A modelling study of the budget impact of improved glycaemic control in adults with Type 1 diabetes in the UK.

AIMS: To develop a novel interactive budget impact model that assesses affordability of diabetes treatments in specific populations, and to test the model in a hypothetical scenario by estimating cost savings resulting from reduction in HbA1c from ≥69 mmol/mol (8.5%) to a target of 53 mmol/mol (7.0%) in adults with Type 1 diabetes in the UK. METHODS: A dynamic, interactive model was created using the projected incidence and progression over a 5-year horizon of diabetes-related complications (micro- and macrovascular disease, severe hypoglycaemia and diabetic ketoacidosis) for different HbA1c levels, with flexible input of population size, complications and therapy costs, HbA1c distribution and other variables. The model took a National Health Service and societal perspective. RESULTS: The model was developed, and in the proposed hypothetical situation, reductions in complications and expected costs evaluated. Achievement of target HbA1c in individuals with HbA1c ≥69 mmol/mol (8.5%) would reduce expected chronic complications from 6.8 to 1.2 events per 100 person-years, and diabetic ketoacidosis from 14.5 to 1.0 events per 100 person-years. Potential cumulative direct cost savings achievable in the modelled population were estimated at £687 m over 5 years (£5,585/person), with total (direct and indirect) savings of £1,034 m (£8,400/person). CONCLUSIONS: Implementation of strategies aimed at achieving target glucose levels in people with Type 1 diabetes in the UK has the potential to drive a significant reduction in complication costs. This estimate may provide insights into the potential for investment in achieving savings through improved diabetes care in the UK.

Is insulin pump therapy effective in Type 1 diabetes?

There continues to be uncertainty about the effectiveness in Type 1 diabetes of insulin pump therapy (continuous subcutaneous insulin infusion, CSII) vs. multiple daily insulin injections (MDI). This narrative review discusses the reasons for this uncertainty, summarizes the current evidence base for CSII and suggests some future research needs. There are difficulties in interpreting trials of CSII because effectiveness varies widely due to factors such as differing baseline control, suboptimal use of best CSII practices, and psychological factors, for example, high external locus of control, non-adherence and lack of motivation. Many summary meta-analyses are also misleading because of poor trial selection (e.g. short duration, obsolete pumps, low baseline rate of hypoglycaemia) and reliance on mean effect size for decision-making. Both MDI and CSII can achieve strict glycaemic control without hypoglycaemia in some people with Type 1 diabetes, especially those who are motivated and have undergone structured diabetes education, and with high levels of ongoing input from healthcare professionals. CSII is particularly effective in those people with Type 1 diabetes who have not achieved target HbA1c levels without disabling hypoglycaemia using best attempts with MDI, and here there can be valuable and substantial improvement. Insulin pumps are safe, effective and accepted when used in newly diagnosed diabetes, particularly in children, where MDI may not be practicable. Future research needs include more studies on mortality associated with insulin pumps where registry data have suggested lower rates vs. MDI; and psychological strategies to improve non-adherence and suboptimal glycaemic outcomes on CSII.

Investigating incretin-based therapies as a novel treatment for depression in type 2 diabetes: Findings from the South London Diabetes (SOUL-D) Study.

We aimed to investigate the association between incretin-based therapies and 1-year change in depressive symptoms in a cohort of 1735 patients with newly diagnosed type 2 diabetes. The incretin group experienced significant reduction in depressive symptoms compared to controls. This was independent of HbA1c and may be mediated by an anti-inflammatory mechanism.

Cost-effectiveness of continuous subcutaneous insulin infusion versus multiple daily injections of insulin in Type 1 diabetes: a systematic review.

AIM: Continuous subcutaneous insulin infusion (CSII) is increasingly used in clinical practice for the management of selected patients with Type 1 diabetes. Several cost-effectiveness studies comparing CSII vs. multiple insulin injections (MDI) have been reported. The aim was systematically to review these analyses and test the hypothesis that CSII is a cost-effective use of healthcare resources across settings. METHODS: A literature review was performed using MEDLINE, Cochrane Library and other databases. No time limit or language restrictions were applied. After two rounds of screening, 11 cost-effectiveness analyses were included in the final review, of which nine used the CORE Diabetes Model. A narrative synthesis was conducted and mean cost effectiveness calculated. RESULTS: CSII was considered cost-effective vs. MDI in Type 1 diabetes in all 11 studies in 8 countries, with a mean (95% CI) incremental cost effectiveness ratio of €30 862 (17 997-43 727), US$40 143 (23 409-56 876) per quality-adjusted life year (QALY) gained. CSII was associated with improved life expectancy and quality-adjusted life expectancy (0.4-1.1 QALYs in adults), driven by lower HbA(1c) and lower frequency of hypoglycaemic events vs. MDI. CSII was associated with higher lifetime direct costs due to higher treatment costs but this was partially offset by cost-savings from reduced diabetes-related complications. CONCLUSIONS: Published cost-effectiveness analyses show that in Type 1 diabetes CSII is cost-effective vs. MDI across a number of settings for patients who have poor glycaemic control and/or problematic hypoglycaemia on MDI, with cost-effectiveness highly sensitive to the reduction in HbA1c and hypoglycaemia frequency associated with CSII.

