Imperial College London

Dr Shivani Misra

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Senior Lecturer in Diabetes and Endocrinology
 
 
 
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Contact

 

+44 (0)20 7594 6136s.misra

 
 
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Location

 

G4Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

67 results found

Misra S, DiMeglio LA, 2022, COVID-19 and Incident Type 1 Diabetes: Deciphering the Associations., Diabetes, Vol: 71, Pages: 2480-2482

Journal article

Khunti K, Valabhji J, Misra S, 2022, Diabetes and the COVID-19 pandemic., Diabetologia

Almost immediately after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged, it was evident that people with chronic diseases, including diabetes, were disproportionately affected, with an increased risk of hospitalisation and mortality. Over the ensuing 2 years, the indirect effects of the pandemic on healthcare delivery in the short term have become prominent, along with the lingering effects of the virus in those directly infected. In the wake of the pandemic and without any evidence from high quality studies, a number of national and international consensus recommendations were published, which were subsequently rapidly updated based on observational studies. There have been unprecedented disruptions from both direct and indirect impacts of coronavirus disease-2019 (COVID-19) in people with diabetes. In this review, we summarise the impact of acute COVID-19 in people with diabetes, discuss how the presentation and epidemiology during the pandemic, including presentation of diabetic ketoacidosis and new-onset diabetes, has changed, and we consider the wider impact of the pandemic on patients and healthcare service delivery, including some of the areas of uncertainty. Finally, we make recommendations on prioritising patients as we move into the recovery phase and also how we protect people with diabetes for the future, as COVID-19 is likely to become endemic.

Journal article

Thomas NJ, Walkey HC, Kaur A, Misra S, Oliver NS, Colclough K, Weedon MN, Johnston DG, Hattersley AT, Patel KAet al., 2022, The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes., Diabetologia

AIMS/HYPOTHESIS: The reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults. METHODS: We analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants. RESULTS: The T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than a

Journal article

Misra S, 2022, Rise in diabetic ketoacidosis during the COVID-19 pandemic: several questions remain., Lancet Diabetes Endocrinol, Vol: 10, Pages: 763-765

Journal article

Misra S, Holman N, Barron E, Knighton P, Warner J, Kar P, Young B, Valabhji Jet al., 2022, Characteristics and care of young people with type 2 diabetes included in the national diabetes audit datasets for England, DIABETIC MEDICINE, ISSN: 0742-3071

Journal article

Misra S, Gable D, Khunti K, Barron E, Young B, Kar P, Valabhji Jet 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

Journal article

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.

Journal article

Eng PC, Distaso W, Durreshahwar H, Shaikhali Y, Narendranathan D, Cassin-Scott R, Misra S, Hill NE, Tharakan G, Oliver NS, Tan TM, Izzi-Engbeaya C, Salem Vet 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

Journal article

Thomas NJ, Dennis JM, Sharp SA, Kaur A, Misra S, Walkey HC, Johnston DG, Oliver NS, Hagopian WA, Weedon MN, Patel KA, Oram RAet 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

Journal article

Misra S, Barron E, Vamos E, Thomas S, Dhatariya K, Kar P, Young B, Khunti K, Valabhji Jet 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

Journal article

Grace SL, Bowden J, Walkey HC, Kaur A, Misra S, Shields BM, McKinley TJ, Oliver NS, McDonald T, Johnston DG, Jones AG, Patel KAet 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

Journal article

Thomas NJ, Dennis JM, Sharp SA, Kaur A, Misra S, Walkey HC, Johnston DG, Oliver NS, Hagopian WA, Weedon MN, Patel KA, Oram RAet 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.

Journal article

Ansari S, Abdel-Malek M, Kenkre J, Choudhury SM, Barnes S, Misra S, Tan T, Cegla Jet 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

Journal article

Takis PG, Jiménez B, Al-Saffar NMS, Harvey N, Chekmeneva E, Misra S, Lewis MRet 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.

