Publications by authors named "John C Pickup"

50 Publications

SITAgliptin for Depressive Symptoms (SITADS) in type 2 diabetes: a feasibility randomized controlled trial.

Psychosom Med 2021 Jul 21. Epub 2021 Jul 21.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RJ, UK Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL and SE5 9RJ, UK Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.

Objective: We tested the feasibility of using sitagliptin - a dipeptidyl peptidase-IV inhibitor - for depressive symptoms in type 2 diabetes (T2D).

Methods: In a feasibility, double-blind, randomised controlled trial, we recruited people aged 18-75 with T2D (HbA1c ≥53 and ≤ 86 mmol/mol prescribed oral hypoglycaemic therapy) and comorbid depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥ 10) from family practices in South London. Eligible patients were randomised to sitagliptin 100 mg per day or matched placebo for 12 weeks. The primary feasibility outcomes were participation rates, attrition rates and adverse events. The primary clinical outcomes were depressive symptoms (PHQ-9 and Quick Inventory of Depressive Symptomatology [QIDS-SR-16] scores) at 12 weeks as assessed using ANCOVA analyses. Ranges of treatment effects were estimated using Cohen's d and associated 95% confidence intervals, where negative values favoured sitagliptin over placebo.

Results: Of 153 people screened across 32 practices, 44 were randomised (22 to each arm). The mean age was 58.8 (SD = 8.3) years, 46% were female and 52% of non-white ethnicity. Of those treated, 1 patient (4.5%) in each arm withdrew and there were no group differences in adverse events. Despite improving 12-week HbA1c (d = -1.19 [95% CI -1.90, -0.48]), improvement in 12-week QIDS-SR-16 score with sitagliptin was inferior to placebo across the range of estimated treatment effects (d = 0.71 [0.13, 1.30]). Effects of sitagliptin on inflammation were inconsistent (d = -0.32 [-0.81, 0.17] for hs-CRP).

Conclusions: Repositioning of oral hypoglycaemic therapy for depressive symptoms in T2D is feasible. However, in this under-powered feasibility study, we did not detect evidence of superiority of sitagliptin over placebo. The results are cautioned by the small sample size and limited treatment duration.Trial RegistrationEudraCT: 2015-004527-32.
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http://dx.doi.org/10.1097/PSY.0000000000000985DOI Listing
July 2021

Advances in technology for management of type 1 diabetes.

Lancet 2019 10 15;394(10205):1265-1273. Epub 2019 Sep 15.

King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, UK.

Technological advances have had a major effect on the management of type 1 diabetes. In addition to blood glucose meters, devices used by people with type 1 diabetes include insulin pumps, continuous glucose monitors, and, most recently, systems that combine both a pump and a monitor for algorithm-driven automation of insulin delivery. In the next 5 years, as many advances are expected in technology for the management of diabetes as there have been in the past 5 years, with improvements in continuous glucose monitoring and more available choices of systems that automate insulin delivery. Expansion of the use of technology will be needed beyond endocrinology practices to primary-care settings and broader populations of patients. Tools to support decision making will also need to be developed to help patients and health-care providers to use the output of these devices to optimise diabetes management.
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http://dx.doi.org/10.1016/S0140-6736(19)31142-0DOI Listing
October 2019

The Prospective Association Between Inflammation and Depressive Symptoms in Type 2 Diabetes Stratified by Sex.

Diabetes Care 2019 10 15;42(10):1865-1872. Epub 2019 Aug 15.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, U.K.

Objective: We tested whether inflammation is associated with worsening depressive symptoms in type 2 diabetes and examined whether sex moderated this association.

Research Design And Methods: In a prospective cohort study of people with newly diagnosed type 2 diabetes, we measured depressive symptoms over a 2-year follow-up using the Patient Health Questionnaire-9 (PHQ-9). The independent variable was a composite inflammation burden score at diagnosis of diabetes, derived from hs-CRP, white cell count, interleukin (IL)-1β, IL-1 receptor antagonist, monocyte chemotactic protein-1, and vascular endothelial growth factor concentrations. General linear models assessed ) the association between overall inflammation burden and estimated marginal mean PHQ-9 score (ln transformed) at 2 years and ) whether sex interacted with elevated inflammation burden (above-median score) in predicting change in PHQ-9 score. Models were adjusted for age, ethnicity, BMI, blood pressure, cholesterol, HbA, antidepressants, anti-inflammatory medications, and baseline ln PHQ-9 score.

Results: Of 1,174 people with complete inflammation data, mean (SD) age was 56.7 (11.0) years and 46.1% were of nonwhite ethnicity and 44.1% female. After full adjustment, inflammation burden was not associated with worsening ln PHQ-9 score ( = 0.65). However, female sex interacted with elevated inflammation in predicting higher 2-year ln PHQ-9 score (β = 0.32, = 0.005), showing that the difference by inflammation burden in females was 0.32 larger than in males. In post hoc comparisons, ln PHQ-9 score was higher in females than males with elevated inflammation ( = 0.003) but not with low inflammation ( = 0.34) burden.

