Case report: Exceptional transmission of congenital hyperinsulinism from a focal CHI mother to her diffuse CHI dichorionic diamniotic twins.

We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was performed at the age of three weeks. Later, histological analysis of her pancreas in a research setting revealed a focal form of CHI. Genetic testing was not available at that time. The patient developed pancreatic exocrine deficiency and insulin-dependent diabetes at the age of 9 years. In 2016, a genetic test revealed a missense heterozygous variant in the ABCC8 gene inherited from her father and classified as having a recessive inheritance. The geneticist concluded that the risk of CHI for her offspring would be low (1/600), making pregnancy favourable. As there was no consanguinity in the family, testing the future father was deemed unnecessary (carrier frequency 1/150 in the general population). The pregnancy occurred spontaneously in 2020 and at a gestational age of 28 weeks, the mother went into premature labour. An emergency C-section was performed in April 2021 resulting in the birth of bichorial bi-amniotic male twins. Following birth, both newborns experienced persistent severe hypoglycaemia which required glucagon treatment and intravenous glucose infusion initially, followed by Diazoxide from day 51 after birth, without satisfactory response. Continuous intravenous Octreotide treatment was introduced on day 72. Due to the recurrence of hypoglycaemia episodes despite reaching maximum doses of Octreotide, from day 92 the treatment was switched to Pasireotide. Genetic tests revealed the same genotypes for both infants: the exon 39 missense variant (c.4716C>A; p.Ser1572Arg) inherited from their mother and a truncating variant in exon 28 (c.3550del; p.Val1184*), inherited from their asymptomatic father. As a result of inheriting two recessive variants of the ABCC8 gene, the children were diagnosed with a diffuse form of CHI, consistent with the diazoxide-unresponsive presentation. This situation is very rare outside consanguinity. This case emphasises the significance of genetic counselling for individuals with a history of rare diseases outside the context of consanguinity, as there is a potential risk of recurrence. Prenatal diagnosis can lead to better outcomes for affected neonates, as well as help families make informed decisions about future pregnancies.

Clinical management of diazoxide-unresponsive congenital hyperinsulinism: A single-center experience.

The most common cause of persistent hypoglycemia in newborns and children is congenital hyperinsulinism (CHI). Remarkable advancements in diagnostic tools and treatments, including novel imaging and genetic techniques, and continuous subcutaneous octreotide administration, have improved the prognosis of diazoxide-unresponsive CHI; however, in clinical practice, some issues remain. Here, we report a case series consisting of four adenosine triphosphate-sensitive potassium-associated CHI cases, discuss the practical use of new international guidelines published in 2023, and suggest clinical issues associated with CHI management. Based on the clinical experience of two diffuse and two focal CHI cases, we employed an updated treatment strategy, including genetic diagnosis to determine treatment plans, careful catheter management, switching from octreotide to long-acting somatostatin, effective utilization of a continuous glucose monitoring (CGM) device, measures for feeding problems, and individualized and systematic developmental follow-up. Particularly, our cases suggest a safe method of switching from octreotide to lanreotide, elucidate the efficacy of home-based CGM monitoring, and indicate need for personalized support for feeding problems. Severe CHI is a rare and challenging disorder; thus, further accumulation of experience according to new treatment strategies is essential in generating high-quality evidence for the development and approval of new treatment options.

Congenital Hyperinsulinism Caused by Mutations in ABCC8 Gene Associated with Early-Onset Neonatal Hypoglycemia: Genetic Heterogeneity Correlated with Phenotypic Variability.

Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset HH caused by ABCC8 gene mutations. In the first patient, who presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330-1)del] that correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C>T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of the focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) positron emission tomography/computed tomography (PET/CT) was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.

[Congenital hyperinsulinism : contributions of chemistry, therapeutic response, genetics and imaging]. / Hyperinsulinisme congénital : apports de la biologie, de la réponse thérapeutique, de la génétique et de l'imagerie.

Congenital hyperinsulinism is the most common cause of recurrent hypoglycemia in newborns and children. Early diagnosis and rapid management are essential to avoid hypoglycaemic brain injury and later neurological complications. Management of those patients involves biological evaluation, molecular genetics, imaging techniques and surgical advances. We report the case of a newborn with recurrent hypoglycemia due to congenital hyperinsulinism (CHI) caused by a new variant in the ABCC8 gene. Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography (18F-DOPA PET/CT scan) reported a focal lesion at the isthmus of the pancreas which has been removed by laparoscopic surgery with a complete recovery for the patient.

