Imperial College London

Dr Shivani Misra

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Clinical Senior Lecturer
 
 
 
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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

56 results found

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

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

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, 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

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

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

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

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

Walkey HC, Kaur A, Godsland IF, Williams AJ, Oliver N, Johnston DG, Misra Set al., 2019, The impact of ethnicity on clinical characteristics and autoantibody status at clinical onset of Type 1 diabetes-from the ADDRESS-2 study, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, Pages: 1-2, ISSN: 0012-1797

Introduction: The phenotype of type 1 diabetes (T1D) has been explored mainly in white populations. People of non-white ethnicity are reportedly less likely to be antibody positive, but phenotypic differences are not well characterised. We investigated ethnic group differences in the clinical characteristics and antibody (Ab) status at clinical onset of T1D.Methods: We studied people of white European (WE), Asian (A) and black African/Caribbean (AC) ethnicity with clinically-assigned T1D, age ≥5 years, recruited ≤ 6 months after diagnosis, and with Abs (GADA, IA-2A and ZnT8A) measured by radioimmunoassay.Results: Ethnic breakdown: WE n=1,997, A n=50, AC n=41. Median (IQR) ages were: WE 23(14-24), A 18(12-29), AC 26 (15-41) years p=0.007. Presentation with DKA was more common in AC (65%) than WE (42%) or A (53%) p=0.006; otherwise clinical presentation (polyuria/dipsia, weight loss, fatigue, symptom duration) was similar. Proportions with 0, 1 and ≥2 Abs differed by ethnicity: WE (15%, 24%, 61%); A (28%, 26%, 46%); AC (36%, 32%, 32%) p<0.001. For Ab negative (0 Abs), ethnic groups differed in BMI (p=0.001) and presentation with DKA (<0.001), but other characteristics, including daily insulin dose, were similar. For Ab positive (≥1 Ab), there were differences in parental history of diabetes p=0.02; otherwise ethnicity had no impact. Also, differences were seen in the frequency of IA-2A: WE (67%), A (53%), AC (50%) p=0.03 and ZnT8A: WE (60%), A (39%), AC (42%) p=0.01, but not GADA: WE (83%), A (94%) AC (92%) p=0.09.Conclusion: Although clinical presentation of T1D was remarkably similar across ethnic groups, variations were found in the proportions with Ab positivity and frequencies of individual Abs. Antibody negativity was more common in non-white ethnic groups and the presence of >1 Ab most common in white ethnicity. Practitioners should be alert to differences in phenotype according to antibody status that may impact classification in some ethn

Conference paper

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

Misra S, Owen K, 2018, Genetics of monogenic diabetes: present clinical challenges, Current Diabetes Reports, Vol: 18, ISSN: 1534-4827

Purpose of ReviewMonogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that remain, including improving case-finding strategies, particularly those that have transethnic applicability, and understanding the interpretation of genetic variants as pathogenic, with clinically meaningful impacts.Recent FindingsBiomarker approaches to the stratification for genetic testing now appear to be most effective in identifying cases of monogenic diabetes, and use of genetic risk scores may also prove useful. However, applicability in all ethnic groups is lacking. Challenges remain in the classification of genes as diabetes-causing and the interpretation of genetic variants at the clinical interface.SummarySince the discovery that genetic defects can cause neonatal or young-onset diabetes, multiple causal genes have been identified and there have been many advances in strategies to detect genetic forms of diabetes and their treatments. Approaches learnt from monogenic diabetes are now being translated to polygenic diabetes.

Journal article

Misra S, vedovato N, cliff E, de franco E, hattersley A, ashcroft F, Oliver Net al., 2018, Permanent neonatal diabetes: combining sulphonylureas with insulin may be an effective treatment, Diabetic Medicine, Vol: 35, Pages: 1291-1296, ISSN: 0742-3071

BackgroundPermanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high‐dose sulfonylureas. Complete transfer to sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements.CaseA 22‐year‐old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin‐pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose‐titration with C‐peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C‐peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose‐titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once‐daily long‐acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability.ConclusionIn people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy.

