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Flanagan D, Avari P, Choudhary P, et al., 2023, Using Technology to Improve Diabetes Care in Hospital: The Challenge and the Opportunity., J Diabetes Sci Technol, Vol: 17, Pages: 503-508
The past 10 years have seen a revolution in technology improving the lives of people with diabetes. This has implications for diabetes care in hospitalized inpatients. These technological developments have the potential to significantly improve the care of people with diabetes in hospital. Combining point of care glucose monitoring, electronic prescribing, electronic observations with electronic referral, and electronic health records allow teams to daily oversee the whole hospital population. To make the most of these tools as well as developing the use of pumps and glucose sensors in hospital, the diabetes team needs to work in new ways. To date, very little work has described how these should be combined. We describe how this technology can be combined to improve diabetes care in hospital.
Chan J, Blane D, Choudhary P, et al., 2022, Addressing health inequalities in diabetes through research: Recommendations from Diabetes UK's 2022 health inequalities in diabetes workshop, DIABETIC MEDICINE, ISSN: 0742-3071
Avari P, Lumb A, Flanagan D, et al., 2022, Insulin Pumps and Hybrid Close Loop Systems Within Hospital: A Scoping Review and Practical Guidance From the Joint British Diabetes Societies for Inpatient Care., J Diabetes Sci Technol
This article is the second of a two-part series providing a scoping review and summary of the Joint British Diabetes Societies for Inpatient Care (JBDS-IP) guidelines on the use of diabetes technology in people with diabetes admitted to hospital. The first part reviewed the use of continuous glucose monitoring (CGM) in hospital. In this article, we focus on the use of continuous subcutaneous insulin infusion (CSII; insulin pumps) and hybrid closed-loop systems in hospital. JBDS-IP advocates enabling people who can self-manage and are willing and capable of using CSII to continue doing so as they would do out of hospital. CSII should be discontinued if the individual is critically ill or hemodynamically unstable. For individuals on hybrid closed-loop systems, the system should be discontinued from auto-mode, and may be used individually (as CGM only or CSII only, if criteria are met). Continuing in closed-loop mode may only be done so under specialist guidance from the Diabetes Team, where the diabetes teams are comfortable and knowledgeable about the specific devices used. Health care organizations need to have clear local policies and guidance to support individuals using these wearable technologies, and ensure the relevant workforce is capable and skilled enough to ensure their safe use within the hospital setting.
Misra S, DiMeglio LA, 2022, COVID-19 and Incident Type 1 Diabetes: Deciphering the Associations, DIABETES, Vol: 71, Pages: 2480-2482, ISSN: 0012-1797
Avari P, Lumb A, Flanagan D, et al., 2022, Continuous Glucose Monitoring Within Hospital: A Scoping Review and Summary of Guidelines From the Joint British Diabetes Societies for Inpatient Care., J Diabetes Sci Technol
Increasing numbers of people, particularly with type 1 diabetes (T1D), are using wearable technologies. That is, continuous subcutaneous insulin infusion (CSII) pumps, continuous glucose monitoring (CGM) systems, and hybrid closed-loop systems, which combine both these elements. Given over a quarter of all people admitted to hospital have diabetes, there is a need for clinical guidelines for when people using them are admitted to hospital. The Joint British Diabetes Societies for Inpatient Care (JBDS-IP) provide a scoping review and summary of guidelines on the use of diabetes technology in people with diabetes admitted to hospital.JBDS-IP advocates enabling people who can self-manage and use their own diabetes technology to continue doing so as they would do out of hospital. Whilst people with diabetes are recommended to achieve a target of 70% time within range (3.9-10.0 mmol/L [70-180 mg/dL]), this can be very difficult to achieve whilst unwell. We therefore recommend targeting hypoglycemia prevention as a priority, keeping time below 3.9 mmol/L (70 mg/dL) at < 1%, being aware of looming hypoglycemia if glucose is between 4.0 and 5.9 mmol/L (72-106 mg/dL), and consider intervening, particularly if there is a downward CGM trend arrow.Health care organizations need clear local policies and guidance to support individuals using diabetes technologies, and ensure the relevant workforce is capable and skilled enough to ensure their safe use within the hospital setting. The current set of guidelines is divided into two parts. Part 1, which follows below, outlines the guidance for use of CGM in hospital. The second part outlines guidance for use of CSII and hybrid closed-loop in hospital.
