-L1 therapy and the onset of diabetes mellitus with positive pancreatic autoantibodies.

An 84-year-old woman with metastatic squamous cell carcinoma of the nasopharynx and no history of diabetes was started on the antiprogrammed cell death ligand-1 (anti-PD-L1) antibody durvalumab. Four months later, she presented in diabetic ketoacidosis with glucose 488 mg/dL, anion gap 16, positive serum ketones and A1C9.1%. Antiglutamic acid decarboxylase 65 (GAD) antibody was 13 U/mL (normal, <0.5 U/mL), c-peptide 0.4 ng/dL (normal, 1.1-4.3 ng/mL) and glucose 142 mg/dL. A man with metastatic papillary urothelial carcinoma was treated with the PD-L1 inhibitor atezolizumab. He had no history of diabetes. Nine weeks after initiation, he developed fatigue and polyuria with blood glucose 336 mg/dL, c-peptide 0.6 ng/mL, A1C8.2% and GAD antibodies 28.4 U/mL (normal, <1 U/mL). Due to the diagnosis of autoimmune diabetes, both patients were treated with insulin. Autoimmune diabetes is a rare immune-related adverse effect of PD-L1 inhibitors. We present the first two cases with documented positive pancreatic autoantibodies.

Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial.

Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro.

Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under "flow" conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

Evaluation of cytokines and hormones in dogs before and after treatment of diabetic ketoacidosis and in uncomplicated diabetes mellitus.

In human beings, diabetes mellitus (DM) and diabetic ketoacidosis (DKA) are recognized as proinflammatory states and dysregulation of cytokines has been linked to some potentially fatal complications. Cytokine profiles of dogs with DM or DKA have not been reported. The objectives of this study were to compare cytokine and hormone concentrations in dogs with DKA before and after resolution of ketoacidosis, to compare these concentrations before treatment of DKA to those measured in dogs with uncomplicated DM and healthy dogs, and to compare concentrations in dogs with uncomplicated DM to those measured in healthy dogs. 27 dogs were included in this prospective clinical study. 18 dogs had naturally-occurring disease (9 DKA and 9 DM) and 9 dogs were healthy. Serum GMCSF, IL-2, IL-4, IL-6, IL-7, CXCL8, IL-10, IL-15, IL-18, IFNγ, IP-10, TNFα, Monocyte Chemoattractant Protein-1 (MCP-1), Keratinocyte Chemoattractant (KC), glucagon, leptin, adiponectin, and resistin were assayed using Milliplex MAP Canine kits.(2)(,)(3) IL-18, resistin, and GMCSF concentrations were significantly higher in dogs with DKA before treatment compared to after resolution of ketoacidosis. CXCL8, MCP-1, KC, and resistin were significantly higher in DKA dogs compared to healthy controls, and KC was also significantly higher in DKA compared to DM dogs. Additionally, CXCL8 and MCP-1 were significantly higher in dogs with DM compared to healthy controls. Significant differences were not detected in concentrations of the other measured analytes, including glucagon. It is concluded that IL-18, resistin, GMCSF, and KC may be involved in the pathogenesis of canine DKA, and their importance in this pathogenesis may be as great as that of glucagon. Dysregulation of CXCL8 and MCP-1 may be involved in the pathogenesis of DM in dogs.

Insulitis in human type 1 diabetes.

Pancreatic tissues were analyzed immunohistologically in patients with autoimmune and fulminant type 1 diabetes (T1D) and control subjects. Both beta and alpha cells were decreased in fulminant T1D, but only beta cells were significantly decreased in autoimmune T1D. Insulitis was seen in both subtypes of T1D, but it remained longer in autoimmune than in fulminant T1D. Lymphocytic infiltration to the exocrine pancreatic tissue was observed only in fulminant T1D, whereas immunologically abnormal findings, such as increased expression of MHC class I molecule and Fas antigen in islet cells and Fas-ligand expression in infiltrating lymphocytes, were detected only in autoimmune T1D. From these findings, together with clinical features, it could be concluded that in autoimmune T1D, beta cells are assumed to be destroyed through a long-standing autoimmune process, whereas in fulminant T1D, beta cells seem to be destroyed very rapidly, probably by a destructive process triggered by viral infection.

Cytokine response to diabetic ketoacidosis and its treatment.

