Understanding the different stages of type 1 diabetes and their management: a plain language summary

This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10mg or 100mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2weeks. This method of administration is known as intravenous (IV) infusion. In the group given 10mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6months without their cancer growing or getting worse.The most common side effect was CRS, which occurred in 51% of participants in the group given 10mg tarlatamab and 61% of participants in the group given 100mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell-associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab. The study found that tarlatamab given every 2weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10mg tarlatamab dose had fewer side effects than those given the 100mg tarlatamab dose.Clinical Trial Registration: NCT05740566 (DeLLphi-304) (ClinicalTrials.gov).

BackgroundAdvances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.Case PresentationA 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.ConclusionNew onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM.

Diabetes Mellitus

This plain language summary describes the results of a phase 1 research study (or clinical trial) called MonumenTAL-1 published in the New England Journal of Medicine in December 2022. A phase 1 study is an early clinical trial where researchers evaluate how safe a medicine is at different doses in a small number of people. In the MonumenTAL-1 study, researchers looked at a new medicine under development called talquetamab, for people living with multiple myeloma (a type of blood cancer) who did not respond (refractory), stopped responding (relapsed), or who had difficulty dealing with their previous treatments. The phase 1 MonumenTAL-1 study was performed in 2 parts. Safety was the main focus of Part 1 in which side effects, and how serious they were, were assessed. The results of Part 1 were used to identify doses of talquetamab that were well tolerated, without a need to stop treatment or reduce the doses, for further study in Part 2. Part 2 of the study examined how well talquetamab worked to decrease signs of the cancer and what side effects, and their severity, people experienced at the doses identified in Part 1. In Part 1 of the study, researchers identified 2 doses of talquetamab for further study: 405 micrograms for every kilogram of body weight (μg/kg) given weekly and 800μg/kg every other week. All participants experienced at least one side effect of treatment at these 2 doses. Less than half of participants (43% at 405μg/kg weekly dose and 34% at the 800μg/kg every other week dose) experienced serious side effects which are those side effects that led to hospitalization, death, or permanent or life-threatening damage). The most common side effects at both doses were a condition known as cytokine release syndrome (CRS); changes in blood cell levels (where different types of cells in the blood were measured); changes in skin such as itching, dry skin, eczema, ulcers or shedding; changes in nails such as discoloration or ridging (lines or dents); and changes in sense of taste such as food tasting sour or metallic. CRS is caused by the overactivation of the immune system (the body's natural defense system) and can result in fever, feeling sick (nausea), being tired (fatigue), low blood pressure, low blood oxygen levels and body aches. Most cases of CRS, as well as most other side effects, were mild or moderate. Most common serious events were CRS, fever and bone pain. Most people had fewer signs of the cancer after taking talquetamab, and the response was similar between the 2 doses. The median duration of response at the 2 identified doses was 8-10months. Most of the side effects people experienced when taking talquetamab were mild or moderate. Most people who took talquetamab responded to the treatment even though they hadn't responded or stopped responding to previous multiple myeloma treatments or stopped taking those treatments because they were unable to tolerate them. These results demonstrate the potential of talquetamab as a treatment option in people who have used up other available therapy options. The 2 doses of talquetamab identified here are being examined in a larger group of participants to further test for safety and to test how well people respond.

This is a summary of the results of 2 clinical studies that looked at a medicine called tezepelumab. Tezepelumab is approved in the United States of America (USA), the European Union (EU) and several other countries for the treatment of severe, uncontrolled asthma in people aged 12 and above. The results of these 2 studies, called PATHWAY and NAVIGATOR, formed the basis for tezepelumab's approval for use. Tezepelumab is a type of biologic treatment called an antibody. Biologics are treatments that target certain cells or proteins in the body and often in the immune system - the body's natural defence system against infections and diseases - to reduce patients' disease. It works by blocking a key first step in the body's chain reaction leading to inflammation in the airways of people with severe asthma. The clinical studies were done to learn if tezepelumab can be used to treat people with severe, uncontrolled asthma and to find out about its safety. In both studies, tezepelumab was compared to placebo. A placebo is a dummy treatment that looked like tezepelumab but did not have any medicine in it. In both studies, tezepelumab reduced the number of severe asthma attacks that the participants had per year compared with placebo. It also increased the volume of air that the participants could breathe out in 1second compared with placebo. Tezepelumab was well-tolerated, and a similar number of participants had health issues in the tezepelumab and placebo treatment groups. The most common health issues that the participants had during the PATHWAY study were: Worsening of asthma, common cold, headache, and inflammation of the airways. The most common health issues that the participants had during the NAVIGATOR study were: Common cold, infection of the sinuses, throat and airways, headache, worsening of asthma, and inflammation of the airways. The results showed that participants who had monthly doses of tezepelumab had fewer severe asthma attacks and better lung function than those who had placebo. In both studies, the health issues that the participants had were similar between the tezepelumab and placebo treatment groups. Overall, the studies showed that tezepelumab worked in a broad population of people with severe asthma and that the study participants had an acceptable level of health issues during the studies. These results led to the approval of tezepelumab for people with severe asthma aged 12 and above in the USA, EU and other countries. Clinical Trial Registration: PATHWAY study: NCT02054130; NAVIGATOR study: NCT03347279 (ClinicalTrials.gov).