Journal article

Hill NE, Deighton K, Matu J, Misra S, Oliver NS, Newman C, Mellor A, O'Hara J, Woods Det al., 2018, Continuous glucose monitoring at high altitude effects on glucose homeostasis, Medicine and Science in Sports and Exercise, Vol: 50, Pages: 1679-1686, ISSN: 0195-9131

PURPOSE: Exposure to high altitude has been shown to enhance both glucose and lipid utilization depending on experimental protocol. In addition, high and low blood glucose levels have been reported at high altitude. We hypothesized that gradual ascent to high altitude results in changes in glucose levels in healthy young adults. METHODS: 25 adult volunteers, split into two teams, took part in the British Services Dhaulagiri Medical Research Expedition completing 14 days of trekking around the Dhaulagiri circuit in Nepal reaching a peak altitude of 5300m on Day 11 of the trek. Participants wore blinded continuous glucose monitors (CGM) throughout. Blood samples for c-peptide, pro-insulin and triacylglycerides were taken at sea level (UK) and in acclimatisation camps at 3600m, 4650m and 5120m. Energy intake was determined from food diaries. RESULTS: There was no difference in time spent in hypoglycemia stratified by altitude. Nocturnal CGM readings (22.00-06.00 hrs) were chosen to reduce the short-term impact of physical activity and food intake and showed a significant (p<0.0001) increase at 3600m (5.53±0.22mmol/L), 4650m (4.77±0.30mmol/L) and 5120m (4.78±0.24mmol/L) compared to baseline altitude 1100m (vs 4.61±0.25mmol/L). Energy intake did not differ by altitude. Insulin resistance and B-cell function, calculated by homeostatic model assessment, was reduced at 3600m compared to sea level. CONCLUSIONS: We observed a significant increase in nocturnal CGM glucose at 3600m and above despite gradual ascent from 1100m. Taken with the changes in insulin resistance and B-cell function, it is possible that the stress response to high altitude dominates exercise enhanced insulin sensitivity, resulting in relative hyperglycemia.

Journal article

Misra S, Kaur A, Godsland IF, Walkey HC, Johnston DG, Oliver Net al., 2018, Overweight individuals with Type 1 diabetes are less likely to present with diabetic ketoacidosis-data from the after diabetes diagnosis research support system (ADDRESS-2) cohort, 78th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: 1-2, ISSN: 0012-1797

Introduction: Insulin resistance has been proposed to accelerate progression to type 1 diabetes (T1D) in antibody positive relatives of affected individuals. We hypothesised that overweight individuals with confirmed T1D would be less likely to present with diabetic ketoacidosis (DKA), signifying an earlier onset of T1D, due to concomitant insulin resistance.Methods: The ADDRESS-2 study recruits incident clinician-assigned T1D cases within 6-months of diagnosis and systematically assesses pancreatic autoimmunity by GAD-65, IA-2 and ZnT8 antibodies. People with at least two positive antibodies were selected to confirm diagnosis of T1D and categorised for adiposity according to BMI (adults) or Z-scores (children). Odds ratios (OR) for presentation with DKA were compared, adjusted for potential confounders and sub-analysed by whether adult or child at recruitment.Results: 31% (969/ 3132) were positive for two or more pancreatic antibodies. Of these 44% (424/969) presented with DKA. The proportions with DKA varied significantly by adiposity: 59% underweight (16/27), 47% normal (280/601), 39% overweight (103/263), 30% obese (19/63) and 40% severely obese (6/15) (p=0.02). When adjusted for age, being overweight or obese was associated with lower risk of DKA in adults (OR 0.58, p=0.006; 0.44, p=0.03, respectively) not children (OR 0.9, p=0.81; 0.51, p=0.12, respectively). Higher adiposity category was associated with higher daily insulin-requirements independent of age, with obesity associated with a 4 unit/day increase (p=0.03) and severe obesity, 11 units/day increase (p=0.008).Conclusion: Adults with T1D are less likely to present with DKA if overweight or obese. Despite smaller proportions of DKA, insulin requirements are higher. These data suggest that, in adults, T1D presentation is unmasked by the insulin resistance of obesity prior to absolute insulin deficiency and ketoacidosis.

Conference paper

Walkey HC, Bravis V, Akaal K, Godsland I, Misra S, Williams AJK, Bingley PJ, Dunger DB, Dayan CM, Peakman M, Oliver N, Johnston Det al., 2018, The relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort, BMJ Open, Vol: 8, ISSN: 2044-6055

Objectives:Todescribethecharacteristicsofchildrenandadultswithincidenttype1diabetesincontemporary,multi-ethnicUK,focusingondifferencesbetweentheisletautoantibodynegativeandpositive.Design:Observationalcohortstudy.Setting:146mainlysecondarycarecentresacrossEnglandandWales.Participants:3,312peopleaged≥5yearswererecruitedwithin6monthsofaclinicaldiagnosisoftype1diabetesviatheNationalInstituteforHealthResearchClinicalResearchNetwork.3,021wereofwhiteEuropeanethnicityand291(9%)werenon-white.Therewasasmallmalepredominance(57%).Youngpeople<17yearscomprised59%.Mainoutcomemeasures:Autoantibodystatusandcharacteristicsatpresentation.Results:Themajoritypresentedwithclassicalosmoticsymptoms,weightloss,andfatigue.Ketoacidosiswascommon(42%),especiallyinadults,andirrespectiveofethnicity.35%wereoverweightorobese.Ofthe1,778participantswhodonatedabloodsample,85%werepositiveforoneormoreautoantibodiesagainstglutamatedecarboxylase,isletantigen-2,andzinctransporter8.Presentingsymptomsweresimilarintheautoantibodypositiveandnegativeparticipants,aswasthefrequencyofketoacidosis(43%vs40%,p=0·3).Autoantibodypositivitywaslesscommonwithincreasingage(p=0·0001),inmalescomparedwithfemales(82%vs90%,p<0·0001)andinpeopleofnon-whitecomparedwithwhiteethnicity(73%vs86%,p<0·0001).Bodymassindexwashigherinautoantibodynegativethanpositiveadults(median,IQR25·5,23·1-29·2vs23·9,21·4-26·7kg/m2;p=0·0001).Autoantibodynegativeparticipants weremorelikelytohaveaparentwithdiabetes(28%vs16%,p<0·0001)andlesslikelytohaveanotherautoimmunedisease(4%vs8%,p=0.01).Conclusions:Mostpeopleassignedadiagnosisoftype1diabetespresentedwithclassicalclinicalfeaturesandisletautoantibodies.Althoughindistinguishableatanindividuallevel,autoantibodynegativeparticipantsasagroupdemonstratedfeaturesmoretypicallyassociatedwithotherdiabetessubtypes.

Journal article

Srivanichakorn W, Godsland IF, Thomson H, Misra S, Phisalprapa P, Charatcharoenwitthaya P, Pramyothin P, Washirasaksiri C, Snehalatha C, Ramachandran A, George Mm Alberti K, Johnston DG, Oliver NSet al., 2017, Fasting plasma glucose and variation in cardiometabolic risk factors in people with high-risk HbA1c-defined prediabetes: a cross-sectional multiethnic study., Diabetes Research and Clinical Practice, Vol: 134, Pages: 183-190, ISSN: 0168-8227

AIMS: Variation in cardiometabolic risk in prediabetes and any impacts of ethnicity on such variation have been little studied. In an ethnically diverse dataset, selected according to a high-risk HbA1c-based definition of prediabetes, we have investigated relationships between glycaemia and cardiometabolic risk factors and the influence of ethnicity on these relationships. METHODS: We undertook a cross-sectional analysis of baseline data from a diabetes prevention study in the UK and a chronic care clinic in Thailand, selected for people without diabetes (fasting plasma glucose <7.0 mmol/l) with HbA1c 6.0% - 6.4% (42-47 mmol/mol). Thai (n=158) and UK White (n=600), South Asian (n=112), Black (n=70) and other/mixed (n=103) groups were distinguished and measurements included fasting plasma glucose (FPG), blood pressure (BP), lipids and insulin resistance-related risk factors (IRFs). RESULTS: Independently of individual characteristics including ethnicity, only systolic BP was weakly associated with FPG (beta coefficient 1.76 (95%CI 0.10 to 3.42), p=0.03), and only LDL-c with IFG (FPG 5.6-<7) (adjusted -0.14 (-0.27, -0.003) p 0.04). There were no significant independent associations with cardiometabolic risk factors when categories of impaired fasting glucose (FPG ≥ 6.1 to <7.0 mmol/L) were considered. Relative to White, South Asian ethnicity was independently associated with lower systolic and diastolic BP, Black with lower triglycerides, cholesterol/HDL-c ratio and having 2 or more IRFs, and Thai with lower cholesterol/HDL-c ratio and all three non-white ethnicities with lower total and LDL cholesterol. CONCLUSION: In high-risk HbA1c-defined prediabetes additional measurement of FPG will add little to evaluation of cardiometabolic risk. Additionally, UK Whites tend to have the most adverse cardiometabolic profile of any ethnic group.