Conclusions: In type 2 diabetes, female sex confers specific vulnerability to the effects of inflammation on depressive symptoms.
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http://dx.doi.org/10.2337/dc19-0813DOI Listing
October 2019

Insulin Pumps.

Authors:
John C Pickup

Diabetes Technol Ther 2019 02;21(S1):S32-S41

1 Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.

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http://dx.doi.org/10.1089/dia.2019.2503DOI Listing
February 2019

Insulin Pumps.

Authors:
John C Pickup

Diabetes Technol Ther 2018 02;20(S1):S30-S40

1 Faculty of Life Sciences and Medicine, King's College London , Guy's Hospital, London, United Kingdom .

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http://dx.doi.org/10.1089/dia.2018.2503DOI Listing
February 2018

Diabetes: Insulin pumps after injections and CGM in T1DM.

Authors:
John C Pickup

Nat Rev Endocrinol 2017 10 18;13(10):568-569. Epub 2017 Aug 18.

Division of Diabetes and Nutritional Sciences, King's College London Faculty of Life Sciences and Medicine, Guy's Hospital, London SE1 1UK, UK.

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http://dx.doi.org/10.1038/nrendo.2017.108DOI Listing
October 2017

The association of depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years in newly diagnosed type 2 diabetes: a prospective cohort study.

Diabetologia 2017 10 3;60(10):2092-2102. Epub 2017 Aug 3.

Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Aims/hypothesis: We examined the associations between depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years, after diagnosis of type 2 diabetes.

Methods: In a multi-ethnic, primary care cohort (n = 1735) of adults, all with recent (<6 months) diagnosis of type 2 diabetes, we measured the associations between depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) and diabetes distress (Problem Areas in Diabetes [PAID] score ≥40), with change in 2 year HbA as the primary outcome and with incident rates of diabetes complications as secondary outcomes. Multivariate models were used to account for potential confounders.

Results: Of the 1651 participants (95.2%) of the total primary care cohort with available baseline PHQ-9 and PAID scores, mean ± SD age was 56.2 ± 11.1 years, 55.1% were men and 49.1% were of non-white ethnicity; 232 (14.1%) and 111 (6.7%) had depressive symptoms and diabetes distress, respectively. After adjustment for confounders, depressive symptoms were not associated with worsening HbA. After adjustment for age, sex, ethnicity, vascular risk factors and diabetes treatments, depressive symptoms were associated with increased risk of incident macrovascular complications (OR 2.78 [95% CI 1.19, 6.49], p = 0.018) but not microvascular complications. This was attenuated (p = 0.09) after adjustment for IL-1 receptor antagonist concentration. Diabetes distress was not associated with worsening HbA or incident complications.

Conclusions/interpretation: In the first 2 years of type 2 diabetes, the effect of depressive symptoms and diabetes distress on glycaemic control is minimal. There was, however, an association between depressive symptoms and incidence of macrovascular complications. Elevated innate inflammation may be common to both depression and macrovascular diabetes complications, but these findings require replication.
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http://dx.doi.org/10.1007/s00125-017-4367-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448879PMC
October 2017

Glycemic Control During Continuous Subcutaneous Insulin Infusion Versus Multiple Daily Insulin Injections in Type 2 Diabetes: Individual Patient Data Meta-analysis and Meta-regression of Randomized Controlled Trials.

Diabetes Care 2017 05;40(5):715-722

Department of Health Sciences, College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, U.K.

Objective: To compare glycemic control during continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) in people with type 2 diabetes to identify patient characteristics that determine those best treated by CSII.

Research Design And Methods: Randomized controlled trials were selected comparing HbA during CSII versus MDI in people with type 2 diabetes. Data sources included Cochrane database and Ovid Medline. We explored patient-level determinants of final HbA level and insulin dose using Bayesian meta-regression models of individual patient data and summary effects using two-step meta-analysis. Hypoglycemia data were unavailable.

Results: Five trials were identified, with 287 patients randomized to receive MDI and 303 to receive CSII. Baseline HbA was the best determinant of final HbA: HbA difference (%) = 1.575 - (0.216 [95% credible interval 0.371-0.043] × baseline HbA) for all trials, but with largest effect in the trial with prerandomization optimization of control. Baseline insulin dose was best predictor of final insulin dose: insulin dose difference (units/kg) = 0.1245 - (0.382 [0.510-0.254] × baseline insulin dose). Overall HbA difference was -0.40% (-0.86 to 0.05 [-4.4 mmol/mol (-9.4 to 0.6)]). Overall insulin dose was reduced by -0.25 units/kg (-0.31 to -0.19) (26% reduction on CSII), and by -24.0 units/day (-30.6 to -17.5). Mean weight did not differ between treatments (0.08 kg [-0.33 to 0.48]).

