The impaired insulin secretion and increased insulin resistance (or decreased insulin sensitivity) play a major role in the pathogenesis of all types of diabetes mellitus (DM). It is very important ...to assess the pancreatic β-cell function and insulin resistance/ sensitivity to determine the type of DM and to plan an optimal management and prevention strategy for DM. So far, various methods and indices have been developed to assess the β-cell function and insulin resistance/sensitivity based on static, dynamic test and calculation of their results. In fact, since the metabolism of glucose and insulin is made through a complex process related with various stimuli in several tissues, it is difficult to fully reflect the real physiology. In order to solve the theoretical and practical difficulties, research on new index is still in progress. Also, it is important to select the appropriate method and index for the purpose of use and clinical situation. This review summarized a variety of traditional methods and indices to evaluate pancreatic β-cell function and insulin resistance/sensitivity and introduced novel indices.
Aims/hypothesis
Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a ...major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown.
Methods
We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10–31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation.
Results
The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th–75th percentile: 25.0–32.7) kg/m
2
; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin–angiotensin–aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA
1c
, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 1.10, 1.47). On admission, dyspnoea (OR 2.10 1.31, 3.35), as well as lymphocyte count (OR 0.67 0.50, 0.88), C-reactive protein (OR 1.93 1.43, 2.59) and AST (OR 2.23 1.70, 2.93) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 1.74, 3.53), treated obstructive sleep apnoea (OR 2.80 1.46, 5.38), and microvascular (OR 2.14 1.16, 3.94) and macrovascular complications (OR 2.54 1.44, 4.50) were independently associated with the risk of death on day 7.
Conclusions/interpretations
In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days.
Trial registration
clinicaltrials.gov
NCT04324736.
Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal ...immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.
Aim
To assess the relationship between body mass index (BMI) classes and early COVID‐19 prognosis in inpatients with type 2 diabetes (T2D).
Methods
From the CORONAvirus‐SARS‐CoV‐2 and Diabetes ...Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID‐19–related outcomes (i.e. intubation for mechanical ventilation IMV, death and discharge by day 7 D7) were analysed according to BMI status.
Results
Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5‐24.9 kg/m2, reference group), 726 (36.9%) overweight (25‐29.9 kg/m2) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30‐34.9 kg/m2) and 314 (16.0%) with class II/III obesity (≥35 kg/m2). In a multivariable‐adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 1.05‐2.59), class I (OR 1.93 1.19‐3.14) and class II/III obesity (OR 1.98 1.11‐3.52). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years.
Conclusions
Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID‐19. Importantly, the deleterious impact of obesity on COVID‐19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.
Aims/hypothesis
This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic ...factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19).
Methods
The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days.
Results
We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th–75th percentile) 28.4 (25.0–32.4) kg/m
2
. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5–14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors.
Conclusions/interpretation
In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period.
Trial registration
Clinicaltrials.gov
identifier: NCT04324736
Graphical abstract
Early in the COVID‐19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in ...immune responses can mitigate or aggravate disease course. Identifying at‐risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID‐19 severity in T2D. Broad‐spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID‐19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8+ lymphocytes were associated with severe COVID‐19 and requirement for intensive care in both non‐diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14Hi CD16− monocytes was specifically associated with severe COVID‐19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID‐19 in T2D. These findings allow precise identification of T2D patients with severe COVID‐19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.
Synopsis
The study demonstrates that COVID‐19 affects different circulating immune cells depending on diabetic status. Type‐2 diabetic (T2D) patients with COVID‐19 lose a specific subtype of monocytes, which is associated with changes in cell morphology and highly inflammatory gene expression profile.
Patients with T2D are at higher risk of dying or suffering from severe forms of COVID‐19.
COVID‐19 infection causes a decrease in circulating lymphocyte and monocyte populations associated with severity of disease in patients with T2D.
Monocytes undergo morphological changes and highly express inflammatory markers reminiscent of the type‐1 interferon response in T2D.
Inflammatory and cellular responses to COVID‐19 from patients with T2D are associated with a need for intensive care.
The study demonstrates that COVID‐19 affects different circulating immune cells depending on diabetic status. Type‐2 diabetic (T2D) patients with COVID‐19 lose a specific subtype of monocytes, which is associated with changes in cell morphology and highly inflammatory gene expression profile.
Aim
To describe baseline characteristics and follow‐up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real‐life setting.
Patients and ...Methods
Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow‐up during treatment.
Results
Forty‐seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range IQR) patient age was 29.3 (16.6‐47.6) years, body mass index was 23.8 (21.2‐25.7) kg/m2 and serum leptin was 3.2 (1.0‐4.9) ng/mL, 94% of patients had diabetes (66% insulin‐treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2‐76.0) months, was ongoing in 77% of patients at the latest follow‐up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5‐9.9)% 68 (48‐85) mmol/mol to 6.8 (5.6‐7.4)% 51(38‐57) mmol/mol, and 3.6 (1.7‐8.5) mmol/L to 2.2 (1.1‐3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 7.1‐9.1% 61 (54‐76) mmol/mol at baseline vs. 7.7 7.4‐9.5% 61(57‐80) mmol/mol at 1 year), and the decrease in fasting triglycerides (from 3.3 1.9‐9.9 mmol/L to 2.5 1.6‐5.3 mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 2.2‐11.3 mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group.
Conclusions
In this real‐life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which ...include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.
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