Journal article

Thomas NJ, Walkey HC, Kaur A, Misra S, Oliver NS, Colclough K, Weedon MN, Johnston DG, Hattersley AT, Patel KAet 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 (&gt;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 (&lt;18years (n=702), 18-30years (n=524) and &gt;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 &lt;18years, 55%(37/67) of 18-30years and just 23%(34/151) of &gt;30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% &lt;18years, 92% 18-30years, 93% &gt;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 &lt;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

Journal article

Misra S, Khozoee B, Huang-Jiawei P, Mitsaki K, Reddy M, Salem V, Tan T, Tharakan G, Gable D, Bravis V, Valabhji Jet 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

Journal article

Izzi-Engbeaya C, Distaso W, Amin A, Kenkre J, Abdel-Malek M, Hope D, Oliver N, Misra S, Tan T, Hill N, Salem Vet 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.

Journal article

Muniangi-Muhitu H, Akalestou E, Salem V, Misra S, Oliver NS, Rutter GAet 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.

Journal article

Misra S, Hassanali N, Bennett AJ, Juszczak A, Caswell R, Colclough K, Valabhji J, Ellard S, Oliver NS, Gloyn ALet 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

Journal article

Hu M, Cherkaoui I, Misra S, Rutter GAet 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.

Journal article

Izzi-Engbeaya C, Distaso W, Amin A, Yang W, Idowu O, Kenkre JS, Shah RJ, Woin E, Shi C, Alavi N, Bedri H, Brady N, Blackburn S, Leczycka M, Patel S, Sokol E, Toke-Bjolgerud E, Qayum A, Abdel-Malek M, Hope DCD, Oliver NS, Bravis V, Misra S, Tan TM, Hill N, Salem Vet 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>

Journal article

Misra S, Godsland IF, Bhardwaj N, Oliver N, Owen KR, Johnston DGet 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

Conference paper

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.

Journal article

Misra S, hassanali N, Bennet A, Juszczak A, Caswell R, Colclough K, Valabhji J, Ellard S, Oliver N, Gloyn Aet 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.

Journal article

Guemes M, Rahman SA, Kapoor RR, Flanagan S, Houghton JAL, Misra S, Oliver N, Dattani MT, Shah Pet 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.

Journal article

Barron E, Misra S, English E, John WG, Sampson M, Bachmann MO, Barth J, Oliver N, Alberti KGMM, Bakhai C, O'Neill S, Young B, Wareham NJ, Khunti K, Jebb S, Smith J, Valabhji Jet al., 2020, Experience of point-of-care HbA1c testing in the English National Health Service Diabetes Prevention Programme: an observational study, BMJ OPEN DIABETES RESEARCH & CARE, Vol: 8

Journal article

Humphreys A, Bravis V, Kaur A, Walkey HC, Godsland IF, Misra S, Johnston DG, Oliver NSet al., 2019, Individual and diabetes presentation characteristics associated with partial remission status in children and adults evaluated up to 12 months following diagnosis of type 1 diabetes: An ADDRESS-2 (After Diagnosis Diabetes Research Support System-2) study analysis, Diabetes Research and Clinical Practice, Vol: 155, ISSN: 0168-8227

AIMS: People with recently-diagnosed type 1 diabetes mellitus (T1D) may undergo a transient period of glycaemic control with less exogenous insulin. Identification of predictors of this 'remission' could inform a better understanding of glycaemic control. METHODS: Participants in the ADDRESS-2 study were included who had 1 or 2 assessments of remission status (coincident insulin dose and HbA1c measurement, with remission defined by ≤0.4 units insulin/kg-body-weight/day with HbA1c < 53 mmol/mol). Demographic and clinical presentation characteristics were compared according to remission status and predictors of remission were explored by logistic regression analysis. RESULTS: 1470 first and 469 second assessments of remission status were recorded within 12 months of diagnosis of T1D. Step increases in the probability of remission were identified at age-at-diagnosis 20 years and 3 months after diagnosis (both p < 0.001). Among those aged < 20 years, remission was associated with male gender (p = 0.02), no ketoacidosis (p = 0.02) and fewer than 2 symptoms at presentation (p = 0.004). None of these characteristics predicted remission in those aged ≥ 20 years. In the subgroup with two assessments, transition to remission was independently associated with first remission assessment in months 1-2 post-diagnosis (p = 0.01), with age-at-diagnosis ≥ 20 years (p = 0.01) and, in those aged < 20 years, with an early HbA1c of <57 mmol/mol. Adiposity, ethnicity, autoantibody status and other autoimmune disease were unrelated to remission. CONCLUSIONS: For those diagnosed before 20 years of age, males, ketoacidosis-free, with fewer symptoms and low early HbA1c were more likely to experience remission, but remission was most likely in anyone aged ≥ 20 at diagnosis.

