optimized-protocol-for-generating-functional-pancreatic-insulin

Optimized Protocol for Generating Functional Pancreatic Insulin-secreting Cells from Human Pluripotent Stem Cells

Human pluripotent stem cells (hPSCs) can differentiate into any kind of cell, making them an excellent alternative source of human pancreatic ...

Cell Biology and Functional Genomics

Imperial College Healthcare NHS Trust

Clinical guidelines are ubiquitous, manifold and form an integral component of evidence-based clinical practice. Guidelines on test selection are often considered a useful adjunct to aid clinical decision-making, as test selection is a complex process that is influenced by many patient, clinician and laboratory factors. However, it is important to carefully evaluate several aspects of these guidelines, which include the context of the test in the guideline, the quality of the studies underpinning recommendations, the extent of the evaluation of effectiveness (or performance) of the specific test and in the clinical pathway, its applicability and ease of implementation. A robust evaluation of a diagnostic test should incorporate several stages including evaluation in healthy, symptomatic but unaffected and affected populations, and importantly a measurement of impact on patient outcomes. Few diagnostic studies meet these criteria, and therefore crucial aspects of test evaluation are overlooked prior to incorporation into clinical guidelines. Whilst efforts are made to standardise reporting of studies, strength of evidence and quality of guidelines, further work is required to improve the quality of the diagnostic studies that formulate these guidelines. It is important that clinicians using guidelines for test selection appreciate the limitations of the diagnostic test, and the guidelines themselves.

How good is the evidence base for test selection in clinical guidelines?

South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people.

Optimal glycaemic control benefits risk of microvascular and macrovascular complications in type 1 diabetes (T1DM) but the importance of other components of metabolic health is less certain, particularly in the context of routine clinical practice.

Metabolic health and vascular complications in type 1 diabetes.

Heterozygous loss-of-function mutations in  cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous  mutations causing MODY have not been reported.

Homozygous Hypomorphic  Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes.

Response to Comment on Misra et al. Homozygous Hypomorphic  Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes. Diabetes Care 2020;43:909-912.

Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R, typically 2-4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action.

Covid-19 and Diabetes: A Complex Bidirectional Relationship.

The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.

Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.

Comparison of Diabetic Ketoacidosis in Adults During the SARS-CoV-2 Outbreak and Over the Same Time Period for the Preceding 3 Years.

Rise in diabetic ketoacidosis during the COVID-19 pandemic: several questions remain.

The SARS-CoV-2 pandemic has had an unprecedented effect on global health, mortality and healthcare provision. Diabetes has emerged as a key disease entity over the pandemic period, influencing outcomes from COVID-19 but also a tantalising hypothesis that the virus itself may be inducing diabetes. An uptick in diabetes cases over the pandemic has been noted for both type 1 diabetes (in children) and type 2 diabetes but understanding how this increase in incidence relates to the pandemic is challenging. It remains unclear whether indirect effects of the pandemic on behaviour, lifestyle and health have contributed to the increase; whether the virus itself has somehow mediated new-onset diabetes or whether other factors such as stress hyperglycaemic of steroid treatment during COVID-19 infection have played a roll. Within the myriad possibilities are some real challenges in interpreting epidemiological data, assigning diabetes type and understanding what in vitro data are telling us. In this review article we address the issue of newly-diagnosed diabetes during the pandemic, reviewing both epidemiological and basic science data and bringing together both strands of this emerging story.

Newly detected diabetes during the COVID-19 pandemic: What have we learnt?

Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.

Current insights and emerging trends in early-onset type 2 diabetes.

Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.

Article	Year
How good is the evidence base for test selection in clinical guidelines? Clinica chimica acta; international journal of clinical chemistry\| PubMed ID: 24513545	2014
South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people. Diabetologia\| PubMed ID: 27435864	2016
Metabolic health and vascular complications in type 1 diabetes. Journal of diabetes and its complications\| PubMed ID: 31248795	2019
Homozygous Hypomorphic Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes. Diabetes care\| PubMed ID: 32001615	2020
Response to Comment on Misra et al. Homozygous Hypomorphic Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes. Diabetes Care 2020;43:909-912. Diabetes care\| PubMed ID: 32958621	2020
Covid-19 and Diabetes: A Complex Bidirectional Relationship. Frontiers in endocrinology\| PubMed ID: 33133024	2020
Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research. Frontiers in endocrinology\| PubMed ID: 33162936	2020
Comparison of Diabetic Ketoacidosis in Adults During the SARS-CoV-2 Outbreak and Over the Same Time Period for the Preceding 3 Years. Diabetes care\| PubMed ID: 33334810	2021
Rise in diabetic ketoacidosis during the COVID-19 pandemic: several questions remain. The lancet. Diabetes & endocrinology\| PubMed ID: 36202117	2022
Newly detected diabetes during the COVID-19 pandemic: What have we learnt? Best practice & research. Clinical endocrinology & metabolism\| PubMed ID: 37468405	2023
Current insights and emerging trends in early-onset type 2 diabetes. The lancet. Diabetes & endocrinology\| PubMed ID: 37708901	2023
Precision subclassification of type 2 diabetes: a systematic review. Communications medicine\| PubMed ID: 37798471	2023

Shivani Misra

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