The objectives of this study were to monitor plasma cytokines as markers of cellular activation and as potential markers for the progression of the acute complications of diabetic ketoacidosis (DKA). Blood samples were obtained prior to, during and after treatment of severe DKA (pH < 7.2) in six children and adolescents. Plasma IL-10, IL-1beta, TNF-alpha, IL-6, IL-8 and IL-2 cytokine levels were assayed by ELISA at each of the time points. Prior to treatment, elevations of multiple cytokines were found, the highest being IL-10. Treatment of DKA resulted in a significant decrease of IL-10 at 6-8 h (p = 0.0062), and further increases in the inflammatory cytokines at 6-8 h and/or 24 h vs 120 h (baseline): IL-1beta (p =.0048); TNF-alpha (p =.0188) and IL-8 (p =.0048). This study strengthens the hypothesis that the metabolic crisis of DKA, and its treatment, have differential effects on cellular activation and cytokine release. The time frame for the increase in inflammatory cytokines correlates with the reported progression of subclinical brain edema, interstitial pulmonary edema and the development of clinical brain edema.

Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes.

OBJECTIVE: Diabetic patients have elevated blood levels of interleukin-6 (IL-6), which is known to increase inflammation and the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the circulating levels of IL-6 in type 1 diabetic patients as well as the secretion of IL-6 in vitro in a cell culture model using U937 monocytes. RESEARCH DESIGN AND METHODS: Fasting blood was obtained from type 1 diabetic patients and healthy siblings. To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], beta-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37 degrees C for 24 h. IL-6 was determined by the sandwich enzyme-linked immunosorbent assay method, and intracellular reactive oxygen species (ROS) generation was detected using dihydroethidium dye. RESULTS: The blood level of IL-6 was higher in hyperketonemic (HK) diabetic patients than in normoketonemic (NK) diabetic patients (P < 0.05) and normal control subjects (P < 0.05). There was a significant correlation between ketosis and IL-6 levels (r = 0.36, P < 0.04, n = 34) in the blood of diabetic patients. Cell culture studies found that exogenous addition of the ketone body AA, but not BHB, increases IL-6 secretion and ROS generation in U937 cells. N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes. CONCLUSIONS: This study demonstrates that hyperketonemia increases IL-6 levels in the blood of type 1 diabetic patients and that NAC can inhibit IL-6 secretion by U937 monocytic cells cultured in a ketotic medium.

Cetoacidose diabética desencadeada por resistência imunológica à insulina / Diabetic ketoacidosis induced by immunologic insulin resistance

A cetoacidose diabética (CAD) é a emergência endocrinológica mais freqüente e de boa evoluçäo, na maior parte dos casos. Os autores apresentam evoluçäo atípica de três casos de CAD precipitada por resistência imunológica à insulina (RII). RELATO DE CASO. Três pacientes: H.M.L. (46 anos, diabetes mellitus (DM) tipo II, há 6 anos), D.R.J (39 anos, DM, secundário à pancreatopatia, há 11 anos) e D.L.S. (54 sanos, DM tipo II, há 9 anos) foram admitidos na Unidade de primeiro Atendimento do Hospital Säo Paulo em CAD: H.M.L. (glicemia: 716mg/dL, pH: 6,8), D.R.J. (glicemia: 684mg/dL, pH 6,.9) e D.L.S. (glicemia: 384mg/dL, pH: 7,2), todos apresentavam cetonúria. As necessidades de insulina para o controle metabólico foram: H.M.L.: 1.369UI, D.R.J.: 1.496UI, D.I.S. 1.369UI em, respectivamente: 212, 206 e 72 horas. Os anticorpos antiinsulina (AI) foram dosados por RE e ELISA: H.M.L.: 7.186nU/ml, 3,6IE; D.R.J.: 7,879nU/mL, 3,24IE; D.I.S: 8.377nU/mL, 2,88IE. O seguimento ambulatorial revelou queda progressiva dos níveis de AI:H.M.L.: 3.393nU/mL, 1,39, após dez meses da CAD; d.r.j.: 4,673Nu/Ml, 2,34 E d.i.s.: 1,510nU/mL, ambos após 18 meses da CAD. A queda nos níveis de anticorpos foi significativa nos três pacientes e foi acompanhada de melhor controle metabólico. Discussäo. A ausência de fator desencadeante, o elevado tempo, as altas doses de insulina empregadas para a compensaçäo metabólica levaram os autores à suspeita diagnóstica de RII. O diagnóstico foi confirmado pelos altos níveis séricos dos AI. O controle metabólico nestes pacientes foi obtido somente após a introduçäo de insulina na humanizada. CONCLUSAO. A resistência imunológica à insulina pode ser uma das causas de CAD sem fator precipitante aparente e má resposta às medidas terapêuticas habituais

Severe insulin-resistant diabetes mellitus associated with hypereosinophilic syndrome.

