Neonatal diabetes mellitus

WASHINGTON, July 20, 2023 /PRNewswire/ -- Today, AACC—in collaboration with the American Diabetes Association (ADA)—released evidence-based guidelines to help diagnose and manage patients with diabetes using the latest laboratory-analysis tools. The guidelines replace previous versions published in 2002 and 2011. The new document features extensive updates on continuous glucose monitoring and more precise recommendations for measuring glucose and hemoglobin A1c, a marker of average blood glucose. Written by a cross-disciplinary team of medical experts, the guidelines provide specific, actionable advice that will enhance collaboration among healthcare professionals and improve care for millions of people. Read the guidelines here: Read the Executive Summary here: Diabetes affects approximately 37.3 million people in the United States and 537 million worldwide. It is a disorder in which glucose (or sugar) from food builds up in the blood because insulin—a hormone produced by the pancreas that signals the body to metabolize glucose—is underproduced or underutilized. Diabetes increases people's risk of heart attacks, stroke, vision loss, kidney disease, and other conditions. These new guidelines are based on a thorough assessment of the quality and strength of research on state-of-the-art diabetes lab tests. Among the most significant additions to the 2023 document is its detailed recommendations around continuous glucose monitoring (CGM). In this technology, a device measures patients' blood glucose every 5-15 minutes. "The field has really advanced dramatically," said Dr. David Sacks, the guidelines' primary author. "The goal is to develop what people have termed the artificial pancreas," he said, "where basically you have a sensor under your skin that measures your glucose every few minutes—and that information is fed to your computer or phone." A pump is then used to automatically deliver insulin when people need it most. The expert team strongly recommends using real-time CGM in conjunction with insulin as a tool in certain teens and adults with type 1 diabetes—a form of the disease in which the body doesn't produce insulin. This recommendation applies to patients with type 1 diabetes who are not meeting their blood sugar (glycemic) targets, are unaware of when their blood sugar is low, and/or are prone to low blood sugar. CGM is not used frequently for patients with type 2 diabetes, the more common form of diabetes in which the body doesn't use insulin well. However, the guidelines suggest that providers consider CGM for type 2 patients using insulin and not meeting glycemic targets. The new document also recommends that healthcare workers use blood-collection tubes that contain a citrate buffer to minimize the breakdown of glucose after blood samples are taken. This is important because such glucose breakdown compromises the accuracy of measurements. "We're trying to encourage manufacturers of blood-collection tubes to make these available in the U.S.," said Sacks. When the tubes aren't an option, the team recommends an alternate technique that uses an ice-water bath and other steps. "We've also recommended improving the accuracy of both glucose and hemoglobin A1c measurements and have come up with tighter analytic (measurement) criteria … again to improve patient care," said Sacks. The guidelines state that fasting glucose values of more than 7.0 mmol/L (>126 mg/dL), and hemoglobin A1c measures of at least 6.5% (>48 mmol/mol), should be considered diagnostic of diabetes. In addition, the team provides new guidance for standardizing measurements of insulin and C-peptide, a marker that helps distinguish between type 1 and type 2 diabetes. Further updates cover autoimmune and genetic markers for type 1 diabetes, including a promising analysis of gene mutations that can detect rare forms of neonatal diabetes. The new guidelines are intended to help the full healthcare team make the best possible clinical decisions. This requires cultivating a sophisticated understanding of lab tests' strengths and limitations. "It's important to measure accurately—but it's also very important to communicate the relevance to clinicians and to listen to them and share information," said Sacks. "Patient care is a team effort." About AACC Dedicated to achieving better health through laboratory medicine, AACC brings together more than 70,000 clinical laboratory professionals, physicians, research scientists, and business leaders from around the world focused on clinical chemistry, molecular diagnostics, mass spectrometry, translational medicine, lab management, and other areas of progressing laboratory science. Since 1948, AACC has worked to advance the common interests of the field, providing programs that advance scientific collaboration, knowledge, expertise, and innovation. For more information, visit . Bill Malone AACC Director, Communications & News Publications (p) 202.835.8756 [email protected] Molly Polen AACC Senior Director, Communications & PR (p) 202.420.7612 (c) 703.598.0472 [email protected] SOURCE AACC