Conclusions: CSII achieves better glycemic control than MDI in people with poorly controlled type 2 diabetes, with ∼26% reduction in insulin requirements and no weight change. The best effect is in those worst controlled and with the highest insulin dose at baseline.
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http://dx.doi.org/10.2337/dc16-2201DOI Listing
May 2017

Insulin Pumps.

Authors:
John C Pickup

Diabetes Technol Ther 2017 02;19(S1):S19-S26

1 Diabetes Research Group, King's College London Faculty of Medicine and Life Sciences , Guy's Hospital, London, UK .

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http://dx.doi.org/10.1089/dia.2017.2503DOI Listing
February 2017

Insulin Pumps.

Authors:
John C Pickup

Diabetes Technol Ther 2016 Feb;18 Suppl 1:S22-8

1 Diabetes Research Group, King's College London , Faculty of Life Sciences and Medicine, Guy's Hospital, London, UK .

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http://dx.doi.org/10.1089/dia.2016.2503DOI Listing
February 2016

Long-term health economic benefits of sensor-augmented pump therapy vs continuous subcutaneous insulin infusion alone in type 1 diabetes: a U.K. perspective.

J Med Econ 2016 19;19(3):236-42. Epub 2015 Nov 19.

e e Faculty of Life Sciences and Medicine , King's College London, Guy's Hospital , London , UK.

Aims/hypothesis: Continuous subcutaneous insulin infusion (CSII) is an important treatment option for type 1 diabetes patients unable to achieve adequate glycemic control with multiple daily injections (MDI). Combining CSII with continuous glucose monitoring (CGM) in sensor-augmented pump therapy (SAP) with a low glucose-suspend (LGS) feature may further improve glycemic control and reduce the frequency of hypoglycemia. A cost-effectiveness analysis of SAP + LGS vs. CSII plus self-monitoring of blood glucose (SMBG) was performed to determine the health economic benefits of SAP + LGS in type 1 diabetes patients using CSII in the U.K.

Methods: Cost-effectiveness analysis was performed using the CORE diabetes model. Treatment effects were sourced from the literature, where SAP + LGS was associated with a projected HbA1c reduction of -1.49% vs. -0.62% for CSII, and a reduced frequency of severe hypoglycemia. The time horizon was that of patient lifetimes; future costs and clinical outcomes were discounted at 3.5% and 1.5% per annum, respectively.

Results: Projected outcomes showed that SAP + LGS was associated with higher mean quality-adjusted life expectancy (17.9 vs. 14.9 quality-adjusted life years [QALYs], SAP + LGS vs. CSII), and higher life expectancy (23.8 vs. 21.9 years), but higher mean lifetime direct costs (GBP 125,559 vs. GBP 88,991), leading to an incremental cost-effectiveness ratio (ICER) of GBP 12,233 per QALY gained for SAP + LGS vs. CSII. Findings of the base-case analysis remained robust in sensitivity analyses.

Conclusions/interpretation: For UK-based type 1 diabetes patients with poor glycemic control, the use of SAP + LGS is likely to be cost-effective compared with CSII plus SMBG.
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http://dx.doi.org/10.3111/13696998.2015.1113979DOI Listing
December 2016

The link between depression and diabetes: the search for shared mechanisms.

Lancet Diabetes Endocrinol 2015 Jun 17;3(6):461-471. Epub 2015 May 17.

Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK.

Depression is twice as common in people with type 1 or type 2 diabetes as in the general population, and is associated with poor outcomes. Evidence is growing that depression and type 2 diabetes share biological origins, particularly overactivation of innate immunity leading to a cytokine-mediated inflammatory response, and potentially through dysregulation of the hypothalamic-pituitary-adrenal axis. Throughout the life course, these pathways can lead to insulin resistance, cardiovascular disease, depression, increased risk of type 2 diabetes, and increased mortality. Proinflammatory cytokines might directly affect the brain, causing depressive symptoms. In type 1 diabetes, mediators of depression are not well studied, with research hindered by inconsistent definitions of depression and scarcity of observational, mechanistic, and interventional research along the life course. Despite few studies, evidence suggests that familial relationships and burden of a lifelong disorder with an onset early in personality development might contribute to increased vulnerability to depression. Overall, longitudinal research is needed to identify risk factors and mechanisms for depression in patients with diabetes, particularly early in the life course. Ultimately, improved understanding of shared origins of depression and diabetes could provide the potential to treat and improve outcomes of both disorders simultaneously. These shared origins are targets for primary prevention of type 2 diabetes.
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http://dx.doi.org/10.1016/S2213-8587(15)00134-5DOI Listing
June 2015

Real-time continuous glucose monitoring in type 1 diabetes: a qualitative framework analysis of patient narratives.