Khunti K, Valabhji J, Misra S, 2022, Diabetes and the COVID-19 pandemic, DIABETOLOGIA, Vol: 66, Pages: 255-266, ISSN: 0012-186X
Thomas NJ, Walkey HC, Kaur A, et al., 2022, The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes, DIABETOLOGIA, Vol: 66, Pages: 310-320, ISSN: 0012-186X
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Misra S, 2022, Rise in diabetic ketoacidosis during the COVID-19 pandemic: several questions remain., Lancet Diabetes Endocrinol, Vol: 10, Pages: 763-765
Misra S, Holman N, Barron E, et al., 2022, Characteristics and care of young people with type 2 diabetes included in the national diabetes audit datasets for England, DIABETIC MEDICINE, Vol: 40, ISSN: 0742-3071
Grace SL, Bowden J, Walkey HC, et al., 2022, Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association With Genetic and Clinical Characteristics, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 107, Pages: E4341-E4349, ISSN: 0021-972X
Misra S, Gable D, Khunti K, et al., 2022, Developing services to support the delivery of care to people with early-onset type 2 diabetes, DIABETIC MEDICINE, Vol: 39, ISSN: 0742-3071
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Misra S, Florez JC, 2022, Extending precision medicine tools to populations at high risk of type 2 diabetes., PLoS Med, Vol: 19
In this Perspective, Shivani Misra and Jose C Florez discuss the application of precision medicine tools in under-represented populations.
Eng PC, Distaso W, Durreshahwar H, et al., 2022, The benefit of dexamethasone in patients with COVID-19 infection is preserved in patients with diabetes., Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 1385-1389, ISSN: 1462-8902
Dexamethasone significantly reduces mortality1 and is now standard treatment for patients with COVID-19 who require supplemental oxygen and/or mechanical ventilation. However, supraphysiological doses of glucocorticoids may exacerbate dysglycaemia and precipitate hyperglycaemic complications, particularly in those with or at risk of Type 2 diabetes2. The RECOVERY trial1 reported a low incidence of hyperglycaemic complications (2/1996, 0.1%), although the real-world incidence is likely to be much higher3. Type 2 diabetes itself increases the risk of severe COVID-194, and hyperglycaemia independently predicts poor outcomes5. We investigated the possibility that patients with diabetes may derive less survival benefit from steroid therapy in the setting of severe COVID-19 infection
Thomas NJ, Dennis JM, Sharp SA, et al., 2021, DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life (vol 64, pg 2258, 2021), DIABETOLOGIA, Vol: 65, Pages: 258-258, ISSN: 0012-186X
Misra S, Barron E, Vamos E, et al., 2021, Temporal trends in emergency admissions for diabetic ketoacidosis in people with diabetes in England before and during the COVID-19 pandemic: a population-based study, The Lancet Diabetes and Endocrinology, ISSN: 2213-8595
BACKGROUND: Diabetic ketoacidosis (DKA) has been reported to be increasing in frequency during the COVID-19 pandemic. We aimed to examine the rates of DKA hospital admissions and the patient demographics associated with DKA during the pandemic compared with in prepandemic years. METHODS: Using a comprehensive, multiethnic, national dataset, the Secondary Uses Service repository, we extracted all emergency hospital admissions in England coded with DKA from March 1 to June 30, 2020 (first wave of the pandemic), July 1 to Oct 31, 2020 (post-first wave), and Nov 1, 2020, to Feb 28, 2021 (second wave), and compared these with DKA admissions in the equivalent periods in 2017-20. We also examined baseline characteristics, mortality, and trends in patients who were admitted with DKA. FINDINGS: There were 8553 admissions coded with DKA during the first wave, 8729 during the post-first wave, and 10 235 during the second wave. Compared with preceding years, DKA admissions were 6% (95% CI 4-9; p<0·0001) higher in the first wave of the pandemic (from n=8048), 6% (3-8; p<0·0001) higher in the post-first wave (from n=8260), and 7% (4-9; p<0·0001) higher in the second wave (from n=9610). In the first wave, DKA admissions reduced by 19% (95% CI 16-21) in those with pre-existing type 1 diabetes (from n=4965 to n=4041), increased by 41% (35-47) in those with pre-existing type 2 diabetes (from n=2010 to n=2831), and increased by 57% (48-66) in those with newly diagnosed diabetes (from n=1072 to n=1681). Compared with prepandemic, type 2 diabetes DKA admissions were similarly common in older individuals and men but were higher in those of non-White ethnicities during the first wave. The increase in newly diagnosed DKA admissions occurred across all age groups and these were significantly increased in men and people of non-White ethnicities. In the post-first wave, DKA admissions did not return to the baseline level of previous years; DKA admissions w
