Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism : A Finnish Population-Based Study

Context: The management of congenital hyperinsulinism (CHI) has improved. Objective: To examine the treatment and long-term outcome of Finnish patients with persistent and transient CHI (P-CHI and T-CHI). Design: A population-based retrospective study of CHI patients treated from 1972 to 2015. Patients: 106 patients with P-CHI and 132 patients with T-CHI (in total, 42 diagnosed before and 196 after year 2000) with median follow-up durations of 12.5 and 6.2 years, respectively. Main outcome measures: Recovery, diabetes, pancreatic exocrine dysfunction, neurodevelopment. Results: The overall incidence of CHI (n = 238) was 1:11 300 live births (1972-2015). From 2000 to 2015, the incidence of P-CHI (n = 69) was 1:13 500 and of T-CHI (n = 127) 1:7400 live births. In the 21st century P-CHI group, hyperinsulinemic medication was initiated and normoglycemia achieved faster relative to earlier. Of the 74 medically treated P-CHI patients, 68% had discontinued medication. Thirteen (12%) P-CHI patients had partial pancreatic resection and 19 (18%) underwent near-total pancreatectomy. Of these, 0% and 84% developed diabetes and 23% and 58% had clinical pancreatic exocrine dysfunction, respectively. Mild neurological difficulties (21% vs 16%, respectively) and intellectual disability (9% vs 5%, respectively) were as common in the P-CHI and T-CHI groups. However, the 21st century P-CHI patients had significantly more frequent normal neurodevelopment and significantly more infrequent diabetes and pancreatic exocrine dysfunction compared with those diagnosed earlier. Conclusions: Our results demonstrated improved treatment and long-term outcome in the 21st century P-CHI patients relative to earlier.Peer reviewe

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

This is the final version. Available from Nature Research via the DOI in this record. Data availability: All data used in this review is available from publicly available and herein referenced sources. A list of included studies is provided in Supplementary Data 1. All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data for the figures are available as Supplementary Data 2.BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology. METHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. RESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions. CONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.Wellcome TrustWellcome Trus

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Clinical and Genetic Characterization of 153 Patients with Persistent or Transient Congenital Hyperinsulinism

Context: Major advances have been made in the genetics and classification of congenital hyperinsulinism (CHI). Objective: To examine the genetics and clinical characteristics of patients with persistent and transient CHI. Design: A cross-sectional study with the register data and targeted sequencing of 104 genes affecting glucose metabolism. Patients: Genetic and phenotypic data were collected from 153 patients with persistent (n = 95) and transient (n = 58) CHI diagnosed between 1972 and 2015. Of these, 86 patients with persistent and 58 with transient CHI participated in the analysis of the selected 104 genes affecting glucose metabolism, including 10 CHI-associated genes, and 9 patients with persistent CHI were included because of their previously confirmed genetic diagnosis. Main outcome measures: Targeted next-generation sequencing results and genotype-phenotype associations. Results: Five novel and 21 previously reported pathogenic or likely pathogenic variants in ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 genes were found in 68% (n = 65) and 0% of the patients with persistent and transient CHI, respectively. K-ATP channel mutations explained 82% of the mutation positive cases. Conclusions: The genetic variants found in this nationwide CHI cohort are in agreement with previous studies, mutations in the KATP channel genes being the major causes of the disease. Pathogenic CHI-associated variants were not identified in patients who were both diazoxide responsive and able to discontinue medication within the first 4 months. Therefore, our results support the notion that genetic testing should be focused on patients with inadequate response or prolonged need for medication.Peer reviewe

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10(−5)). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non‐genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow‐up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non‐genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.</p

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.</p