Diabetes Care 2015 Apr 31;38(4):544-50. Epub 2014 Dec 31.

Social Care Workforce Research Unit, School of Social Science and Public Policy, King's College London, London, U.K.

Objective: This study analyzed narratives about experiences of real-time continuous glucose monitoring (CGM) in people with type 1 diabetes.

Research Design And Methods: People with type 1 diabetes using CGM and caregivers completed an online survey. Questions included duration of CGM, frequency of sensor wear, funding, and a free narrative about experiences or views about CGM. We used qualitative framework analysis to analyze 100 responses; 50% of participants were aged ≥ 18 years.

Results: Most participants (87%) used CGM with insulin pump therapy, 71% used sensors ≥ 75% of the time, and 66% received funding for CGM from the National Health Service. Four themes were identified: 1) metabolic control, 2) living with CGM (work and school, sleep, exercise, nutrition, frequency of self-monitoring of blood glucose [SMBG]), 3) psychological issues and patient/caregiver attitudes, and 4) barriers to CGM use (technical issues, financial issues, attitudes of healthcare professionals toward CGM). Despite some hassles, experiences were overwhelmingly positive, with improved glycemic control, diet and exercise management, quality of life, and physical and psychological well-being, as well as reduced frequency of SMBG. Technical problems included sensor inaccuracy and unreliability, and "alarm fatigue." The advantages of CGM used with an insulin pump with automatic suspension of insulin delivery during hypoglycemia were recorded by several participants, noting reduced hypoglycemia frequency and fear of nocturnal hypoglycemia.

Conclusions: Patient and caregiver narratives indicate that CGM is a valuable addition to diabetes care for many with type 1 diabetes.
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http://dx.doi.org/10.2337/dc14-1855DOI Listing
April 2015

A novel fluorescent sensor protein for detecting changes in airway surface liquid glucose concentration.

Biochem J 2014 Dec;464(2):213-20

†Institute for Infection and Immunity, St George's, University of London, London SW17 0RE, U.K.

Both lung disease and elevation of blood glucose are associated with increased glucose concentration (from 0.4 to ~4.0 mM) in the airway surface liquid (ASL). This perturbation of ASL glucose makes the airway more susceptible to infection by respiratory pathogens. ASL is minute (~1 μl/cm(2)) and the measurement of glucose concentration in the small volume ASL is extremely difficult. Therefore, we sought to develop a fluorescent biosensor with sufficient sensitivity to determine glucose concentrations in ASL in situ. We coupled a range of environmentally sensitive fluorophores to mutated forms of a glucose/galactose-binding protein (GBP) including H152C and H152C/A213R and determined their equilibrium binding properties. Of these, GBP H152C/A213R-BADAN (Kd 0.86 ± 0.01 mM, Fmax/F0 3.6) was optimal for glucose sensing and in ASL increased fluorescence when basolateral glucose concentration was raised from 1 to 20 mM. Moreover, interpolation of the data showed that the glucose concentration in ASL was increased, with results similar to that using glucose oxidase analysis. The fluorescence of GBP H152C/A213R-BADAN in native ASL from human airway epithelial cultures in situ was significantly increased over time when basolateral glucose was increased from 5 to 20 mM. Overall our data indicate that this GBP is a useful tool to monitor glucose homoeostasis in the lung.
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http://dx.doi.org/10.1042/BJ20141041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357280PMC
December 2014

Diabetes: insulin pump therapy for type 2 diabetes mellitus.

Authors:
John C Pickup

Nat Rev Endocrinol 2014 Nov 12;10(11):647-9. Epub 2014 Aug 12.

Diabetes Research Group, King's College London School of Medicine, Hodgkin Building, Guy's Hospital, London SE1 1UL, UK.

The evidence base for the efficacy of insulin pump therapy in type 2 diabetes mellitus (T2DM) has been inconsistent to date. However, a recent large-scale randomized controlled trial comparing pump treatment with multiple daily insulin injections in patients with poorly controlled T2DM has shown substantial improvement in glycaemic control with pump therapy.
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http://dx.doi.org/10.1038/nrendo.2014.142DOI Listing
November 2014

The association between depressive symptoms and systemic inflammation in people with type 2 diabetes: findings from the South London Diabetes Study.

Diabetes Care 2014 Aug 19;37(8):2186-92. Epub 2014 May 19.

Department of Psychological Medicine, King's College London, Institute of Psychiatry, London, U.K.

Objective: The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers.