Grace SL, Bowden J, Walkey HC, et al., 2021, Islet autoantibody level distributions in type 1 diabetes and their association with genetic and clinical characteristics
<jats:title>Abstract</jats:title><jats:p>Positivity for islet autoantibodies is used for diagnosis of type 1 diabetes. However, the importance of the autoantibody level at diagnosis of type 1 diabetes is not clear. Here, we assessed the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) autoantibody levels, measured using radiobinding assays, on genetic and clinical characteristics at diagnosis of 1536 participants with diabetes who were positive for these autoantibodies. We show that GADA and IA-2A levels had bimodal distributions, but ZnT8A level did not. The comparison of genetic and clinical characteristics between high and low level categories showed high GADA level was associated with older age at diagnosis, female sex and <jats:italic>HLA-DR3-DQ2</jats:italic>, whereas high IA-2A level was associated with younger age of diagnosis, ZnT8A positivity and <jats:italic>HLA-DR4-DQ8</jats:italic>. We replicated our findings in an independent cohort of 427 people with type 1 diabetes where autoantibodies were measured using enzyme-linked immunosorbent assays. In conclusion, Islet autoantibody levels provide additional information over positivity in type 1 diabetes at diagnosis. The bimodality of islet autoantibody levels highlights the novel aspect of heterogeneity of type 1 diabetes which may have implications on prediction, treatment and prognosis.</jats:p><jats:p>Islet autoantibodies are commonly used in the diagnosis and prediction of type 1 diabetes. They are well established as the biomarkers of the underlying autoimmune pathogenesis (1). Autoantibodies to islet cell antigen (ICA), glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A) are the most commonly used islet autoantibodies at diagnosis (2). As detectable islet autoantibodies overlap between health and disease, a test is usually considered positive for
Thomas NJ, Dennis JM, Sharp SA, et al., 2021, DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life, Diabetologia, Vol: 64, Pages: 2258-2265, ISSN: 0012-186X
Aims/hypothesisAmong white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased.MethodsIn two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years.ResultsDR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes.Conclusions/interpretationHLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.
Ansari S, Abdel-Malek M, Kenkre J, et al., 2021, The use of whole blood capillary samples to measure 15 analytes for a home-collect biochemistry service during the SARS-CoV-2 pandemic: A proposed model from North West London Pathology, ANNALS OF CLINICAL BIOCHEMISTRY, Vol: 58, Pages: 411-421, ISSN: 0004-5632
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Takis PG, Jiménez B, Al-Saffar NMS, et al., 2021, A computationally lightweight algorithm for deriving reliable metabolite panel measurements from 1D 1H NMR., Analytical Chemistry, Vol: 93, Pages: 4995-5000, ISSN: 0003-2700
Small Molecule Enhancement SpectroscopY (SMolESY) was employed to develop a unique and fully automated computational solution for the assignment and integration of 1H nuclear magnetic resonance (NMR) signals from metabolites in challenging matrices containing macromolecules (herein blood products). Sensitive and reliable quantitation is provided by instant signal deconvolution and straightforward integration bolstered by spectral resolution enhancement and macromolecular signal suppression. The approach is highly efficient, requiring only standard one-dimensional 1H NMR spectra and avoiding the need for sample preprocessing, complex deconvolution, and spectral baseline fitting. The performance of the algorithm, developed using >4000 NMR serum and plasma spectra, was evaluated using an additional >8800 spectra, yielding an assignment accuracy greater than 99.5% for all 22 metabolites targeted. Further validation of its quantitation capabilities illustrated a reliable performance among challenging phenotypes. The simplicity and complete automation of the approach support the application of NMR-based metabolite panel measurements in clinical and population screening applications.
