Summary Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. Interventions to preserve β cells have been tested, and several methods to improve clinical disease management have been assessed. However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.

Type 1 diabetes

American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

/pdf/glp-1-receptor-agonists-beyond-their-pancreatic-effects-58xbi4c2fp.pdf

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Objective To identify factors that contribute to the increased susceptibility and severity of COVID-19 in obese children and adolescents, and its health consequences. Sources Studies published between 2000 and 2020 in the PubMed, MEDLINE, Scopus, SciELO, and Cochrane databases. Summary of findings Obesity is a highly prevalent comorbidity in severe cases of COVID-19 in children and adolescents; social isolation may lead to increase fat accumulation. Excessive adipose tissue, deficit in lean mass, insulin resistance, dyslipidemia, hypertension, high levels of proinflammatory cytokines, and low intake of essential nutrients are factors that compromise the functioning of organs and systems in obese individuals. These factors are associated with damage to immune, cardiovascular, respiratory, and urinary systems, along with modification of the intestinal microbiota (dysbiosis). In severe acute respiratory syndrome coronavirus 2 infection, these organic changes from obesity may increase the need for ventilatory assistance, risk of thromboembolism, reduced glomerular filtration rate, changes in the innate and adaptive immune response, and perpetuation of the chronic inflammatory response. Conclusions The need for social isolation can have the effect of causing or worsening obesity and its comorbidities, and pediatricians need to be aware of this issue. Facing children with suspected or confirmed COVID-19, health professionals should 1) diagnose excess weight; 2) advise on health care in times of isolation; 3) screen for comorbidities, ensuring that treatment is not interrupted; 4) measure levels of immunonutrients; 5) guide the family in understanding the specifics of the situation; and 6) refer to units qualified to care for obese children and adolescents when necessary.

http://www.scielo.br/pdf/jped/v96n5/0021-7557-jped-96-05-0546.pdf

COVID-19 and obesity in childhood and adolescence: a clinical review.

Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions. 

http://www.metabolismjournal.com/article/S0026049522001019/pdf

Metformin: Is it a drug for all reasons and diseases?

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to be associated with an increased risk of pancreatitis and pancreatic cancer. The aim of this meta-analysis was to collect data from large-scale cardiovascular outcome trials (CVOTs) to assess the effect of GLP-1RAs on the incidence of acute pancreatitis and pancreatic cancer. Database of Medline, Embase, and the Cochrane Central Register of Controlled Trials were extensively searched up to October 10, 2019. Randomized controlled trials were eligible if they compared GLP-RA with placebo as add-on therapy to standard care in T2DM patients, and reported outcomes required for cardiovascular safety studies and events of acute pancreatitis and/or pancreatic cancer. Peto odds ratio (OR) with 95% confidence interval (CI) was calculated for acute pancreatitis and pancreatic cancer. Seven CVOTs enrolling 56,004 patients with T2DM were identified, with a median follow-up time ranging from 1.3 to 5.4 years. A total of 180 cases of acute pancreatitis and 108 cases of pancreatic cancer were reported. The risk of either acute pancreatitis or pancreatic cancer with GLP-1-RA treatment was not significantly different from that observed in placebo arm (Peto OR [95% CI] 1.05 [0.78–1.40], P = 0.76, and 1.12 [0.77–1.63], P = 0.56, respectively), and the results remained robust to sensitivity analyses. Pooled analysis of CVOTs did not suggest any increased risk of either acute pancreatitis or pancreatic cancer with GLP-1RA treatment in T2DM patients.

GLP-1 receptor agonists and pancreatic safety concerns in type 2 diabetic patients: data from cardiovascular outcome trials.

Some preliminary studies reported a link between GLP-1 receptor agonists (GLP-1RAs) and thyroid/pancreatic neoplasms, while its human relevance remained undetermined. The present meta-analysis was performed to collect information on cancers associated with GLP-1RAs in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov were extensively searched to identify randomized controlled trials that reported cancer events in T2DM patients treated with GLP-1RAs for at least 52 weeks, up to March 18, 2019. Odds ratio (OR) with 95% Confidence Interval (CI) was calculated for overall cancer (primary outcome), thyroid and pancreatic cancer. A total of 37 eligible trials were identified. The OR for overall cancer associated with GLP-1RAs was 1.03 (95% CI 0.95–1.12; p = 0.41) compared with comparators. Subgroup analyses showed that treatment with albiglutide was associated with a lower risk of overall cancer (OR 0.76 [95% CI 0.60–0.97]; p = 0.03), and no elevated risk of overall cancer was identified for other GLP-1RAs. No significant differences in the risks of thyroid nor pancreatic cancer were disclosed between GLP-1RAs and comparators. This meta-analysis did not suggest any increased risk of cancers associated with GLP-1RAs use in T2DM. The reduction in the risk of overall cancer associated with albiglutide needs to be examined further.

GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials

Context This study applied the Swedish novel data-driven classification in Chinese newly diagnosed diabetic patients and validated its adoptability. Objective This study aimed to validate the practicality of the Swedish diabetes regrouping scheme in Chinese adults with newly diagnosed diabetes. Design Patients were classified into 5 subgroups by K-means and Two-Step methods according to 6 clinical parameters. Setting Ambulatory care. Patients A cross-sectional survey of 15 772 patients with adult-onset newly diagnosed diabetes was conducted in China from April 2015 to October 2017. Intervention None. Main outcome measures Six parameters including glutamate decarboxylase antibodies (GADA), age of onset, body mass index (BMI), glycated hemoglobin A1c (HbA1c), homoeostatic model assessment 2 estimates of β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR) were measured to calculate the patient subgroups. Results Our patients clustered into 5 subgroups: 6.2% were in the severe autoimmune diabetes (SAID) subgroup, 24.8% were in the severe insulin-deficient diabetes (SIDD) subgroup, 16.6% were in the severe insulin-resistance diabetes (SIRD) subgroup, 21.6% were in the mild obesity-related diabetes (MOD) subgroup and 30.9% were in the mild age-related diabetes (MARD) subgroup. When compared with the Swedish population, the proportion of SIDD subgroup was higher. In general, Chinese patients had younger age, lower BMI, higher HbA1c, lower HOMA2-B and HOMA2-IR, and higher insulin use but lower metformin usage than the Swedish patients. Conclusion The Swedish diabetes regrouping scheme is applicable to adult-onset diabetes in China, with a high proportion of patients with the severe insulin deficient diabetes. Further validations of long-term diabetes complications remain warranted in future studies.

/pdf/validation-of-the-swedish-diabetes-re-grouping-scheme-in-zsb191mm6j.pdf

Validation of the Swedish Diabetes Re-Grouping Scheme in Adult-Onset Diabetes in China

Diabetes mellitus is a common systematic chronic disease amongst dental patients. The elevated glucose microenvironment can prolong the healing of tooth extraction sockets. Therefore, the promotion of healing up tooth extraction sockets is of great clinical importance to the patients with diabetes mellitus. The current evidence indicates the mechanism of the recovery period of extraction sockets in hyperglycaemia conditions from physiological, inflammation, immune, endocrine and neural aspects. New advancements have been made in varied curative approaches and drugs in the management of wound healing of tooth extraction sockets in diabetes. However, most of the interventions are still in the stage of animal experiments, and whether it can be put into clinical application still needs further explorations. Specifically, our work showed topical administration of plasma-rich growth factor, advanced platelet-rich fibrin, leukocyte- and platelet-rich fibrin and hyaluronic acid as well as maxillary immediate complete denture is regarded as a promising approach for clinical management of diabetic patients requiring extractions. Overall, recent studies present a blueprint for new advances in novel and effective approaches for this worldwide health ailment and tooth extraction sockets healing.

/pdf/pathogenesis-and-treatment-of-wound-healing-in-patients-with-2tblm074.pdf

Pathogenesis and treatment of wound healing in patients with diabetes after tooth extraction

Background Type 1 diabetes is an autoimmune disease strongly related to genetic factors. Although studies on T1D susceptibility genes have achieved great progress, the molecular mechanism of T1D remains to be explained. Methods To explore the underlying mechanisms of T1D, bioinformatic analysis based on a microarray database was used to determine the key biomarkers of T1D as well as their biofunctions and interactions. The microarray database GSE55100 was downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were processed by packages in R Software. The database for Annotation, Visualization, and Integrated Discovery (DAVID, version 6.8) was used to conduct gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The protein-protein interaction network was analyzed with the Search Tool for the Retrieval of Interacting Genes (STRING), and the module analysis was performed using Cytoscape. Results Seventy-eight DEGs and 13 hub genes were identified. The biofunctions and pathways of these DEGs were enriched in immune response, extracellular exosome, cytokine activity and antigen processing and presentation. Thirteen DEGs with MCODE score ≥2 were selected as hub genes including MMP9, ARG1, CAMP, CHI3L1, CRISP3, SLPI, LCN2, PGLYRP1, LTF, RETN, CEACAM1, CEACAM8 and MS4A3. Conclusions The identification and analyses of the DEGs and hub genes from database GSE55100 provide novel prospectives of the pathogenesis of T1D.

Analysis of potential hub genes involved in the pathogenesis of Chinese type 1 diabetic patients

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