Banting Memorial Lecture 2014* Technology and diabetes care: appropriate and personalized.

Continuous subcutaneous insulin infusion was initially developed as a research procedure in the 1970s but quickly became a routine treatment for selected people with Type 1 diabetes. Continuous subcutaneous insulin infusion and other diabetes technologies, such as continuous glucose monitoring, are now an established and evidence-based part of diabetes care, but there has been some confusion about effectiveness and best use, particularly because of conflicting results from meta-analyses. This is because literature summary meta-analyses (including all trials) are inappropriate for therapeutic and economic decision-making; such meta-analyses should only include trials representative of groups likely to benefit. For example, for continuous subcutaneous insulin infusion, this would be those with continued disabling hypoglycaemia or elevated HbA1c levels. Alternatively, individual patient data meta-analysis allows modelling of covariates that determine effect size, e.g. in the case of continuous glucose monitoring, baseline HbA1c and frequency of sensor usage. Diabetes technology is therefore an example of personalized medicine, where evaluation and use should be both appropriate and targeted. This will also apply to future technologies such as new 'patch' pumps for Type 2 diabetes, closed-loop insulin delivery systems and nanomedicine applications in diabetes that we are currently researching. These include fluorescence lifetime-based non-invasive glucose monitoring and nanoencapsulation of islets for improved post-transplant survival.

Variations in the quality and sustainability of long-term glycaemic control with continuous subcutaneous insulin infusion.

AIMS: To investigate the pattern of changes in HbA1c in people with Type 1 diabetes managed by long-term Continuous subcutaneous insulin infusion. METHODS: We studied HbA1c changes using computerized clinic records in 35 adult people with Type 1 diabetes and an elevated HbA1c (≥ 64 mmol/mol, 8.0%) on multiple daily insulin injections, who were then switched to continuous subcutaneous insulin infusion for at least 5 years. RESULTS: We identified three subgroups with similar baseline HbA1c but different long-term responses to pump therapy: group A--those with improvement followed by deterioration (57%); group B--those with improvement that was sustained throughout the 5 years (31%); and group C-those where HbA1c did not change significantly from baseline (12%). The patients in group C had a higher BMI: 31.0 ± 5.2 vs. 25.9 ± 3.3 vs. 25.2 ± 3.1 kg/m² (group C vs. group A and group B; P = 0.02). CONCLUSIONS: Improved glycaemic control with continuous subcutaneous insulin infusion was maintained over 5 years by 88% of people with Type 1 diabetes in this study, but there were variations in the long-term efficacy, with some people improving and worsening, others maintaining strict control and a few subcutaneous insulin infusion 'non-responders'.

Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes.

AIMS/HYPOTHESIS: The success of islet transplantation as a treatment for type 1 diabetes is currently hampered by post-transplantation loss of functional islets through adverse immune and non-immune reactions. We aimed to test whether early islet loss can be limited and transplant survival improved by the application of conformal nano-coating layers to islets. METHODS: Our novel coating protocol used alternate layers of phosphorylcholine-derived polysaccharides (chitosan or chondroitin-4-sulphate) and alginate as coating materials, with the binding based on electrostatic complexation. The in vitro function of encapsulated mouse islets was studied by analysing islet secretory function and cell viability. The in vivo function was evaluated using syngeneic and allogeneic transplantation in the streptozotocin-induced mouse model of diabetes. RESULTS: Nano-scale encapsulated islets retained appropriate islet secretory function in vitro and were less susceptible to complement- and cytokine-induced apoptosis than non-encapsulated control islets. In in vivo experiments using a syngeneic mouse transplantation model, no deleterious responses to the coatings were observed in host animals, and the encapsulated islet grafts were effective in reversing hyperglycaemia. Allo-transplantation of the nano-coated islets resulted in preserved islet function post-implantation in five of seven mice throughout the 1 month monitoring period. CONCLUSIONS/INTERPRETATION: Nano-scale encapsulation offers localised immune protection for implanted islets, and may be able to limit early allograft loss and extend survival of transplanted islets. This versatile coating scheme has the potential to be integrated with tolerance induction mechanisms, thereby achieving long-term success in islet transplantation.

Innate immunity, insulin resistance and type 2 diabetes.

In this edition of 'Then and now' the initial studies by J.C. Pickup and colleagues supporting the hypothesis that type 2 diabetes is caused by activated innate immunity, published in Diabetologia in 1997 (40:1286-1292), are discussed. These initial findings led to research that has uncovered links between insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to the altered production or function of circulating innate immune proteins, cellular pattern recognition receptors and inflammatory cytokines are linked to obesity, insulin resistance and type 2 diabetes. Components of the innate immune system in the muscle, bone, liver and adipose tissue, as well as macrophages, have been revealed to play a role in systemic insulin action. Evolutionary pressures, such as acute infections at the population level (pandemics) and chronic low exposure to environmental products or infectious agents, may have contributed to increased susceptibility and to the current increase in the prevalence of insulin resistance and type 2 diabetes.

Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion.

AIMS: Continuous subcutaneous insulin infusion (CSII) is a recommended treatment for reducing severe hypoglycaemia in Type 1 diabetes, but the change in hypoglycaemia compared with multiple daily insulin injections (MDI) is unclear. We therefore conducted a meta-analysis comparing severe hypoglycaemia and glycaemic control during CSII and MDI. METHODS: Databases and literature (1996-2006) were searched for randomized controlled trials (RCTs) and before/after studies of > or = 6 months' duration CSII and with severe hypoglycaemia frequency > 10 episodes/100 patient years on MDI. RESULTS: In 22 studies (21 reports), severe hypoglycaemia during MDI was related to diabetes duration (P = 0.038) and was greater in adults than children (100 vs. 36 events/100 patient years, P = 0.036). Severe hypoglycaemia was reduced during CSII compared with MDI, with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs and 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19 (2.86 to 6.13) for all studies]. The reduction was greatest in those with the highest initial severe hypoglycaemia rates on MDI (P < 0.001). The mean difference in glycated haemoglobin (HbA(1c)) between treatments was less for RCTs [0.21% (0.13-0.30%)] than in before/after studies [0.72% (0.55-0.90%)] but strongly related to the initial HbA(1c) on MDI (P < 0.001). CONCLUSIONS: The severe hypoglycaemia rate in Type 1 diabetes was markedly less during CSII than MDI, with the greatest reduction in those with most severe hypoglycaemia on MDI and those with the longest duration of diabetes. The biggest improvement in HbA(1c) was in those with the highest HbA(1c) on MDI.

Relationship between plasma sialic acid and fibrinogen concentration and incident micro- and macrovascular complications in type 1 diabetes. The EURODIAB Prospective Complications Study (PCS).

AIMS/HYPOTHESIS: Type 1 diabetes is associated with an increased risk of vascular complications. This increased risk could be explained by sialic acid and/or fibrinogen. It is also not clear what explains the abolition of sex-related differences affecting risk of CHD in the presence of type 1 diabetes. Therefore, we examined whether fibrinogen and sialic acid are related to incident micro- and macrovascular complications in patients with type 1 diabetes. METHODS: A subset (n=2329) of the EURODIAB Prospective Complications Study was analysed. Sialic acid and fibrinogen concentrations were measured at baseline. The main outcomes after 7 years were development of albuminuria, retinopathy, neuropathy and CHD. RESULTS: Univariable and multivariable models using Cox proportional survival analyses showed that an SD unit increase in sialic acid and fibrinogen levels was significantly associated with CHD in men only. Adjusted standardised hazard ratios (sHRs) were 1.50 (95% CI 1.05-2.15) and 1.40 (95% CI 1.06-1.86) for sialic acid and fibrinogen, respectively. Initial associations between (1) sialic acid and incident retinopathy [standardised odds ratio (sOR) men 1.68, 95% CI 1.10-2.57], (2) fibrinogen and retinopathy (sOR women 1.37, 95% CI 1.06-1.78) and (3) sialic acid and neuropathy (sOR men 1.37, 95% CI 1.06-1.77) were shown, but became non-significant in multivariable models. CONCLUSIONS/INTERPRETATION: Sialic acid and fibrinogen are strong predictors of CHD in men with type 1 diabetes, beyond the effect of established risk factors. The associations found with microvascular complications were not independent of other risk factors.

Glucose-dependent changes in NAD(P)H-related fluorescence lifetime of adipocytes and fibroblasts in vitro: potential for non-invasive glucose sensing in diabetes mellitus.

The aim of this study was to test the hypothesis that glucose can be monitored non-invasively by measuring NAD(P)H-related fluorescence lifetime of cells in an in vitro cell culture model. Autofluorescence decay functions were measured in 3T3-L1 adipocytes by time-correlated single-photon counting (excitation 370nm, emission 420-480nm). Free NADH had a two-exponential decay but cell autofluorescence fitted best to a three-exponential decay. Addition of 30mM glucose caused a 29% increase in autofluorescence intensity, a significantly shortened mean lifetime (from 7.23 to 6.73ns), and an increase in the relative amplitude and fractional intensity of the short-lifetime component at the expense of the two longer-lifetime components. Similar effects were seen with rotenone, an agent that maximizes mitochondrial NADH. 3T3-L1 fibroblasts stained with the fluorescent mitochondrial marker, rhodamine 123 showed a 16% quenching of fluorescence intensity when exposed to 30mM glucose, and an increase in the relative amplitude and fractional intensity of the short lifetime at the expense of the longer lifetime component. We conclude that, though the effect size is relatively small, glucose can be measured non-invasively in cells by monitoring changes in the lifetimes of cell autofluorescence or of a dye marker of mitochondrial metabolism. Further investigation and development of fluorescence intensity and lifetime sensing is therefore indicated for possible non-invasive metabolic monitoring in human diabetes.

Performance assessment of the Medtronic-MiniMed Continuous Glucose Monitoring System and its use for measurement of glycaemic control in Type 1 diabetic subjects.

AIMS: To assess the accuracy, reliability and measurement of glycaemic control associated with the Medtronic-MiniMed Continuous Glucose Monitoring System (CGMS) in comparison with blood glucose self-monitoring (BGSM) in Type 1 diabetic patients. METHODS: Type 1 diabetic patients (n = 18) underwent glucose monitoring by the CGMS for up to 3 days, when control was also assessed by BGSM performed eight times daily. RESULTS: Ninety-five per cent of paired non calibration samples were in the clinically acceptable zones of the Clarke error grid, and 97% in a consensus grid. The median bias was 0.1 mmol/l and relative bias 15%. The failure rate of sensors was 28% of those initially inserted. The CGMS detected significantly more hypoglycaemia and post-prandial hyperglycaemia, but total duration of hyperglycaemia, blood glucose oscillations and day-to-day variability were similarly assessed by CGMS and BGSM. CONCLUSIONS: The CGMS has acceptable clinical accuracy. Detection by the CGMS of more hypoglycaemia and post-prandial hyperglycaemia than BGSM promises a valuable tool for control assessment and optimization of treatment.

Activation of the innate immune system as a predictor of cardiovascular mortality in Type 2 diabetes mellitus.

AIMS: Activation of innate immunity may play a major role in the development and pathophysiology of Type 2 diabetes; we therefore investigated whether a marker of innate immunity (serum sialic acid) predicts cardiovascular disease (CVD) and all-cause mortality in Type 2 diabetes. METHODS: Type 2 diabetic subjects (n=128, age 31-64 years at outset) participating in the Lewisham Diabetes Survey were followed up for a mean of 12.8 years. Baseline measurements were made of serum sialic acid and known or putative risk factors for CVD. Cause of death was coded from death certificates, post mortem examination and hospital records. RESULTS: Fifty-six (43%) subjects had died after 12.8 years. The major cause of death was CVD (71.4%), predominantly coronary heart disease (62.5%). Baseline variables significantly associated with CVD mortality were sialic acid and CVD (borderline significance smoking and cholesterol). In multivariate analysis, significant independent predictors of CVD mortality were sialic acid [standardized relative risk (95% confidence interval) 1.53 (1.12, 2.10)], age, male sex and existing CVD. CONCLUSIONS: Activated innate immunity (low-grade inflammation) is a risk factor for CVD mortality in Type 2 diabetes, independently of other known risk factors, including existing CVD. Since activation of the innate immune system predicts Type 2 diabetes, it may be a common antecedent of both Type 2 diabetes and CVD.

Fluorescence nanotomography using resonance energy transfer: demonstration with a protein-sugar complex.

A new approach to structural sensing, fluorescence resonance energy transfer nanotomography, which interprets fluorescence decay measurement in terms of site density analysis of molecular distributions, has been applied to a glucose sensor based on competitive binding with malachite green labelled dextran to the sugar binding protein concanavalin A labelled with allophycocyanin. Opportunities for structural sensing in clinical medicine are highlighted.

Molecular distribution sensing in a fluorescence resonance energy transfer based affinity assay for glucose.

A newly developed method for determining molecular distribution functions is applied to a widely researched glucose affinity sensor. The reduction in fluorescence resonance energy transfer (FRET) to a malachite green (MG)-dextran complex from allophycocyanin (APC) bound to concanavalin A (ConA) due to displacement of the complex by glucose from ConA provides the basis of the assay. The higher sensitivity and specificity of a new approach to fluorescence decay analysis, over the methods based on conventional Forster-type models, is demonstrated and critical parameters in competitive binding FRET sensing derived.

Near-infrared fluorescence lifetime assay for serum glucose based on allophycocyanin-labeled concanavalin A.

We describe an assay scheme for glucose based on fluorescence resonance energy transfer (FRET) between concanavalin A (con A), labeled with the near-infrared fluorescent protein allophycocyanin (APC) as donor, and dextran labeled with malachite green (MG) as acceptor. Glucose competitively displaces dextran-MG and leads to reduction in FRET, assessed by time-domain fluorescence lifetime measurements using time-correlated single-photon counting. The assay is operative in the glucose concentration range 2.5-30 mM, and therefore suitable for use in monitoring diabetes control. Albumin and serum inhibit FRET but the interference can be prevented by removal of high molecular weight substances by membrane filters. APC shows promise for incorporation in an implanted glucose sensor which can be interrogated from outside the body.

Relationship between plasma sialic acid concentration and microvascular and macrovascular complications in type 1 diabetes: the EURODIAB Complications Study.

OBJECTIVE: To test the hypothesis that an increased plasma concentration of sialic acid, a marker of the acute-phase response, is related to the presence of diabetic micro- and macrovascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS: We investigated the relationship between plasma sialic acid concentration and nephropathy, retinopathy, neuropathy, and coronary heart disease (CHD) in a cross-sectional survey of 1,369 people with type 1 diabetes. Subjects were participants in the EURODIAB IDDM Complications Study, which involved 31 centers in 16 European countries. RESULTS: There was a significantly increasing trend of plasma sialic acid with severity of retinopathy (P < 0.001 in men) and with degree of urinary albumin excretion (P < 0.001 men, P < 0.01 women). Plasma sialic acid correlated with increasing plasma creatinine concentration (P < 0.009 men, P < 0.0002 women), and men with neuropathy had a higher plasma sialic acid concentration than those without (P < 0.006). There was no significant correlation between plasma sialic acid and CHD in either sex. Elevated plasma sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, plasma triglyceride and cholesterol concentrations, waist-to-hip ratio, hypertension and smoking (in men), and low physical exercise (in women). In multiple logistic regression analysis, plasma sialic acid was independently related to proliferative retinopathy and urinary albumin excretion rate in men. CONCLUSIONS: We conclude that an elevated plasma sialic concentration is strongly related to the presence of microvascular complications in type 1 diabetes, especially retinopathy and nephropathy. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified.

Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes.

Type 2 diabetes is associated with increased circulating concentrations of markers of the acute-phase response and interleukin-6 (IL-6). An augmented acute-phase response may be a mechanism which explains many of the clinical and biochemical features of type 2 diabetes and its complications. We sought to confirm that circulating concentrations of the cytokine acute-phase mediators IL-6 and tumour necrosis factor alpha [TNFalpha] are elevated in type 2 diabetes, and investigated blood as a source of cytokines in type 2 diabetes. Blood samples from 20 type 2 diabetic and 17 age-matched healthy subjects were incubated in vitro for 24 hr with and without lipopolysaccharide (LPS) stimulation and secreted cytokines measured. Plasma IL-6 and TNFalpha were significantly increased in type 2 diabetes compared to normal subjects. However, basal production of IL-6 and TNFalpha in cultured diabetic blood was markedly depressed in comparison with non-diabetic samples. IL-6 and TNFalpha production was increased in blood in response to LPS, reaching similar levels in diabetic and non-diabetic subjects, though IL-6 was slightly but significantly higher in controls. We conclude that circulating levels of IL-6 and TNFalpha are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells in type 2 diabetes. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFalpha concentrations may be from non-circulating cells.

A time-resolved near-infrared fluorescence assay for glucose: opportunities for trans-dermal sensing.

We report a time-resolved near-infrared fluorescence assay for glucose detection that incorporates pulsed diode laser excitation. Reduction in fluorescence resonance energy transfer to a malachite green-Dextran complex from allophycocyanin bound to concanavalin A (ConA) due to displacement of the complex by glucose from ConA provides the basis of the assay. The fluorescence quenching kinetics are analysed and discussed in detail. The change in fluorescence decay kinetics in the presence of glucose is found from dimensionality studies to be brought about by a change in the distribution of malachite green-Dextran acceptors. Glucose concentrations are measured in solution to within +/- 10% over the range 0-30 mM.