New onset diabetes and diabetic ketoacidosis have been reported with administering atypical antipsychotics. Whereas clozapine and olanzapine are associated with a relatively high incidence of new onset diabetes and diabetic ketoacidosis, there are few case reports that have has been documented implicating quetiapine as the contributor to causing diabetes and diabetic ketoacidosis. I report here on a case of diabetic ketoacidosis that developed in a patient who was associated with quetiapine therapy. A 32-year-old woman with schizophrenia was transferred to the emergency room with diabetic ketoacidosis and vaginal bleeding. Seventeen months before this episode, she was hospitalized in an inpatient psychiatric institution and treated with quetiapine 1200mg, halo-peridol 3mg, diazepam 5mg and benztropine 3mg with normal blood glucose levels. She had no personal and familial history of di-abetes mellitus. She had no risk factors for diabetes mellitus and she also had no precipitating factor for diabetic ketoacidosis except for taking the atypical antipsychotic quetiapine. I believe that this case is the first case report of quetiapine associated diabetic keto-acidosis in Korea. Considering the unpredictability of hyperglycemia associated with quetiapine, monitoring the blood glucose should be part of the routine care when administering quetiapine. (

Role of immune system in type 1 diabetes mellitus pathogenesis.

Neuromyelitis optica spectrum disorder (NMOSD for short) is a rare autoimmune health condition, meaning that the body's natural defense system (the immune system) attacks the body's own tissues. This summary describes NMOSD and the results of three studies of the effects of treatment with two medicines called eculizumab and ravulizumab. Eculizumab and ravulizumab are approved to treat people with a type of NMOSD called AQP4-Ab+ NMOSD. The three studies included in this summary are the PREVENT and CHAMPION-NMOSD clinical studies and a study done in everyday clinical practice in Japan. The PREVENT study was a phase 3 study (a large study testing safety and effectiveness of a treatment before it is approved) with three parts. The PREVENT main study compared eculizumab to a placebo (a treatment with no active ingredients, used to test how well a new treatment works). A long-term follow-up study assessed the safety and effectiveness of eculizumab over time, without a placebo group. Another long-term follow-up focused on people taking eculizumab alone, without other immunosuppressive treatments. The CHAMPION-NMOSD study was another phase 3 study testing ravulizumab, a treatment based on eculizumab but given less often, using the placebo group from the PREVENT study for comparison. A daily clinical practice study with eculizumab in Japan looked at how eculizumab works in everyday medical practice (outside of controlled clinical trials) after the medication was already approved. The studies found eculizumab and ravulizumab to be safe and effective for preventing relapses in AQP4-Ab+ NMOSD. More than 95% of people treated with these medicines stayed relapse-free during the months or years of the studies follow-up periods. Most people reported side effects that were mild or moderate. The most common side effects were headache, runny nose or sore throat (nasopharyngitis), and infections in the upper respiratory system. The daily practice study confirmed that eculizumab works well in everyday medical practice. These studies suggest that eculizumab and ravulizumab are safe and effective treatments for people with AQP4-Ab+ NMOSD. Eculizumab may help reduce or stop the need for other treatments that weaken the immune system (immunosuppressive therapies). These treatments help people maintain their ability to carry out daily activities and their quality of life.