Research Design And Methods: Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-α [TNF-α], IL-1β, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA1c, and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression.

Results: The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1β (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms.

Conclusions: Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group.
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http://dx.doi.org/10.2337/dc13-2522DOI Listing
August 2014

Nanolayer encapsulation of insulin-chitosan complexes improves efficiency of oral insulin delivery.

Int J Nanomedicine 2014 2;9:2127-36. Epub 2014 May 2.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.

Current oral insulin formulations reported in the literature are often associated with an unpredictable burst release of insulin in the intestine, which may increase the risk for problematic hypoglycemia. The aim of the study was to develop a solution based on a nanolayer encapsulation of insulin-chitosan complexes to afford sustained release after oral administration. Chitosan/heparin multilayer coatings were deposited onto insulin-chitosan microparticulate cores in the presence of poly(ethylene) glycol (PEG) in the precipitating and coating solutions. The addition of PEG improved insulin loading and minimized an undesirable loss of the protein resulting from redissolution. Nanolayer encapsulation and the formation of complexes enabled a superior loading capacity of insulin (>90%), as well as enhanced stability and 74% decreased solubility at acid pH in vitro, compared with nonencapsulated insulin. The capsulated insulin administered by oral gavage lowered fasting blood glucose levels by up to 50% in a sustained and dose-dependent manner and reduced postprandial glycemia in streptozotocin-induced diabetic mice without causing hypoglycemia. Nanolayer encapsulation reduced the possibility of rapid and erratic falls of blood glucose levels in animals. This technique represents a promising strategy to promote the intestinal absorption efficiency and release behavior of the hormone, potentially enabling an efficient and safe route for oral insulin delivery of insulin in diabetes management.
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http://dx.doi.org/10.2147/IJN.S59075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014370PMC
December 2014

The evidence base for diabetes technology: appropriate and inappropriate meta-analysis.

Authors:
John C Pickup

J Diabetes Sci Technol 2013 Nov 1;7(6):1567-74. Epub 2013 Nov 1.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London SE1 1UL, United Kingdom.

When we are interested in making decisions about best use, comparative therapeutic efficacy, or cost-effectiveness of diabetes technologies such as insulin pump therapy [continuous subcutaneous insulin infusion (CSII)] or continuous glucose monitoring, meta-analysis for the purpose of literature summary is inappropriate and may be misleading. Instead, "decision-making meta-analysis" is more appropriate and should involve either preselection of trials based on intended use [e.g., elevated baseline hemoglobin A1c or hypoglycemia rate for trials of multiple daily injections (MDI) versus CSII] or metaregression of summary effect sizes in different trials against potential effect-modifying covariates such as baseline risk, or models of the covariates that determine effect size using individual patient data. Appropriate meta-analysis should also only include trials that are of sufficient duration to accurately measure outcomes such as severe hypoglycemia, and they should not use obsolete technology that is of proven inferiority to current technology. The use of appropriate decision-making meta-analysis is illustrated by the change in the rate ratio for severe hypoglycemia in randomized controlled trials of MDI versus CSII in type 1 diabetes from 1.56 (95% confidence interval 0.96-2.55; p = .074) for literature-summary meta-analysis to 2.0 (1.08-3.69; p = .027) for decision-making meta-analysis of all patients and 3.91 (1.35-11.36; p = .01) for trials in children.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876335PMC
http://dx.doi.org/10.1177/193229681300700617DOI Listing
November 2013

Nonmetabolic complications of continuous subcutaneous insulin infusion: a patient survey.

Diabetes Technol Ther 2014 Mar 1;16(3):145-9. Epub 2013 Nov 1.

1 Diabetes Research Group, King's College London School of Medicine , Guy's Hospital, London, United Kingdom .

Background: Little is known about the frequencies and types of nonmetabolic complications occurring in type 1 diabetes patients being treated by modern insulin pump therapy (continuous subcutaneous insulin infusion [CSII]), when recorded by standardized questionnaire rather than clinical experience.

Subjects And Methods: A self-report questionnaire was completed by successive subjects with type 1 diabetes attending an insulin pump clinic, and those with a duration of CSII of ≥6 months were selected for analysis (n=92). Questions included pump manufacturer, insulin, infusion set type and duration of use, frequency of infusion set and site problems, pump malfunctions, and patient-related problems such as weight change since starting CSII.