Journal article

Bhattarai S, Godsland IF, Misra S, Johnston DG, Oliver Net al., 2019, Metabolic health and vascular complications in type 1 diabetes, Journal of Diabetes and its Complications, Vol: 33, Pages: 634-640, ISSN: 1056-8727

AIMS: Optimal glycaemic control benefits risk of microvascular and macrovascular complications in type 1 diabetes (T1DM) but the importance of other components of metabolic health is less certain, particularly in the context of routine clinical practice. METHODS: Data for this cross-sectional analysis derived from a database covering inner North West London adult diabetes clinics. People with T1DM and with complete information for height, weight, blood pressure and serum high and low-density lipoprotein cholesterol (HDL-c and LDL-c) and triglyceride concentration measurements were included. RESULTS: Among the 920 participants, those with complications were older and had longer duration of diabetes but had similar HbA1c to people without complications. Systolic hypertension and low HDL-c were independently associated with complications. From having 0 risk factors, the prevalence of micro and macrovascular disease increased with increasing number of risk factors. Relative to those with ≥1 risk factor, those with 0 risk factors (n = 179) were at lower risk of retinopathy (OR 0.6 (0.4-0.9), p = 0.01) and nephropathy [OR 0.1 (0.04-0.3), p = 0.002], independent of individual characteristics. CONCLUSIONS: In routine clinical management of T1DM, associations between lipid and blood pressure risk factors and prevalent micro and macrovascular disease remain, implying that more intensive risk factor management may be beneficial.

Journal article

Patel KA, Thomas N, Weedon MN, Walkey HC, Kaur A, Williams AJ, Misra S, Oliver N, Esq DGJ, Hattersley ATet al., 2019, Analysis of Type 1 Diabetes Genetic Risk Score Shows 1 in 8 People with Clinically Diagnosed Adult-Onset T1D Are Misdiagnosed, and Presenting Features at Diagnosis Do Not Identify Those Misdiagnosed, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Huddy JR, Ni M, Misra S, Mavroveli S, Barlow J, Hanna GBet al., 2019, Development of the Point-of-Care Key Evidence Tool (POCKET): a checklist for multi-dimensional evidence generation in point-of-care tests, Clinical Chemistry and Laboratory Medicine, Vol: 57, Pages: 845-855, ISSN: 1434-6621

BackgroundThis study aimed to develop the Point-of-Care Key Evidence Tool (POCKET); a multi-dimensional checklist to guide the evaluation of point-of-care tests (POCTs) incorporating validity, utility, usability, cost-effectiveness and patient experience. The motivation for this was to improve the efficiency of evidence generation in POCTs and reduce the lead-time for the adoption of novel POCTs.MethodsA mixed qualitative and quantitative approach was applied. Following a literature search, a three round Delphi process was undertaken incorporating a semi-structured interview study and two questionnaire rounds. Participants included clinicians, laboratory personnel, commissioners, regulators (including members of National Institute for Health and Care Excellence [NICE] committees), patients, industry representatives and methodologists. Qualitative data were analysed based on grounded theory. The final tool was revised at an expert stakeholder workshop.ResultsForty-three participants were interviewed within the semi-structured interview study, 32 participated in the questionnaire rounds and nine stakeholders attended the expert workshop. The final version of the POCKET checklist contains 65 different evidence requirements grouped into seven themes. Face validity, content validity and usability has been demonstrated. There exists a shortfall in the evidence that industry and research methodologists believe should be generated regarding POCTs and what is actually required by policy and decision makers to promote implementation into current healthcare pathways.ConclusionsThis study has led to the development of POCKET, a checklist for evidence generation and synthesis in POCTs. This aims to guide industry and researchers to the evidence that is required by decision makers to facilitate POCT adoption so that the benefits they can bring to patients can be effectively realised.

Journal article

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