In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in The New England Journal of Medicine in 2022. The goal of CheckMate 816 was to find out if nivolumab, an immunotherapy that activates a person's immune system (the body's natural defense system) to fight cancer, plus chemotherapy works better than chemotherapy alone when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC). Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive nivolumab plus chemotherapy, and 179 people were randomly assigned to receive chemotherapy alone. The researchers assessed whether people who received nivolumab plus chemotherapy lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe. Researchers found that people who took nivolumab plus chemotherapy lived longer without the cancer getting worse or coming back compared with those who took chemotherapy alone. More people in the nivolumab plus chemotherapy group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took nivolumab plus chemotherapy instead of chemotherapy alone had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries. Adding nivolumab to chemotherapy did not lead to an increase in the rate of side effects compared with chemotherapy alone, and side effects were generally mild and manageable. Results from CheckMate 816 support the benefit of using nivolumab plus chemotherapy before surgery for people with resectable NSCLC. Clinical Trial Registration: NCT02998528 (ClinicalTrials.gov).

The immune system protects the body against pathogens and cancer cells, thereby defending it against infections and diseases via three main components: epithelial barriers, immune cells and proteins including antibodies. Immune defences are constantly active and consist of a complex network of coordinated biological responses. Therefore, the immune system needs to be fed properly with energy sources and essential micronutrients serving as cofactors in the development, maintenance and expression of the immune response. The general nutritional status of an individual modulates immune functions, and immunocompetence is regarded as a measure of adequate nutrition. Low levels of vitamins, minerals and trace elements lead to suppressed immunity, predisposing individuals to infections, which in turn aggravate the nutritional status, leading to a vicious cycle. Supplying the deficient micronutrients with the diet or a dietary supplement can re-establish immune function. A sufficient and balanced diet should cover the overall micronutrient requirements. However, many population segments both in developing and industrialized countries do not get adequate amounts of essential micronutrients through the diet. Current environmental and geopolitical developments (i.e. global economic crisis, rice crisis and other food shortages, the increase in maize cultivation for ethanol production, etc.) are exacerbating problems of nutritional status in many parts of the world and represent a serious threat to nutritional health. This review focuses on nutritional aspects of the immune system and discusses the roles of vitamins A, D, E, C, B 6 , B 12 and folate as well as of the trace elements selenium, zinc, iron and copper in supporting the body's natural defence system and restoring resistance to infections by enhancing the three levels of immunity: epithelial barriers, immune cells and antibody production.

To describe checkpoint inhibitor-induced diabetes mellitus (CPI-DM) and to compare with regular type 1 (T1DM), type 2 (T2DM), and medication-induced diabetes mellitus (MI-DM). We included 88 177 adult patients from the Diabetes Patient Follow-Up (DPV) registry with diabetes manifestation between 2011 and 2020. Inclusion criteria were T1DM, T2DM, MI-DM, or CPI-DM. Because of the heterogeneity between the groups, we matched patients by age, sex, and diabetes duration using propensity scores. Patient data were aggregated in the respective first documented treatment year. The matched cohort consisted of 24 164 patients; T1DM: 29, T2DM: 24000, MI-DM: 120, CPI-DM: 15 patients. Median age at manifestation of CPI-DM patients was 63.6 (57.2-72.8) years (53.3% male). Body mass index in CPI-DM patients was significantly lower (26.8 [23.9-28.1] kg/m2 ) compared with T2DM patients (29.8 [26.2-34.3] kg/m2 , P= 0.02). At manifestation, HbA1c was significantly higher in CPI-DM compared with MI-DM, but there was no difference during follow-up. Diabetic ketoacidosis (DKA) was documented in six CPI-DM patients (T1DM: 0%, T2DM: 0.4%, MI-DM: 0.0%). Fourteen CPI-DM patients were treated with insulin, and three received additional oral antidiabetics. The most common therapy in T2DM was lifestyle modification (38.8%), insulin in MI-DM (52.5%). Concomitant autoimmune thyroid disease was present in four CPI-DM patients (T1DM: 0.0%, T2DM: 1.0%, MI-DM: 0.8%). The data from this controlled study show that CPI-DM is characterized by a high prevalence of DKA, autoimmune comorbidity, and metabolic decompensation at onset. Structured diagnostic monitoring is warranted to prevent DKA and other acute endocrine complications in CPI-treated patients.