L'hyperinsulinisme congénital est la cause la plus fréquente d'hypoglycémies récidivantes chez le nouveau-né et l'enfant. Un diagnostic et une prise en charge précoces sont primordiaux pour éviter les conséquences potentielles sur le développement neurologique. Ces derniers reposent sur la conjonction d'éléments biologiques, génétiques et d'imagerie. Nous rapportons le cas d'un nouveau-né présentant des hypoglycémies récidivantes. La mise au point mettra en évidence un hyperinsulinisme congénital (CHI) lié à un variant non encore décrit au sein du gène ABCC8. L'imagerie par Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography/Computed Tomography-scanner (18F-DOPA PET/CT scan) a mis en évidence une forme focale de l'hyperinsulinisme justifiant une prise en charge chirurgicale amenant à une guérison complète et à l'arrêt de tout traitement médicamenteux.

A novel mutation in the ABCC8 gene causing maturity-onset diabetes of the young: A case report.

A 34-year-old woman was diagnosed with type 1 diabetes mellitus and treated with insulin for 24 years. The patient has a family history of diabetes in three consecutive generations. Her Whole exon sequencing showed a heterozygous mutation in the ABCC8 gene, and it also found some of her relatives to carry this mutation. She was diagnosed with MODY12 and received glimepiride therapy with the achievement of good glycaemic control.

An analysis of the relationship between ABCC8 and KCNJ11 gene polymorphisms and diabetic retinopathy in Turkish population.

BACKGROUND: Diabetic retinopathy (DR) occurs due to high blood glucose damage to the retina and leads to blindness if left untreated. KATP and related genes (KCNJ11 and ABCC8) play an important role in insulin secretion by glucose-stimulated pancreatic beta cells and the regulation of insulin secretion. KCNJ11 E23K (rs5219), ABCC8-3 C/T (rs1799854), Thr759Thr (rs1801261) and Arg1273Arg (rs1799859) are among the possible related single nucleotide polymorphisms (SNPs). The aim of this study is to find out how DR and these SNPs are associated with one another in the Turkish population. MATERIALS AND METHODS: This study included 176 patients with type 2 diabetes mellitus without retinopathy (T2DM-rp), 177 DR patients, and 204 controls. Genomic DNA was extracted from whole blood, and genotypes were determined by the PCR-RFLP method. RESULTS: In the present study, a significant difference was not found between all the groups in terms of Arg1273Arg polymorphism located in the ABCC8 gene. The T allele and the TT genotype in the -3 C/T polymorphism in this gene may have a protective effect in the development of DR (p = 0.036 for the TT genotype; p = 0.034 for T allele) and PDR (p = 0.042 and 0.025 for the TT genotype). The AA genotype showed a significant increase in the DR group compared to T2DM-rp in the KCNJ11 E23K polymorphism (p = 0.046). CONCLUSIONS: Consequently, the T allele and TT genotype in the -3 C/T polymorphism of the ABCC8 gene may have a protective marker on the development of DR and PDR, while the AA genotype in the E23K polymorphism of the KCNJ11 gene may be effective in the development of DR in the Turkish population.

Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia.

BACKGROUND: ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH). METHODS: We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations. RESULTS: The age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation. CONCLUSIONS: Gene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene.

Functional characterization of inactivating ABCC8 variants causing congenital hyperinsulinism.

Congenital hyperinsulinism (CHI; OMIM: 256450) is characterized by persistent insulin secretion despite severe hypoglycemia. The most common causes are variants in the ATP-binding cassette subfamily C member 8(ABCC8) and potassium inwardly-rectifying channel subfamily J member 11(KCNJ11) genes. These encode ATP-sensitive potassium (KATP) channel subunit sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) proteins. A 7-day-old male infant presented with frequent hypoglycemic episodes and was clinically diagnosed with CHI, underwent trio-whole-exome sequencing, revealing compound heterozygous ABCC8 variants (c.307C>T, p.His103Tyr; and c.3313_3315del, p.Ile1105del) were identified. In human embryonic kidney 293 (HEK293) and rat insulinoma cells (INS-1) transfected with wild-type and variant plasmids, KATP channels formed by p.His103Tyr were delivered to the plasma membrane, whereas p.Ile1105del or double variants (p.His103Tyr coupled with p.Ile1105del) failed to be transported to the plasma membrane. Compared to wild-type channels, the channels formed by the variants (p.His103Tyr; p.Ile1105del) had elevated basal [Ca2+]i, but did not respond to stimulation by glucose. Our results provide evidence that the two ABCC8 variants may be related to CHI owing to defective trafficking and dysfunction of KATP channels.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience.