Thomas NJ, Walkey HC, Kaur A, et al., 2021, The absence of islet autoantibodies in clinically diagnosed older-adult onset type 1 diabetes suggests an alternative pathology, advocating for routine testing in this age group
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Islet autoantibodies at diagnosis are not well studied in older-adult onset (>30years) type 1 diabetes due to difficulties of accurate diagnosis. We used a type 1 diabetes genetic risk score (T1DGRS) to identify type 1 diabetes aiming to evaluate the prevalence and pattern of autoantibodies in older-adult onset type 1 diabetes.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used a 30 variant T1DGRS in 1866 white-European individuals to genetically confirm a clinical diagnosis of new onset type 1 diabetes. We then assessed the prevalence and pattern of GADA, IA2A and ZnT8A within genetically consistent type 1 diabetes across three age groups (<18years (n=702), 18-30years (n=524) and >30years (n=588)).</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>In autoantibody positive cases T1DGRS was consistent with 100% type 1 diabetes in each age group. Conversely in autoantibody negative cases, T1DGRS was consistent with 93%(56/60) of <18years, 55%(37/67) of 18-30years and just 23%(34/151) of >30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% <18years, 92% 18-30years, 93% >30years)[p=0.87]. GADA was the most common autoantibody in older-adult onset type 1 diabetes, identifying 95% of autoantibody positive cases versus 72% in those <18years.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Older adult-onset type 1 diabetes has identical rates but different patterns of positive autoantibodies to childhood onset. In clinically suspected type 1 diabetes in older-adults, absence of autoantibodies strongly su
Misra S, Khozoee B, Huang-Jiawei P, et al., 2021, Comparison of diabetic ketoacidosis in adults, during the SARS-CoV-2 outbreak and over the same time period for the 3 preceding years, Diabetes Care, Vol: 44, Pages: e29-e31, ISSN: 0149-5992
Izzi-Engbeaya C, Distaso W, Amin A, et al., 2021, Adverse outcomes in COVID-19 and diabetes – a retrospective cohort study from three London Teaching hospitals, BMJ Open Diabetes Research and Care, Vol: 9, Pages: 1-10, ISSN: 2052-4897
INTRODUCTION: Patients with diabetes mellitus admitted to hospital with COVID-19 have poorer outcomes. However, the drivers for this are not fully elucidated. We performed detailed characterisation of COVID-19 patients to determine clinical and biochemical factors that may be the drivers of poorer outcomes. RESEARCH DESIGN AND METHODS: Retrospective cohort study of 889 consecutive inpatients diagnosed with COVID-19 between 9th March 2020 and 22nd April 2020 in a large London NHS Trust. Unbiased multivariate logistic regression analysis was performed to determine variables that were independently and significantly associated with increased risk of death and/or ICU admission within 30 days of COVID-19 diagnosis. RESULTS: 62% of patients in our cohort were of non-White ethnic backgrounds and the diabetes prevalence was 38%. 323 (36%) patients met the primary outcome of death/admission to the intensive care unit (ICU) within 30 days of COVID-19 diagnosis. Male gender, lower platelet count, advancing age and higher Clinical Frailty Scale (CFS) score (but not diabetes) independently predicted poor outcomes on multivariate analysis. Antiplatelet medication was associated with a lower risk of death/ICU admission. Factors that were significantly and independently associated with poorer outcomes in patients with diabetes were co-existing ischaemic heart disease, increasing age and lower platelet count. CONCLUSIONS: In this large study of a diverse patient population, comorbidity (i.e. diabetes with ischaemic heart disease; increasing CFS score in older patients) were major determinants of poor outcomes with COVID-19. Antiplatelet medication should be evaluated in randomised clinical trials amongst high-risk patient groups.
Muniangi-Muhitu H, Akalestou E, Salem V, et al., 2020, Covid-19 and diabetes: a complex bidirectional relationship, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392
Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R0, typically 2-4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action.