We describe a 52-year-old male manifesting severe insulin resistance associated with hypereosinophilic syndrome (HES). Diabetes mellitus was initially well-controlled by an oral hypoglycemic agent, and thereafter by human insulin. Due to the progression of hypereosinophilia, hepatosplenomegaly and peripheral lymphoadenopathy, severe insulin resistance associated with diabetic ketoacidosis occurred repeatedly, despite intravenous administration of over 1,000 U per day of human insulin. A high plasma insulin-binding capacity as determined by Scatchard analysis was consistent with insulin antibody-mediated resistance. The diagnosis of HES was made due to the persistent elevation of eosinophil count and associated liver and cardiac damage. Glucocorticoid therapy successfully achieved both reducing clinical symptoms and improving glycemic control.

Influence of metabolic disturbances of diabetes mellitus on serum CA 19-9 tumor marker.

CA 19-9 is a monoclonal antibody-defined tumor marker expressed by exocrine pancreas. It has been shown that exocrine atrophy was associated with deficiency. Hyperamylasemia has been described during ketoacidosis. Our study aimed at investigating the relationships between CA 19-9 and metabolic control of diabetes. Study was performed on 51 adult consecutive diabetic patients (21 type 1 and 30 type 2), with ketoacidosis or hyperosmolarity (group A, n = 15), poor glycaemic control (group B, n = 19), or good control (group C, n = 17). Serum CA 19-9 and metabolic parameters were evaluated on day 1 and day 30. Analysis of variance showed a very significant global difference between groups for CA 19-9 (p less than 0.0001); group A (66.1 +/- 11.4 u/ml) significantly differed from group B (36.4 +/- 4 u/ml) (p less than 0.01) and group C (22.4 +/- 2.8 u/ml) (p less than 0.001). Simple regression showed a significant correlation between CA 19-9 and fasting blood glucose (r = 0.6, p less than 0.001), plasma creatinine level (r = 0.37, p = 0.01), bicarbonate (r = 0.47, p = 0.001) and HbA 1c (r = 0.33, p = 0.032). The Ca 19-9 decrease on day 30 paralleled the improvement of glycaemic control. We conclude that CA 19-9 in diabetic patients is raised in acute metabolic situations and correlated very well with blood glucose concentration. A careful interpretation of this tumor marker assay is required when screening for pancreatic carcinoma among diabetic patients. CA 19-9 could be a useful and sensitive marker for the severity of exocrine damage and functional cellular disorders following metabolic disturbances in diabetes.

A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability.

The defect in host defense that makes the diabetic ketoacidotic (DKA) patient susceptible to mucormycosis has not been identified. Sera from 10 DKA patients and three normal volunteers were tested for their capacity to support the in vitro growth of a common etiologic agent of mucormycosis, Rhizopus oryzae. After equilibration with room air none of the normal or DKA sera, each of which was now extremely alkaline, supported growth of R. oryzae. When the sera were placed in a CO2 atmosphere that permitted simulation of the in vivo clinical pH (normal 7.40 and DKA 7.3-6.6), four of seven DKA sera supported profuse fungal growth. No growth occurred in normal serum. The three DKA sera that did not support fungal growth at pH less than or equal to 7.3 contained less iron (x = 13 micrograms/dl) than the four sera that supported profuse fungal growth (x = 69 micrograms/dl). Increasing the iron content of iron-poor DKA serum that did not support R. oryzae growth allowed profuse growth at acidotic conditions but not at pH greater than or equal to 7.4. Simulated acidotic conditions (pH 7.3-6.6) also decreased the iron-binding capacity of normal serum stepwise from 266 micrograms/dl to 0. Our data indicate that acidosis temporarily disrupts the capacity of transferrin to bind iron and suggest that this alteration abolishes an important host defense mechanism that permits growth of R. oryzae.