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 infection in 2019 has posed major risks to global health and the economy. This coronavirus disease (COVID‐19) pandemic has changed many of our everyday habits, including how we function and socialize, how we eat, and food preferences and selection. The average intake and status of certain vitamins and minerals can result in reduced immunity, which makes people more susceptible to illnesses and exacerbates malnutrition. The most critical factors in this scenario are individual risk evaluation and management techniques. Until general therapies are administered, the nutritional status of each infected patient should be assessed. The differing clinical severity of COVID‐19 – from asymptomatic, to mild, to severe, to death – depends on the different metabolic status of the hosts who have contracted the virus, which is determined by their diet, age, gender, health, lifestyle, and environmental factors. A broad systematic exploration on studies of this disease was steered by means of electronic databases and was limited to articles published in English (or with an English abstract) in publications using words like ‘health’, ‘diet’, ‘food’, ‘nutritional status’, ‘COVID‐19’, ‘pandemic’, ‘modifiable contributor’, ‘immune system’, ‘micronutrients’, ‘vitamin’, and so on. Careful individual consideration of the potential dietary, nutritional, medical, lifestyle, and environmental hazards, along with any supplementation with micronutrients wherever required to help to boost the body's natural defence system, with the intention to improve all levels of immunity and the use of effective risk management techniques are appropriate ways to handle the COVID‐19 pandemic. © 2021 Society of Chemical Industry.

ObjectivesIn the early stages of various critical infections and diseases, altered association of cortisol and adrenocorticotropic hormone (ACTH) levels occurs, with cortisol levels increasing and ACTH levels remaining normal or decreasing. This study aimed to explore the relationship between ACTH and cortisol levels in patients with diabetic ketoacidosis (DKA) and the influence of the severity of DKA.MethodsA total of 106 type 2 diabetes patients with DKA admitted to the Endocrinology Department of Yantai Yuhuangding Hospital from February 2018 to May 2023 were divided into groups without (n=54) and with bacterial infection (n=52). Twenty type 2 diabetes patients without infection or DKA admitted during the same period were included as the control group. Cortisol and ACTH levels were measured on the first day of admission and the day after DKA correction for patients with DKA and on the first day of admission and the day before discharge for the control group.ResultsCompared with the control group, the DKA groups both with and without infection had significantly higher cortisol levels (P<0.05) and significantly lower ACTH levels (P<0.01) at admission. DKA patients with infection had significantly higher cortisol levels at admission than those without infection (734.51 ± 348.69 nmol/L vs 508.79 ± 268.72 nmol/L, P<0.01), while ACTH levels did not differ significantly between the two groups (P>0.05). After correction of DKA, no differences in cortisol or ACTH levels were observed among the three groups. Compared with levels at admission, DKA patients both with and without infection had lower cortisol levels and higher ACTH levels after DKA correction (all P<0.001). Multiple stepwise regression analysis showed that for all DKA patients and for subgroups with and without infection, the cortisol level at admission was independently positively correlated with the ACTH level and negatively correlated with the bicarbonate level (both P<0.01).ConclusionsIn the early stage of DKA, a phenomenon of altered association between cortisol–ACTH occurs and is especially prominent in DKA patients with infection. This altered association between cortisol–ACTH disappears after DKA correction, and the severity of DKA is an independent influencing factor on the cortisol level in early-stage DKA.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral edema; only a minority of deaths in DKA are attributed to other causes. Cerebral edema occurs in ∼0.3% to 1% of all episodes of DKA, and its etiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral edema and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes. To explore these issues, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) convened a panel‖ of expert physicians for a consensus conference. The meeting was chaired by Mark A. Sperling, MD, representing LWPES, and David B. Dunger, MD, representing ESPE. The Consensus statement was developed with close partnership between the ESPE and LWPES and the International Society for Pediatric and Adolescent Diabetes, all 3 organizations being represented by members who participated in the writing process. The statement also was endorsed by related organizations; the Juvenile Diabetes Research Foundation International, the World Federation of Pediatric Intensive and Critical Care Societies, the European Society for Pediatric Critical Care, the European Society of Pediatric and Neonatal Intensive Care, and the Australian Pediatric Endocrine Group were represented by invited participants. Each of the major topics had a presenter and recorder, responsible for review of the literature and providing evidence-based recommendations according to criteria used by the American Diabetes Association (see Appendix; levels of evidence are indicated in capital letters, in parentheses).1 Type 2 diabetes was not considered. All participants contributed … Address correspondence to David B. Dunger, Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk; or Mark A. Sperling, Department of Pediatrics/Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213. E-mail: masp{at}pitt.edu

ObjectivesIn the UK, about 25% of children with new onset diabetes presented with diabetic ketoacidosis (DKA) in the pre-pandemic era1 DKA increased to 43–50% in the COVID pandemic year.2 3The...