In the vast majority of diseases caused by mutations in a single DNA sequence, the disruption of a gene is to blame. However, many non-coding elements in the genome, which inhabit what is sometimes known as the 'dark genome' are also thought to play a role in disease. New research finds the most clear-cut example to date, identifying a genetic switch that, when mutated, causes severe pancreatic deformation and neonatal diabetes. Researchers at the Centre for Genomic Regulation (CRG) have identified a DNA sequence that is crucial for pancreatic differentiation and function -- and for the first time -- describe how it works. Patients with mutations in a DNA sequence -- which they coin EnhP -- develop pancreas malformations. It is the most clear-cut example to date of an inherited disease that is caused by mutations that do not disrupt the DNA sequence of a gene. Disorders?caused by mutations in a single DNA sequence, for example Huntington disease or sickle cell anaemia, are known as monogenic diseases. In the vast majority of cases, such mutations disrupt a protein-coding gene. In this case, the mutations in EnhP disrupt a single "enhancer" instead of a single gene. Our genomes contain hundreds of thousands of DNA elements that are thought to act as enhancers. These enhancer DNA sequences act as switches to turn on the transcription of their target genes in the right tissues. According to the authors of the study, published today in Developmental Cell, EnhP is by no means the only enhancer defect to cause disease. Mutations in enhancers may be the cause of a monogenic disease in many patients in which laboratory tests have failed to disclose causal gene mutations. Understanding the role of enhancers in disease could change how we practice medicine. "Clinical genetics is shifting from a focus on sequencing protein-coding genes to sequencing whole genomes. It is now theoretically possible to discover disease-causing mutations that lie outside of traditional areas of the genome, although it is still challenging to discern which parts of the genome are truly vulnerable to mutations," explains Dr. Jorge Ferrer, senior author of the study, Coordinator of the Medical Genomics Transversal Programme at the CRG and Group Leader at CIBERDEM. The researchers had previously discovered EnhP when studying developmental disorders across ten different families. In collaboration with a team in Exeter, United Kingdom, they had found that mutations in the enhancer were the most common cause of pancreatic agenesis, a rare congenital disorder causing loss of pancreatic tissue and neonatal diabetes. In this study, researchers developed on their previous work to explain why this particular enhancer is vulnerable to disease-causing mutations. Using CRISPR, the team genetically-engineered mouse models to study the effects of the enhancer. Mice lacking both copies of EnhP were born with a severely underdeveloped pancreas and insulin-deficient diabetes. They also studied human stem cells in vitro. They show that EnhP works by increasing rates of transcription of a nearby gene known as the pancreas associated transcription factor 1a (PTF1A). More specifically, the study revealed that EnhP's only role is to activate a whole cluster of enhancers that also regulate PTF1A in the very first cells that form the pancreas during fetal development. When these other enhancers are activated and PTF1A transcription is turned on, this sets in motion a cascade of molecular events that lead to the formation of normal pancreatic cells. "We show that enhancers operate in a hierarchical manner, and this one sits straight at the top, says Dr. Ferrer. This is a new concept, and it solves a paradox of how mutations in a single enhancer can be catastrophic despite the existence of multiple other enhancers regulating the same gene. This is not just about this particular enhancer or disease, there are probably many other enhancers with this particular function in the human genome. Finding them will help us understand which enhancers are vulnerable to mutations that cause various other monogenic diseases." The discovery also has ramifications for efforts to generate insulin-producing beta cells in laboratory conditions. Cell transplantation is a feasible option for diabetic patients, but the demand for functional cells from dead donors far outstrips supply. Growing beta cells in culture would be one way of addressing this challenge, but these rarely share the same functional features as normal human beta cells. This is in part because we don't know the mechanisms required for proper differentiation. "EnhP sparks a molecular program that is needed for proper formation of human beta cells. This knowledge can be harnessed to improve laboratory conditions to create beta cells" concludes Dr. Ferrer. This research was supported by the Spanish Ministry of Science and Innovation, the Wellcome Trust, CIBERDEM and the European Research Council. The work was co-led by first co-authors Irene Miguel-Escalada, Miguel Ángel Maestro, Diego Balboa and senior author Jorge Ferrer.