OBJECTIVES: To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). METHODS: This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. RESULTS: A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. CONCLUSIONS: The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.

Clinical Case Report of Non-Diabetic Hypoglycemia Due to a Combination of Germline Mutations in the MEN1 and ABCC8 Genes.

INTRODUCTION: Non-diabetic hypoglycemia (NDH) is a collective term including the multiple causes of hypoglycemic syndrome not due to diabetes mellitus. NDH may result from insulinoma, IGF-2-omas, hypocorticism, Hirata's disease, genital disorders of glucose metabolism, etc. One of the most common causes of NDH faced by an endocrinologist is insulinoma, which in turn can be part of the hereditary syndrome of multiple endocrine neoplasia type 1 (MEN1). Congenital disorders of glucose metabolism in adult patients, on the contrary, are diagnosed extremely rarely, since they usually manifest in childhood. This article presents a unique clinical case of a patient with NDH and genetically verified MEN1 in combination with congenital hyperinsulinism due to an ABCC8 gene mutation. CASE REPORT: A 43-year-old patient with hypoglycemic symptoms from childhood is presented, in whom multiple pancreatic tumors and fluctuations in glycemia from 38.7 mg/dL to 329.7 mg/dL (2.15 to 18.3 mmol/L) were detected in adulthood, but a mild course of hypoglycemic syndrome was noted. Numerous examinations that were performed to establish an accurate diagnosis are described, signs that served as a reason for expanding the complex of studies are indicated, possible pathogenetic mechanisms of the mild course of hypoglycemic syndrome and hyperglycemic conditions are discussed. CONCLUSION: This case report is original and highlights that we must always remain intolerant of the inexplicable. Conducting an extended gene study can help perform a correct diagnosis in complex cases.

A beneficial role of GLP-1 receptor agonist therapy in ABCC8-MODY (MODY 12).

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes resulting from a mutation in a single gene. ABCC8-MODY is caused by mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), a regulatory component of the ATP-sensitive potassium (KATP) channel found in beta cells. In ABCC8-MODY, mutations in the ABCC8 gene interfere with insulin secretion in response to glucose. Recent evidence suggests that therapy with GLP-1 receptor agonists (GLP-1 RAs) may be beneficial in ABCC8-MODY. This report presents a successful treatment of a 49-year-old woman diagnosed with ABCC8-MODY using the GLP-1 RA semaglutide. The patient, who had been previously receiving insulin therapy, experienced significant improvements in glycemic control and weight loss after transitioning to semaglutide. GLP-1 RAs potentially enhance insulin secretion in ABCC8-MODY by activating multiple signaling pathways involved in insulin secretion. The report highlights the potential of GLP-1 RA therapy as an alternative to sulfonylureas and insulin for individuals with ABCC8-MODY. GLP-1 RAs have previously demonstrated benefits in other forms of MODY. Understanding the molecular mechanisms through which GLP-1 RAs promote insulin secretion, including their effects on KATP channels and activation of PKA and Epac signaling, offers valuable insights into their therapeutic effects.

Transient Neonatal Diabetes Mellitus and Seizure with an Unknown Etiology.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.

ABCC8-Related Monogenic Diabetes Presenting Like Type 1 Diabetes in an Adolescent.

Background: Identifying cases of diabetes caused by single gene mutations between the more common type 1 diabetes (T1D) and type 2 diabetes (T2D) is a difficult but important task. We report the diagnosis of ATP-binding cassette transporter sub-family C member 8 (ABCC8)-related monogenic diabetes in a 35-year-old woman with a protective human leukocyte antigen (HLA) allele who was originally diagnosed with T1D at 18 years of age. Case Report: Patient A presented with polyuria, polydipsia, and hypertension at the age of 18 years and was found to have a blood glucose > 500 mg/dL (70-199 mg/dL) and an HbA1C (hemoglobin A1C) >14% (4%-5.6%). She had an unmeasurable C-peptide but no urine ketones. She was diagnosed with T1D and started on insulin therapy. Antibody testing was negative. She required low doses of insulin and later had persistence of low but detectable C-peptide. At the age of 35 years, she was found to have a protective HLA allele, and genetic testing revealed a pathogenic mutation in the ABCC8 gene. The patient was then successfully transitioned to sulfonylurea therapy. Discussion: Monogenic diabetes diagnosed in adolescence typically presents with mild to moderate hyperglycemia, positive family history and, in some cases, other organ findings or dysfunction. The patient in this report presented with very high blood glucose, prompting the diagnosis of T1D. When she was found to have a protective HLA allele, further investigation revealed the mutation in the sulfonylurea receptor gene, ABCC8. Conclusion: Patients suspected of having T1D but with atypical clinical characteristics such as negative autoantibodies, low insulin requirements, and persistence of C-peptide should undergo genetic testing for monogenic diabetes.