Misra S, Hassanali N, Bennett AJ, et al., 2020, Response to comment on Misra et al. homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulfonylurea-sensitive diabetes. diabetes care 2020;43:909-912, Diabetes Care, Vol: 43, Pages: E155-E156, ISSN: 0149-5992
Hu M, Cherkaoui I, Misra S, et al., 2020, Functional genomics in pancreatic β cells: recent advances in gene deletion and genome editing technologies for diabetes research., Front Endocrinol (Lausanne), Vol: 11, Pages: 1-20, ISSN: 1664-2392
The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.
Izzi-Engbeaya C, Distaso W, Amin A, et al., 2020, Severe COVID-19 and Diabetes - A Retrospective Cohort Study from Three London Teaching Hospitals
<jats:title>ABSTRACT</jats:title><jats:p>Patients with diabetes mellitus admitted to hospital with COVID-19 caused by infection with the novel coronavirus (SARS-CoV-2) have poorer outcomes. However, the drivers for this are not fully elucidated. We performed a retrospective cohort study, including detailed pre-hospital and presenting clinical and biochemical factors of 889 patients diagnosed with COVID-19 in three constituent hospitals of a large London NHS Trust. 62% of patients with severe COVID-19 were of non-White ethnic backgrounds and the prevalence of diabetes was 38%. 323 (36%) patients met the primary outcome of death or admission to the intensive care unit (ICU) within 30 days of diagnosis. Male gender, advancing age and the Clinical Frailty Scale, an established measure of multimorbidity, independently predicted poor outcomes on multivariate analysis. Diabetes did not confer an independent risk for adverse outcomes in COVID-19, although patients with diabetes and ischaemic heart disease were at particular risk. Additional risk factors which significantly and independently associated with poorer outcomes in patients with diabetes were age, male gender and lower platelet count. Antiplatelet medication was associated with a lower risk of death/ICU admission and should be evaluated in randomised clinical trials amongst high risk patient groups.</jats:p>
Misra S, Godsland IF, Bhardwaj N, et al., 2020, Type 2 Diabetes Diagnosed between 16-30 Years in South Asian and White Individuals Is Phenotypically Similar, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
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Misra S, Mathieu C, 2020, Are newer insulin analogues better for people with Type 1 diabetes?, Diabetic Medicine, Vol: 37, Pages: 522-531, ISSN: 0742-3071
Achieving optimal blood glucose control in Type 1 diabetes is a delicate balance between ensuring tight glycaemic control and achieving this without the expense of hypoglycaemia and weight gain, two major factors impacting quality of life. This is a real challenge for people with Type 1 diabetes and underpins many of the struggles they face in self‐managing on a day‐to‐day basis. The main goals of insulin delivery are to try to simulate the physiology of β‐cell insulin secretion as closely as possible and to overcome the challenges of peripheral insulin administration by achieving rapidity of onset with mealtime insulins and stability of the glucose‐lowering effects of long‐acting insulins. Since the early days of human insulin use, there have been many developments in insulin formulations that aim to achieve these goals as much as possible, thus contributing to better glycaemic control whilst minimizing hypoglycaemia. In the present review we discuss the currently available insulin analogues and the challenges of achieving glucose control using current analogues in those on multiple daily injections, and appraise the evidence base for newer‐generation insulin analogues, such as insulin degludec, glargine U300, faster‐acting insulin aspart and BioChaperone lispro. We also highlight new insulins in development and unmet needs in people with Type 1 diabetes.
Misra S, hassanali N, Bennet A, et al., 2020, Homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulphonylurea sensitive diabetes, Diabetes Care, Vol: 43, Pages: 909-912, ISSN: 0149-5992
OBJECTIVE Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulphonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported.RESEARCH DESIGN AND METHODS We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulphonylurea challenge, and in vitro assays to assess variant protein function.RESULTS A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2–0.8 mg/L), and those tested demonstrated sensitivity to sulphonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A.CONCLUSIONS Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.
Guemes M, Rahman SA, Kapoor RR, et al., 2020, Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management, Reviews in Endocrine and Metabolic Disorders, Vol: 21, Pages: 577-597, ISSN: 1389-9155
Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.
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