Aims/hypothesis
Individuals with heterozygous activating mutations of the
KCNJ11
gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea ...(SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications.
Methods
We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to
KCNJ11
mutations identified through the University of Chicago Monogenic Diabetes Registry (
http://monogenicdiabetes.uchicago.edu/registry
). We assessed the influence of age at initiation of SU therapy on treatment outcomes.
Results
HbA
1c
fell from an average of 8.5% (69 mmol/mol) before transition to 6.2% (44 mmol/mol) after SU therapy (
p
< 0.001). Age of initiation of SU correlated with the dose (mg kg
−1
day
−1
) of SU required at follow-up (
r
= 0.80,
p
< 0.001). Similar associations were observed across mutation subtypes. Ten participants required additional glucose-lowering medications and all had initiated SU at age 13 years or older. No serious adverse events were reported.
Conclusions/interpretation
Earlier age at initiation of SU treatment is associated with improved response to SU therapy. Declining sensitivity to SU may be due to loss of beta cell mass over time in those treated with insulin. Our data support the need for early genetic diagnosis and appropriate personalised treatment in all cases of neonatal diabetes.
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. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of
convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key ...component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
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). In addition, many patients exhibit neurological defects ranging from modest learning disorders to severe cognitive dysfunction and seizures. However, it remains unclear to what extent these neurological deficits are due to direct brain-specific activity of mutant K
. We have generated cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) possessing the KCNJ11 mutation p.Val59Met (V59M) and from non-pathogenic/normal hiPSCs (i.e., control/WT). Control cerebral organoids developed neural networks that could generate stable synchronized bursting neuronal activity whereas those derived from V59M cerebral organoids showed reduced synchronization. Histocytochemical studies revealed a marked reduction in neurons localized to upper cortical layer-like structures in V59M cerebral organoids suggesting dysfunction in the development of cortical neuronal network. Examination of temporal transcriptional profiles of neural stem cell markers revealed an extended window of SOX2 expression in V59M cerebral organoids. Continuous treatment of V59M cerebral organoids with the K
blocker tolbutamide partially rescued the neurodevelopmental differences. Our study demonstrates the utility of human cerebral organoids as an investigative platform for studying the effects of KCNJ11 mutations on neurophysiological outcome.
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes
using recombinant viral vectors, which do not target transgenes to specific genomic sites
. The need for viral ...vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair
. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.
Growth and development in monogenic forms of neonatal diabetes Hammoud, Batoul; Greeley, Siri Atma W
Current opinion in endocrinology, diabetes and obesity./Current opinion in endocrinology, diabetes and obesity,
02/2022, Letnik:
29, Številka:
1
Journal Article
Recenzirano
Odprti dostop
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.
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. A growing list of rare recessive causes of NDM are associated with neurodevelopmental and/or growth problems that can either be related to direct gene effects on brain development, or may be related to a variety of co-morbidities. The most common form of NDM results in spectrum of neurological disability due to expression of mutated KATP channels throughout the brain.
Monogenic causes of neonatal diabetes are characterized by variable degree of restriction of growth in utero because of deficiency of insulin that depends on the specific gene cause. Many forms also include a spectrum of neurodevelopmental disability because of mutation-related effects on brain development. Longer term study is needed to clarify longitudinal effects on growth into adulthood.
Purpose of Review
The goal of this review is to provide updates on the safety and efficacy of long-term sulfonylurea use in patients with
KCNJ11
-related diabetes. Publications from 2004 to the ...present were reviewed with an emphasis on literature since 2014.
Recent Findings
Sulfonylureas, often taken at high doses, have now been utilized effectively in
KCNJ11
patients for over 10 years. Mild–moderate hypoglycemia can occur, but in two studies with a combined 975 patient-years on sulfonylureas, no severe hypoglycemic events were reported. Improvements in neurodevelopment and motor function after transition to sulfonylureas continue to be described.
Summary
Sulfonylureas continue to be an effective, sustainable, and safe treatment for
KCNJ11
-related diabetes. Ongoing follow-up of patients in research registries will allow for deeper understanding of the facilitators and barriers to long-term sustainability. Further understanding of the effect of sulfonylurea on long-term neurodevelopmental outcomes, and the potential for adjunctive therapies, is needed.
Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological ...features of pancreata from patients with monogenic diabetes.
Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology.
We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed.
Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates.
Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.