Results: Median (range) duration of CSII was 3.3 (0.5-32.0) years, and mean ± SD duration of infusion set use was 3.2 ± 0.7 (range 2-6) days. The commonest infusion set problems were kinking (64.1% of subjects) and blockage (54.3%). Blockage was associated with >3 days of use of infusion sets plus lispro insulin in the pump (relative risk [95% confidence interval], 1.71 [1.03-2.85]; P=0.07). The commonest infusion site problem was lipohypertrophy (26.1%), which occurred more often in those with long duration of CSII (4.8 [2.38-9.45] vs. 3.0 [1.50-4.25] years; P=0.01). Pump malfunction had occurred in 48% of subjects (43% in the first year of CSII), with "no delivery," keypad, and battery problems commonly occurring. Although some patients reported weight gain (34%) and some weight loss (15%) on CSII, most patients (51%) reported no change in weight.

Conclusions: Pump, infusion set, and infusion site problems remain common with CSII, even with contemporary technology.
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http://dx.doi.org/10.1089/dia.2013.0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934434PMC
March 2014

Real-time continuous glucose monitoring significantly reduces severe hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes.

Diabetes Care 2013 Dec 8;36(12):4160-2. Epub 2013 Oct 8.

Corresponding author: Pratik Choudhary,

Objective: To evaluate the effect of continuous glucose monitoring (CGM) on the frequency of severe hypoglycemia (SH) in patients with established hypoglycemia unawareness.

Research Design And Methods: We conducted a retrospective audit of 35 patients with type 1 diabetes and problematic hypoglycemia unawareness, despite optimized medical therapy (continuous subcutaneous insulin infusion/multiple daily insulin injections), who used CGM for >1 year.

Results: Over a 1-year follow-up period, the median rates of SH were reduced from 4.0 (interquartile range [IQR] 0.75-7.25) episodes/patient-year to 0.0 (0.0-1.25) episodes/patient-year (P < 0.001), and the mean (±SD) rates were reduced from 8.1 ± 13 to 0.6 ± 1.2 episodes/year (P = 0.005). HbA1c was reduced from 8.1 ± 1.2% to 7.6 ± 1.0% over the year (P = 0.005). The mean Gold score, measured in 19 patients, did not change: 5.1 ± 1.5 vs. 5.2 ± 1.9 (P = 0.67).

Conclusions: In a specialist experienced insulin pump center, in carefully selected patients, CGM reduced SH while improving HbA1c but failed to restore hypoglycemia awareness.
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http://dx.doi.org/10.2337/dc13-0939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836107PMC
December 2013

Near-infrared fluorescence glucose sensing based on glucose/galactose-binding protein coupled to 651-Blue Oxazine.

Biochem Biophys Res Commun 2013 Aug 6;438(3):488-92. Epub 2013 Aug 6.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London SE11UL, UK.

Near-infrared (NIR) fluorescent dyes that are environmentally sensitive or solvatochromic are useful tools for protein labelling in in vivo biosensor applications such as glucose monitoring in diabetes since their spectral properties are mostly independent of tissue autofluorescence and light scattering, and they offer potential for non-invasive analyte sensing. We showed that the fluorophore 651-Blue Oxazine is polarity-sensitive, with a marked reduction in NIR fluorescence on increasing solvent polarity. Mutants of glucose/galactose-binding protein (GBP) used as the glucose receptor were site-specifically and covalently labelled with Blue Oxazine using click chemistry. Mutants H152C/A213R and H152C/A213R/L238S showed fluorescence increases of 15% and 21% on addition of saturating glucose concentrations and binding constants of 6 and 25mM respectively. Fluorescence responses to glucose were preserved when GBP-Blue Oxazine was immobilised to agarose beads, and the beads were excited by NIR light through a mouse skin preparation studied in vitro. We conclude GBP-Blue Oxazine shows proof-of-concept as a non-invasive continuous glucose sensing system.
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http://dx.doi.org/10.1016/j.bbrc.2013.07.111DOI Listing
August 2013

Multilayered nanocoatings incorporating superparamagnetic nanoparticles for tracking of pancreatic islet transplants with magnetic resonance imaging.

Chem Commun (Camb) 2013 Aug 11;49(65):7255-7. Epub 2013 Jul 11.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital Campus, London SE1 1UL, UK.

A novel strategy for delivering functionalised superparamagnetic iron oxide nanoparticles to the outer surface of pancreatic islet grafts, using chemically modified polymeric nanolayers, has been developed for tracking of engrafted pancreatic islets by magnetic resonance imaging.
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http://dx.doi.org/10.1039/c3cc43512aDOI Listing
August 2013

Fluorescence intensity- and lifetime-based glucose sensing using glucose/galactose-binding protein.

J Diabetes Sci Technol 2013 Jan 1;7(1):62-71. Epub 2013 Jan 1.

Diabetes Research Group, King’s College London School of Medicine, Guy’s Hospital, London, United Kingdom.