Neonatal hyperinsulinism with an ABCC8 mutation: A case report.

BACKGROUND: Neonatal hyperinsulinism can result from perinatal stress, genetic disorders, or syndromes, which can lead to persistent or intractable hypoglycemia in newborns. Mutations in the ABCC8 gene result in abnormal functioning of potassium channel proteins in pancreatic ß-cells, leading to an overproduction of insulin and congenital hyperinsulinemia. CASE SUMMARY: We report a case of a high-birth-weight infant with postnatal hypoglycemia and hyperinsulinemia, whose mother had pregestational diabetes mellitus with poor glycemic control and whose sister had a similar history at birth. Whole-exome sequencing revealed a new mutation in the ABCC8 gene in exon 8 (c.1257T>G), which also occurred in his sister and mother; thus, the patient was diagnosed with neonatal hyperinsulinism with an ABCC8 mutation. With oral diazoxide treatment, the child's blood glucose returned to normal, and the pediatrician gradually discontinued treatment because of the child's good growth and development. CONCLUSION: We report a new mutation locus in the ABCC8 gene. This mutation locus warrants attention for genetic disorders and long-term prognoses of hypoglycemic children.

Association of ABCC8 gene variants with response to sulfonylurea in type 2 diabetes mellitus.

Background: Diabetes mellitus (DM) is associated with high blood glucose levels and sulfonylureas (SFUs) are one of the treatment options for DM. SFUs bind to sulfonylurea-1 receptor (SUR1), which is encoded by the ABCC8 gene and leads to blood glucose reduction. Genetic variants like rs757110 and rs1799854 of ABCC8 can influence the response to the drug's efficiency. Therefore, this study aimed to investigate the association between the ABCC8 rs757110 and rs1799854 genetic variants and response to SFUs treatment. Methods: Totally, 61 DM patients with SFUs treatment were included. Baseline characteristics of the patients were recorded and 5 ml of blood was taken from each patient. After DNA extraction, a sequence containing rs757110 and rs1799854 was synthesized by the PCR method, and the PCR products were used for Sanger sequencing. Results: Frequencies of GG, GA, and AA genotypes of rs1799854 variant was 12 (40%), 14 (46.7%), and 4 (13.3%), and the frequencies of CC, AC, and AA genotypes for rs757110 variant was 3 (9.7%), 5 (16.1%) and 23 (74.2%) in, respectively. Patients with different genotypes had the same age, BMI (body mass index), initial FBS (Fasting blood sugar), initial HbA1c, treatment duration, gender and history of smoking, alcohol consumption, and exercise. There was no significant difference in FBS and HbA1c changes after SFUs treatment between patients with rs757110 variant (p = 0.39 for FBS and p = 0.76 for HbA1c) and rs1799854 (p = 0.24 for FBS and p = 0.36 for HbA1c). Conclusion: The rs1799854 and rs757110 variants of the ABCC8 gene had no significant influence on response to SFUs treatment.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.

AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

ABCC8-related maturity-onset diabetes of the young: switching from insulin to sulphonylurea therapy: how long do we need for a good metabolic control?

OBJECTIVES: Activating variants of the ABCC8 gene cause neonatal diabetes or maturity-onset diabetes of the young (MODY). We report three cases of MODY type 12 caused by variants in the ABCC8 encoding sulphonylurea receptor 1, and the experience of switching from insulin therapy to sulphonylurea therapy. CASE PRESENTATIONS: We describe a 12.5-year-old girl with permanent neonatal diabetes mellitus, and two diabetes mellitus cases with variants in the ABCC8 gene. Two of these cases were successfully switched from subcutaneous insulin to oral glibenclamide, with a marked improvement in glycemic control. In permanent neonatal diabetes case, glibenclamide dose was progressively increased to achieve a full dose (2 mg/kg/day) in 9 days. Nine months after starting oral sulphonylurea therapy, her blood glucose control dramatically improved and insulin therapy was discontinued. CONCLUSIONS: We conclude that patients with ABCC8 gene variants can successfully switch from insulin to sulphonylureas.