Phenotype, genotype and glycaemic variability in people with activating mutations in the <i><scp>ABCC</scp>8</i> gene: response to appropriate therapy

Reilly, Francis (Sandy); Sánchez-Lechuga, Begoña; Clinton, Steven K.; Crowe, Gillian; Burke, Marie; Ng, Nicholas Beng Hui; Colclough, Kevin; Byrne, Maria

doi:10.1111/dme.14145

Cited by 14 publications

(27 citation statements)

References 29 publications

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“…This figure is available as part of a downloadable slideset [37]. For example, sulfonylureas are effective as a treatment for MODY caused by mutations in HNF1A or HNF4A and, at low dose, ABCC8 genes [38]. GCK mutations cause stable fasting hyperglycaemia with a higher set point of glucose that does not require treatment except during pregnancy [39].…”

Section: Heterogeneity Of Diabetes Within Types and Clinical Consequementioning

confidence: 99%

The clinical consequences of heterogeneity within and between different diabetes types

et al. 2020

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Advances in molecular methods and the ability to share large population-based datasets are uncovering heterogeneity within diabetes types, and some commonalities between types. Within type 1 diabetes, endotypes have been discovered based on demographic (e.g. age at diagnosis, race/ethnicity), genetic, immunological, histopathological, metabolic and/or clinical course characteristics, with implications for disease prediction, prevention, diagnosis and treatment. In type 2 diabetes, the relative contributions of insulin resistance and beta cell dysfunction are heterogeneous and relate to demographics, genetics and clinical characteristics, with substantial interaction from environmental exposures. Investigators have proposed approaches that vary from simple to complex in combining these data to identify type 2 diabetes clusters relevant to prognosis and treatment. Advances in pharmacogenetics and pharmacodynamics are also improving treatment. Monogenic diabetes is a prime example of how understanding heterogeneity within diabetes types can lead to precision medicine, since phenotype and treatment are affected by which gene is mutated. Heterogeneity also blurs the classic distinctions between diabetes types, and has led to the definition of additional categories, such as latent autoimmune diabetes in adults, type 1.5 diabetes and ketosis-prone diabetes. Furthermore, monogenic diabetes shares many features with type 1 and type 2 diabetes, which make diagnosis difficult. These challenges to the current classification framework in adult and paediatric diabetes require new approaches. The 'palette model' and the 'threshold hypothesis' can be combined to help explain the heterogeneity within and between diabetes types. Leveraging such approaches for therapeutic benefit will be an important next step for precision medicine in diabetes.

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Section: Heterogeneity Of Diabetes Within Types and Clinical Consequementioning

confidence: 99%

The clinical consequences of heterogeneity within and between different diabetes types

et al. 2020

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“…The phenotype of kidney disease among the patients with the variants of ABCC8 was also previously described. [42][43][44] A recent study has shown that homozygous ABCC8 p. E1506K +/+ variant knock-in mice presented with hyperinsulinemia in early life, followed by diabetes and early DKD in late life. The histologic differences in the kidneys of ABCC8 E1506K +/+ mice were well established at 32 weeks compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants of ABCC8 and phenotypic features in Chinese early onset diabetes

Gong

Han

et al. 2021

Journal of Diabetes

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Background: ABCC8 variants cause neonatal diabetes, maturity onset diabetes of the young (MODY), and hyperinsulinemic hypoglycemia because of activating or inactivating variants. In this study we used targeted exon sequencing to investigate genetic variants of ABCC8 and phenotypic features in Chinese patients with early onset diabetes (EOD). Methods: A cross-sectional study of 543 Chinese patients with EOD was recruited and the exons of them were conducted targeted sequencing. The pathogenicity of ABCC8 variants was defined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline. The phenotypes of patients owing to ABCC8 variants (ABCC8-MODY) were characterized. Results: Among the 543 participants, eight (1.5%) patients with ABCC8-MODY were identified. They harbored eight missense ABCC8 variants (p.R306C, p.E1326K, and p.R1379H, previously reported; p.R298C, p.F1176C, p.R1221W, p.K1358R, and p.I1404V) classified as likely pathogenic. Two family members with ABCC8-MODY were also confirmed. The average diagnosed age of the 10 patients was 26.8 ± 12.9 years. The majority of them had unsatisfactory glucose control, 80% of them had diabetic kidney disease, and neurological features were not observed. Conclusion: Using targeted exon sequencing followed by pathogenicity analysis, we could be able to make genetic diagnoses for eight (1.5%) patients with ABCC8-MODY. The phenotype was variable with higher risk of diabetic microvascular complications. Genetic diagnosis is conducive for facilitating the personalized treatment of ABCC8-MODY.

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“…Rafiq et al [85] suggested that all carriers of ABCC8 mutations could be switched to sulphonylureas, also in adulthood. More recently, Reilly et al [86] described ten patients with a mean age of 33.8 years at diagnosis treated with insulin or diet or metformin at recruitment. The HbA1c value was 6.9% after the molecular diagnosis and 6.2% after the switch to the anti-diabetic medication gliclazide (mean daily dose 36.87 ± 32.2 mg).…”

Section: Abcc8-mody or Mody12mentioning

confidence: 99%

Treatment Options for MODY Patients: A Systematic Review of Literature

2020

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Maturity-onset diabetes of the young (MODY) is an unusual form of diabetes with specific features that distinguish it from type 1 and type 2 diabetes. There are 14 known subtypes of MODY, and mutations in three genes (HNF1A, HNF4A, GCK) account for about 95% of all MODY cases. Diagnosis usually occurs before the age of 25 years, although less frequent forms may occur more often-but not necessarilylater in life. The molecular diagnosis may tailor the choice of the most appropriate treatment, with the aim to optimize blood glucose control, reduce the risk of hypoglycemic events and long-term complications, and enable proper genetic counseling. Treatment is usually unnecessary for patients with mutations in the GCK gene, while oral hypoglycemic agents (generally sulphonylureas) are recommended for patients with mutations in the HNF4A and HNF1A genes. More recent data show that other glucose-lowering agents can be effective in the latter patients, and additional and alternative therapies have been proposed. Proper management guidelines during pregnancy have been developed for carriers of GCK gene mutations, but such guidelines are still a subject of debate in other cases, although some recommendations are available. The other subtypes of MODY are even more rare, and very little data are available in the literature. In this review we summarize the most pertinent findings and recommendations on the treatment of patients with the different subtypes of MODY. Our aim is to provide the reader with an easy-to-read update that can be used to drive the clinician's therapeutical approach to these patients after the molecular diagnosis.

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Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy

Cited by 14 publications

References 29 publications

The clinical consequences of heterogeneity within and between different diabetes types

The clinical consequences of heterogeneity within and between different diabetes types

Genetic variants of ABCC8 and phenotypic features in Chinese early onset diabetes

Treatment Options for MODY Patients: A Systematic Review of Literature

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