We review progress in our laboratories toward developing in vivo glucose sensors for diabetes that are based on fluorescence labeling of glucose/galactose-binding protein. Measurement strategies have included both monitoring glucose-induced changes in fluorescence resonance energy transfer and labeling with the environmentally sensitive fluorophore, badan. Measuring fluorescence lifetime rather than intensity has particular potential advantages for in vivo sensing. A prototype fiber-optic-based glucose sensor using this technology is being tested.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692217PMC
http://dx.doi.org/10.1177/193229681300700108DOI Listing
January 2013

Multilayer nanoencapsulation: a nanomedicine technology for diabetes research and management.

Diabetes Res Clin Pract 2013 May 28;100(2):162-9. Epub 2012 Dec 28.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London SE1 1UL, UK.

Nanothickness encapsulation using a layer-by-layer technique has applications in several areas of diabetes research, including improved glucose sensors, islet cell transplantation and oral insulin delivery. We have fabricated microvesicles containing a fluorescence lifetime-based glucose sensing system, with bacterial glucose-binding protein as the glucose receptor. Such sensors are suitable for impregnation in the dermis as a 'smart tattoo' type of non-invasive glucose monitoring technology. Nanoencapsulation of islet cells is intended to alleviate the immediate blood-mediated inflammatory reaction which is responsible for early islet loss post-transplant. In an allogeneic diabetic mouse model, nanoencapsulated islets with phosporylcholine-modified polysaccharide coating, significantly extended survival of transplanted islets. In early studies aimed at formulating an effective oral insulin preparation, insulin-chitosan colloids coated with nanolayers of chitosan and heparin had enhanced acid stability and effectively lowered blood glucose in an animal model.
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http://dx.doi.org/10.1016/j.diabres.2012.11.027DOI Listing
May 2013

Insulin-pump therapy for type 1 diabetes mellitus.

Authors:
John C Pickup

N Engl J Med 2012 Apr;366(17):1616-24

Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London School of Medicine and Guy's Hospital, London, United Kingdom.

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http://dx.doi.org/10.1056/NEJMct1113948DOI Listing
April 2012

Improving cellular function and immune protection via layer-by-layer nanocoating of pancreatic islet β-cell spheroids cocultured with mesenchymal stem cells.

J Biomed Mater Res A 2012 Jun 23;100(6):1628-36. Epub 2012 Mar 23.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London SE1 1UL, United Kingdom.

Islet transplantation as a therapy for type 1 diabetes is currently limited by lack of primary transplant material from human donors and post-transplantation loss of islets caused by adverse immune and nonimmune reactions. This study aimed to develop a novel strategy to create microenvironment for islets via integration of nanoencapsulation with cell cocultures, thereby enhancing their survival and function. The nanoencapsulation was achieved via layer-by-layer deposition of phosphorycholine-modified poly-L-lysine/heparin leading to the formation of nanometer-thick multilayer coating on islets. Spheroids formed by coculturing MIN6 β-cells with mesenchymal stem cells in suspension were used as the tool for testing encapsulation. Coculturing MSCs with MIN6 cells allowed the cell constructs to enhance structural and morphologic stability with improved insulin secretory function and render them less susceptible to inflammatory cytokine-induced apoptosis. Combining nanoencapsulation with coculture of MSCs/MIN6 resulted in higher glucose responsiveness, and lower antibody binding and apoptosis-inducing effects of cytokines. This strategy of nanoencapsulating islet cocultures appears promising to improve cellular delivery of insulin for treating type 1 diabetes.
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http://dx.doi.org/10.1002/jbm.a.34111DOI Listing
June 2012

Management of diabetes mellitus: is the pump mightier than the pen?

Authors:
John C Pickup

Nat Rev Endocrinol 2012 Feb 28;8(7):425-33. Epub 2012 Feb 28.

Diabetes Research Group, King's College London School of Medicine, Guy's Hospital, London SE1 1UL, UK.

Continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) reduces HbA1c levels and hypoglycaemia in patients with type 1 diabetes mellitus (T1DM) compared with multiple daily insulin injections (MDI). The greatest reduction in HbA(1c) levels with CSII occurs in patients with the worst glycaemic control; therefore, the most appropriate and cost-effective use of CSII in adults with T1DM is in those who have continued, elevated HbA(1c) levels or disabling hypoglycaemic episodes with MDI (including the use of long-acting insulin analogues and structured patient education). The disadvantages of CSII include higher costs than MDI and the risk of ketosis in the event of pump failure. In children with T1DM, CSII may be used when MDI is considered impractical or inappropriate. Pumps are not generally recommended for patients with type 2 diabetes mellitus but may improve control in some subgroups. A new generation of smaller insulin infusion pumps with an integrated cannula, called patch pumps, could improve uptake of CSII in general. The important clinical question is not whether CSII is more efficacious than MDI in general adult T1DM, but whether CSII further improves glycaemic control when this control continues to be poor with MDI, and evidence exists that in most cases it does.
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http://dx.doi.org/10.1038/nrendo.2012.28DOI Listing
February 2012

Insulin pumps.