Journal article

Walkey HC, Kaur A, Bravis V, Godsland IF, Misra S, Williams AJK, Bingley PJ, Dunger DB, Oliver N, Johnston DGet al., 2017, Rationale and protocol for the After Diabetes Diagnosis REsearch Support System (ADDRESS): an incident and high risk type 1 diabetes UK cohort study., BMJ Open, Vol: 7, ISSN: 2044-6055

INTRODUCTION: Type 1 diabetes is heterogeneous in its presentation and progression. Variations in clinical presentation between children and adults, and with ethnic group warrant further study in the UK to improve understanding of this heterogeneity. Early interventions to limit beta cell damage in type 1 diabetes are undergoing evaluation, but recruitment is challenging. The protocol presented describes recruitment of people with clinician-assigned, new-onset type 1 diabetes to understand the variation in their manner of clinical presentation, to facilitate recruitment into intervention studies and to create an open-access resource of data and biological samples for future type 1 diabetes research. METHODS AND ANALYSIS: Using the National Institute for Health Research Clinical Research Network, patients >5 years of age diagnosed clinically with type 1 diabetes (and their siblings) are recruited within 6 months of diagnosis. Participants agree to have their clinical, laboratory and demographic data stored on a secure database, for their clinical progress to be monitored using information held by NHS Digital, and to be contacted about additional research, in particular immunotherapy and other interventions. An optional blood sample is taken for islet autoantibody measurement and storage of blood and DNA for future analyses. Data will be analysed statistically to describe the presentation of incident type 1 diabetes in a contemporary UK population. ETHICS AND DISSEMINATION: Ethical approval was obtained from the independent NHS Research Ethics Service. Results will be presented at national and international meetings and submitted for publication to peer-reviewed journals.

Journal article

Misra S, 2017, Pancreatic autoantibodies: who to test and how to interpret the results, PRACTICAL DIABETES, Vol: 34, ISSN: 2047-2897

Journal article

Kaur A, Walkey H, Godsland IF, Bravis V, Misra S, Williams AJK, Bingley PJ, Dunger DB, Oliver NS, Johnston DGet al., 2017, Characteristics Associated with Diabetic Ketoacidosis in Children and Adults Newly Diagnosed with Type 1 Diabetes: Data from the After Diabetes Diagnosis Research Support System (ADDRESS-2) Cohort, 77th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: A467-A467, ISSN: 0012-1797

Conference paper

Walkey HC, Kaur A, Godsland IF, Bravis V, Misra S, Williams AJK, Bingley PJ, Dunger DB, Oliver NS, Johnston DGet al., 2017, Clinical presentation and islet autoantibody status in a UK multi-ethnic cohort of children and adults with new-onset Type 1 diabetes-the after diabetes diagnosis research support system-2 (ADDRESS-2), 77th Scientific Sessions of the American-Diabetes-Association, Publisher: American Diabetes Association, Pages: A467-A468, ISSN: 0012-1797

Conference paper

Misra S, Godsland I, Lupak L, Williams EL, Johnston D, Oliver NSet al., 2017, Predictors of C-Peptide in a Young-Onset Diabetes UK Multiethnic Cohort: Results from the MY DIABETES Study, 77th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: A421-A421, ISSN: 0012-1797

Conference paper

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