Precision treatment of beta-cell monogenic diabetes: a systematic review.

Background: Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.

RFX6 regulates human intestinal patterning and function upstream of PDX1.

The gastrointestinal (GI) tract is complex and consists of multiple organs with unique functions. Rare gene variants can cause congenital malformations of the human GI tract, although the molecular basis of these has been poorly studied. We identified a patient with compound-heterozygous variants in RFX6 presenting with duodenal malrotation and atresia, implicating RFX6 in development of the proximal intestine.

A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life.

Aims/hypothesis: The ATP-sensitive potassium (K) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.

Longitudinal Assessment of Pancreas Volume by MRI Predicts Progression to Stage 3 Type 1 Diabetes.

Objective: This multicenter prospective cohort study compared pancreas volume as assessed by MRI, metabolic scores derived from oral glucose tolerance testing (OGTT), and a combination of pancreas volume and metabolic scores for predicting progression to stage 3 type 1 diabetes (T1D) in individuals with multiple diabetes-related autoantibodies.

Research Design And Methods: Pancreas MRI was performed in 65 multiple autoantibody-positive participants enrolled in the Type 1 Diabetes TrialNet Pathway to Prevention study. Prediction of progression to stage 3 T1D was assessed using pancreas volume index (PVI), OGTT-derived Index60 score and Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), and a combination of PVI and DPTRS.

Systematic Review of Treatment of Beta-Cell Monogenic Diabetes.

Background: Beta-cell monogenic forms of diabetes are the area of diabetes care with the strongest support for precision medicine. We reviewed treatment of hyperglycemia in GCK-related hyperglycemia, HNF1A-HNF4A- and HNF1B-diabetes, Mitochondrial diabetes (MD) due to m.3243A>G variant, 6q24-transient neonatal diabetes (TND) and SLC19A2-diabetes.

Insulin Deficiency From Insulin Gene Mutation Leads to Smaller Pancreas.

Objective: To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth.

Research Design And Methods: Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members.

Acute Recurrent Pancreatitis in a Child With INS-Related Monogenic Diabetes and a Heterozygous Pathogenic CFTR Mutation.

Given the close anatomical and physiological links between the exocrine and endocrine pancreas, diseases of 1 compartment often affect the other through mechanisms that remain poorly understood. Pancreatitis has been associated with both type 1 and type 2 diabetes, but its association with monogenic diabetes is unknown. Patients heterozygous for pathogenic CFTR variants are cystic fibrosis carriers and have been reported to have an increased risk of acute pancreatitis.

Insight on Diagnosis and Treatment From Over a Decade of Research Through the University of Chicago Monogenic Diabetes Registry.

Monogenic diabetes is a category of diabetes mellitus caused by a single gene mutation or chromosomal abnormality, usually sub-classified as either neonatal diabetes or maturity-onset diabetes of the young (MODY). Although monogenic diabetes affects up to 3.5% of all patients with diabetes diagnosed before age 30, misdiagnosis and/or improper treatment occurs frequently.

Novel Kabuki Syndrome Mutation With Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension Requiring ECMO.

Kabuki syndrome (KS) is a multisystem disorder estimated to occur in 1:32 000 newborns. Pathogenic mutations cause the majority but not all cases of KS in either or . KS can be suspected by phenotypic features, including infantile hypotonia, developmental delay, dysmorphic features, congenital heart defects, and others.

Growth and development in monogenic forms of neonatal diabetes.

Purpose Of Review: Neonatal diabetes mellitus (NDM) is a rare disorder in which 80-85% of infants diagnosed under 6 months of age will be found to have an underlying monogenic cause. This review will summarize what is known about growth and neurodevelopmental difficulties among individuals with various forms of NDM.

Recent Findings: Patients with NDM often have intrauterine growth restriction and/or low birth weight because of insulin deficiency in utero and the severity and likelihood of ongoing growth concerns after birth depends on the specific cause.

Developmental defects and impaired network excitability in a cerebral organoid model of KCNJ11 p.V59M-related neonatal diabetes.

The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (K) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM).

Development of a standardized MRI protocol for pancreas assessment in humans.

Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements.

The Do-It-Yourself Artificial Pancreas.

A growing number of people with diabetes are turning to self-built systems to dose and deliver insulin. These do-it-yourself artificial pancreas systems (DIY-APS) use commercially available insulin pumps and continuous glucose monitors and add an algorithm that independently modulates insulin dosing. Frustrated by the pace of diabetes technology development, a group of patients and diabetes advocates developed this technology without formal safety studies and without approval by the US Food and Drug Administration (FDA).

Novel compound heterozygous LRBA deletions in a 6-month-old with neonatal diabetes.

We report a 6-month-old boy with antibody-positive insulin-dependent diabetes mellitus. Sequencing identified compound heterozygous deletions of exon 5 and exons 36-37 in LRBA. At three years, he has yet to exhibit any other immune symptoms.

Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Editors' Expert Forum.

Individualization of therapy based on a person's specific type of diabetes is one key element of a "precision medicine" approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach.

Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated Permanent Neonatal Diabetes.

Objective: mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with PNDM require lower sulfonylurea doses and have milder neurological features than those with PNDM. However, these studies were short-term and included combinations of -PNDM and -TNDM.

Using a Do-It-Yourself Artificial Pancreas: Perspectives from Patients and Diabetes Providers.

Background: A growing number of people with diabetes are choosing to adopt do-it-yourself artificial pancreas system (DIYAPS) despite a lack of approval from the US Food and Drug Administration.We describe patients' experiences using DIYAPS, and patient and diabetes providers' perspectives on the use of such technology.

Methods: We distributed surveys to patients and diabetes providers to assess each group's perspectives on the use of DIYAPS.

A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line.

GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation.