Semaglutide is the first peptide to receive European marketing authorization for oral administration in the treatment of type 2 diabetes. The active molecule is the same as the one marketed for ...weekly subcutaneous administration. It is associated with a new excipient, which protects it from degradation by gastric pepsin and allows its absorption in the stomach. This article presents the pharmacological characteristics of this drug, as well as a critical analysis of the results of the main phase III clinical trials.
Available evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. ...Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8
+
T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo ‘humanised’ mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the ‘benign’ islet autoimmunity of healthy individuals.
Graphical abstract
Abnormal glucagon secretion and functional alterations of the exocrine pancreas have been described in patients with type 1 diabetes (T1D), but their respective anatomical substrata have seldom been ...investigated. Our aim was to develop an automated morphometric analysis process to characterize the anatomy of α-cell and exocrine pancreas in patients with T1D, using the publicly available slides of the Network for Pancreatic Organ Donors (nPOD).
The ratio of β- and α-cell area to total tissue area were quantified in 75 patients with T1D (thereafter patients) and 66 control subjects (thereafter controls), on 2 insulin-stained and 4 glucagon-stained slides from both the head and the tail of the pancreas. The β- and α-cell masses were calculated in the 66 patients and the 50 controls for which the pancreas weight was available. Non-exocrine-non-endocrine tissue area (i.e. non-acinar, non-insular tissue) to total tissue area ratio was evaluated on both insulin- and glucagon-stained slides. Results were expressed as mean ±SD.
An automated quantification method was set up using the R software and was validated by quantification of β-cell mass, a well characterized parameter. β-cell mass was 29.6±112 mg in patients and 628 ±717 mg in controls (p<0.0001). α-cell mass was 181±176 mg in patients and 349 ±241mg in controls (p<0.0001). Non-exocrine-non-endocrine area to total tissue area ratio was 39±9% in patients and 29± 10% in controls (p<0.0001) and increased with age in both groups, with no correlation with diabetes duration in patients.
The absolute α-cell mass was lower in patients compared to controls, in proportion to the decrease in pancreas weight observed in patients. Non-exocrine-non-endocrine area to total tissue area ratio increased with age in both groups but was higher in patients at all ages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate the impact of coronavirus disease 2019 lockdown on glycemic control and associated factors in people living with type 1 diabetes.
An observational evaluation from a self-reported ...questionnaire on behavioral changes and glycemic information from flash glucose monitoring (FGM) during the lockdown in 1,378 individuals living with type 1 diabetes who used a French dedicated nationwide web application (CoviDIAB).
The main outcome was the change of the mean glucose level 2 months before and 1 month after the lockdown. We found that mean glucose improved from 9.1 ± 1.7 mmol/L to 8.7 ± 1.7 mmol/L (
< 0.001). Factors associated with better glycemic control were a decrease of alcohol consumption (odds ratio OR 1.75 95% CI 1.04-2.94), an increase in the frequency of FGM scans (OR 1.48 1.04-2.10) and in the number of hypoglycemia events (OR 1.67 1.13-2.46), and an easier diabetes control perception (OR 1.71 1.18-2.49).
Our findings suggest that lockdown has a positive impact on glycemic control in people with type 1 diabetes.
Adipose tissue angiogenesis in obesity Lemoine, Amal Y.; Ledoux, Séverine; Larger, Etienne
Thrombosis and haemostasis,
10/2013, Letnik:
110, Številka:
4
Journal Article
Recenzirano
Adipose tissue is the most plastic tissue in all multicellular organisms, being constantly remodelled along with weight gain and weight loss. Expansion of adipose tissue must be accompanied by that ...of its vascularisation, through processes of angiogenesis, whereas weight loss is associated with the regression of blood vessels. Adipose tissue is thus among the tissues that have the highest angiogenic capacities. These changes of the vascular bed occur through close interactions of adipocytes with blood vessels, and involve several angiogenic factors. This review presents studies that are the basis of our understanding of the regulation of adipose tissue angiogenesis. The growth factors that are involved in the processes of angiogenesis and vascular regression are discussed with a focus on their potential modulation for the treatment of obesity. The hypothesis that inflammation of adipose tissue and insulin resistance could be related to altered angiogenesis in adipose tissue is presented, as well as the beneficial or deleterious effect of inhibition of adipose tissue angiogenesis on metabolic diseases.
Aims/hypothesis
Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αβ T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered ...in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes.
Methods
MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2–14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes.
Results
MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25
+
MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells,
p
< 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells,
p
< 0.01). Several MAIT cell variables correlated with HbA
1c
level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (
p
< 0.05) and CD127 (IL-7R) (
p
< 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased.
Conclusions/interpretation
Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose homeostasis; and autoimmunity.
Graphical abstract
Studies suggest that cardio-vascular risk factors could foster the development of type 2 diabetes (T2D). This could partly be mediated by pancreatic atherosclerosis resulting in pancreatic ischemia. ...We hypothesized that patients with T2D present with more severe atherosclerosis of pancreas-bound arteries than control patients without T2D.
We performed a retrospective study comparing the abdominal computed tomography of patients with T2D and of control subjects matched for gender and for age. We performed a multivariate logistic regression with adjustment for age, gender, BMI and the presence or absence of hypertension.
Forty-eight patients with T2D and 48 control subjects were included. A calcification score of the splenic artery was defined (from 0: no calcification to 3: continuous linear calcifications). Seventeen percent of the patients with T2D presented with a high calcification score (i.e. 2 or 3), versus only 2% of the control subjects (p = 0.04). The mean number of pancreas-bound branches among the greater pancreatic artery, dorsal pancreatic artery and inferior pancreatic artery (from 0 to 3) was lower in patients with T2D than in control subjects (1.1 vs 1.7, p = 0.003). The mean number of visible intrapancreatic arterial subdivisions (from 0 to 2) was lower in patients with T2D than in control subjects (0.7 vs 1.3, p = 0.0017). All these differences hold true using multivariate logistic regression. None of these differences correlated with the duration of diabetes. The relationship between pancreas volume and BMI seen in control subjects was not confirmed in patients with T2D. Conversely, in patients with T2D but not in control subjects, the splenic artery diameter correlated with the pancreas volume.
Patients with T2D present with more calcifications of the splenic artery and with a less dense pancreatic arterial tree than control subjects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cystic fibrosis related diabetes (CFRD) is observed in 20-50% of adults with cystic fibrosis (CF). Pancreas abnormalities on imaging, e.g. pancreas lipomatosis, are frequent in subjects with CF. We ...hypothesized that specific abnormalities may characterize patients with CFRD. We performed a retrospective study comparing the computed tomography (CT) of participants with CF with or without diabetes ("CFRD" and "CF control" groups). We classified the pancreas on imaging according to 3 categories: normal, partial lipomatosis and complete lipomatosis of the pancreas. We also assessed the presence or absence of pancreatic calcifications. Forty-one CFRD and 53 CF control participants were included. Only 2% of the patients with CFRD had a normal pancreas, as compared with 30% of the participants from the CF control group (p = 0.0016). Lipomatosis was more frequent in subjects with CFRD and was related to exocrine pancreatic insufficiency (EPI) and to severe CFTR mutations (classes I to III). Nine participants with diabetes (22%) presented with pancreatic calcifications, versus none of the control participants (p = 0.0003). In conclusion, pancreas imaging was almost always abnormal in subjects with CFRD, while it was normal in a third of the CF control subjects. Pancreatic calcifications were specific of subjects with CFRD.
Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in ...endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD.
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