Authors:
John C Pickup

Int J Clin Pract Suppl 2012 Feb(175):15-9

King's College London School of Medicine, Guy's Hospital, London, UK.

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http://dx.doi.org/10.1111/j.1742-1241.2011.02849.xDOI Listing
February 2012

Insulin pump therapy with automated insulin suspension in response to hypoglycemia: reduction in nocturnal hypoglycemia in those at greatest risk.

Diabetes Care 2011 Sep;34(9):2023-5

Department of Diabetes, King's College London School of Medicine, London, UK.

Objective: To evaluate a sensor-augmented insulin pump with a low glucose suspend (LGS) feature that automatically suspends basal insulin delivery for up to 2 h in response to sensor-detected hypoglycemia.

Research Design And Methods: The LGS feature of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA) was tested for 3 weeks in 31 adults with type 1 diabetes.

Results: There were 166 episodes of LGS: 66% of daytime LGS episodes were terminated within 10 min, and 20 episodes lasted the maximum 2 h. LGS use was associated with reduced nocturnal duration ≤2.2 mmol/L in those in the highest quartile of nocturnal hypoglycemia at baseline (median 46.2 vs. 1.8 min/day, P = 0.02 [LGS-OFF vs. LGS-ON]). Median sensor glucose was 3.9 mmol/L after 2-h LGS and 8.2 mmol/L at 2 h after basal restart.

Conclusions: Use of an insulin pump with LGS was associated with reduced nocturnal hypoglycemia in those at greatest risk and was well accepted by patients.
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http://dx.doi.org/10.2337/dc10-2411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161284PMC
September 2011

Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data.

BMJ 2011 Jul 7;343:d3805. Epub 2011 Jul 7.

Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London School of Medicine, Guy's Hospital, London SE1 1UL, UK.

Objective: To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes.

Design: Meta-analysis of randomised controlled trials.

Data Sources: Cochrane database for randomised controlled trials, Ovid Medline, Embase, Google Scholar, lists of papers supplied by manufacturers of continuous glucose monitors, and cited literature in retrieved articles. Studies reviewed Randomised controlled trials of two or more months' duration in men and non-pregnant women with type 1 diabetes that compared real time continuous glucose monitoring with self monitoring of blood glucose and where insulin delivery was the same in both arms. Analysis Two step meta-analysis of individual patient data with the primary outcome of final glycated haemoglobin (HbA(1c)) percentage and area under the curve of hypoglycaemia (glucose concentration <3.9 mmol/L) during either treatment, followed by one step metaregression exploring patient level determinants of HbA(1c) and hypoglycaemia.

Results: Six trials were identified, consisting of 449 patients randomised to continuous glucose monitoring and 443 to self monitoring of blood glucose. The overall mean difference in HbA(1c) for continuous glucose monitoring versus self monitoring of blood glucose was -0.30% (95% confidence interval -0.43% to -0.17%) (-3.0, -4.3 to -1.7 mmol/mol). A best fit regression model of determinants of final HbA(1c) showed that for every one day increase of sensor usage per week the effect of continuous glucose monitoring versus self monitoring of blood glucose increased by 0.150% (95% credibility interval -0.194% to -0.106%) (1.5, -1.9 to -1.1 mmol/mol) and every 1% (10 mmol/mol) increase in baseline HbA(1c) increased the effect by 0.126% (-0.257% to 0.0007%) (1.3, -2.6 to 0.0 mmol/mol). The model estimates that, for example, a patient using the sensor continuously would experience a reduction in HbA(1c) of about 0.9% (9 mmol/mol) when the baseline HbA(1c) is 10% (86 mmol/mol). The overall reduction in area under the curve of hypoglycaemia was -0.28 (-0.46 to -0.09), corresponding to a reduction in median exposure to hypoglycaemia of 23% for continuous glucose monitoring compared with self monitoring of blood glucose. In a best fit regression model, baseline area under the curve of hypoglycaemia was only weakly related to the effect of continuous glucose monitoring compared with self monitoring of blood glucose on hypoglycaemia outcome, and sensor usage was unrelated to hypoglycaemia at outcome.

Conclusions: Continuous glucose monitoring was associated with a significant reduction in HbA(1c) percentage, which was greatest in those with the highest HbA(1c) at baseline and who most frequently used the sensors. Exposure to hypoglycaemia was also reduced during continuous glucose monitoring. The most cost effective or appropriate use of continuous glucose monitoring is likely to be when targeted at people with type 1 diabetes who have continued poor control during intensified insulin therapy and who frequently use continuous glucose monitoring.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131116PMC
http://dx.doi.org/10.1136/bmj.d3805DOI Listing
July 2011
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