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The treatment aims for type 2 diabetes are to prevent complications and premature mortality, and improve quality of life. Glycaemic control is central to these aims; clinical guidelines have sought to achieve this with a stepwise approach starting with lifestyle measures and metformin, adding further medications once glycated haemoglobin (HbA1c) levels rise above a predefined threshold. However, treatment intensification can be delayed when HbA1c levels increase, and HbA1c levels become inadequately controlled in many patients. Clinical inertia can result in sustained elevated levels of HbA1c; when combined with a late diagnosis, this negatively impacts patients’ prognosis. Early combination therapy using medications with complementary modes of action could achieve optimal glycaemic targets and alter the course of the disease more than metformin alone. The multinational VERIFY study (clinicaltrials.gov NCT01528254) provided evidence accrued over 5 years, demonstrating the potential of early combination therapy: time to loss of glycaemic control was nearly doubled, and more than twice the number of patients experienced extended glycaemic control, with a vildagliptin–metformin combination therapy versus metformin alone. The study also showed a delay in secondary treatment failure in patients receiving the combination. Early combination therapy therefore offers a different trajectory to the stepwise approach. Translating these findings into clinical practice will require early detection and diagnosis of type 2 diabetes plus a shift in disease management. Nonetheless, the potential benefits of sustained and continuous disease control that early combination therapy offers represent the start of a new era in early diagnosis and intensive management, to achieve the treatment aims of type 2 diabetes., Plain Language Summary Blood glucose progressively increases over time in type 2 diabetes and is currently treated in a stepwise fashion, with more medications added when a single treatment fails. The VERIFY trial studied people with newly or recently diagnosed type 2 diabetes. Treating people early with two glucose-lowering drugs given together could slow the worsening of blood glucose levels, compared with starting with metformin first and then adding a second treatment later. Taking the two treatments together was as well tolerated as taking the single treatment alone. Starting treatment with two glucose-lowering drugs given together lengthened the time before insulin was needed, compared with starting with metformin and then adding a second treatment later. This is important to people with diabetes, as early treatment is straightforward but becomes increasingly complicated in later stages. The long-term benefits of this early combination treatment are awaited. In the meantime, the VERIFY trial has shown that combination therapy given at the start of treatment with medication can improve blood glucose levels and delay the need for insulin.

Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.

Type 2 diabetes mellitus (T2DM) is a complex and progressive chronic disease characterised by elevating hyperglycaemia and as-sociated need to gradually intensify therapy in order to achieve and maintain glycaemic control. Treating hyperglycaemia with se-quential therapy is proposed to allow holistic assessment of the efficacy and risk-to-benefit ratio of each added component. How-ever, there is an array of evidence supporting the scientific rationale for using synergistic, earlier, modern drug combinations to achieve glycaemic goals, delay the deterioration of glycaemic control, and, therefore, potentially preserve or slow down the declin-ing β-cell function. Additionally, implementation of early combination(s) may lead to opportunities to combat clinical inertia and other hurdles to optimised disease management outcomes. This review aims to discuss the latest empirical evidence for long-term clinical benefits of this novel strategy of early combination in people with newly diagnosed T2DM versus the current widely-im-plemented treatment paradigm, which focuses on control of hyperglycaemia using lifestyle interventions followed by sequentially intensified (mostly metformin-based) monotherapy. The recent reported Vildagliptin Efficacy in combination with metfoRmin For earlY treatment of T2DM (VERIFY) study results have provided significant new evidence confirming long-term glycaemic durability and tolerability of a specific early combination in the management of newly diagnosed, treatment-naïve patients world-wide. These results have also contributed to changes in clinical treatment guidelines and standards of care while clinical imple-mentation and individualised treatment decisions based on VERIFY results might face barriers beyond the existing scientific evi-dence.

AIMS To study the association between dietary intake and glycaemia in Type 1 diabetes. METHODS Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution. RESULTS In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (β = -0.428, 95% CI -0.624 to -0.231; P

Sepsis induces profound neuroendocrine and metabolic alterations. During the acute phase, the neuroendocrine changes are directed toward restoration of homeostasis, and also limit unnecessary energy consumption in the setting of restricted nutrient availability. Such changes are probably adaptive. In patients not recovering quickly, a prolonged critically ill phase may ensue, with different neuroendocrine changes, which may represent a maladaptive response. Whether stress hyperglycemia should be aggressively treated or tolerated remains a matter of debate. Until new evidence from randomized controlled trials becomes available, preventing severe hyperglycemia is recommended. Evidence supports withholding parenteral nutrition in the acute phase of sepsis. ispartof: Critical Care Clinics vol:34 issue:1 pages:81-96 ispartof: location:United States status: published

Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes. (C) 2016 Mayo Foundation for Medical Education and Research.

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients.

Background: To evaluate the efficacy of a run-to-run (R2R) adaptive wearable artificial pancreas (AP) after 1 month of closed-loop glucose control in subjects with type 1 diabetes (T1D) under free-living conditions. Methods: Eighteen adults, who had previously completed a 1-month closed-loop study with a non-adaptive artificial pancreas (NA-AP), volunteered for an additional 1-month extension study in which the AP was equipped with an adaptive model predictive control algorithm (R2R-AP). Continuous glucose monitoring data were analyzed on an intention-to-treat basis by comparing the last week of R2R-AP versus the last week of NA-AP. The primary endpoint was the time in target range (3.9-10mmol/L) over 24h. Results: Time in target with R2R-AP is higher than with the NA-AP, although the increase was not significant: mean 66.90% (standard deviation: 13.34) versus 61.82% (11.12), P=0.10. The increase was significant during the night: 74.01% (14.61) versus 64.31% (15.71), P=0.03, and at wake-up time: median 92.43% (25th; 75th percentiles: 78.22; 99.53) versus 84.54% (57.14; 88.52), P=0.02. Time above target (>10mmol/L) during the whole day was 30.98% (13.22) versus 36.17% (11.53), P=0.10. The decrease was significant during the night: 24.23% (15.03) versus 34.49% (16.25), P=0.03, and at wake-up time: 7.57% (0.00; 14.29) versus 14.29% (8.25; 42.86), P=0.05. Time spent below target (

Dietary proteins have an insulinotropic effect and thus promote insulin secretion, which indeed leads to enhanced glucose clearance from the blood. In the long term, however, a high dietary protein intake is associated with an increased risk of type 2 diabetes. Moreover, branched-chain amino acids (BCAA), a prominent group of amino acids, were recently identified to be associated with diabetes. Observational data and intervention studies do not point in the same direction regarding the effect of protein intake on insulin sensitivity and diabetes risk. Therefore, the first aim of this review will be to discuss human studies addressing high dietary protein intake and insulin action, with special attention for BCAA. In the second part, we will highlight the (patho) physiological consequences of high-protein diets regarding insulin action, in particular the role of the mechanistic target of the rapamycin pathway.

Diabetes and heart failure are very prevalent, and affect each other's incidence and severity. Novel therapies to reduce post-myocardial infarction (MI) remodeling that progresses into heart failure are urgently needed, especially in diabetic patients. Clinical studies have suggested that some oral anti-diabetic agents like metformin exert cardiovascular protective effects in heart failure patients with diabetes, whereas other agents may be deleterious. In the current review, we provide an overview of the cardio-specific effects of oral anti-diabetic drugs in animal models of acute MI, post-MI remodeling, and heart failure. Metformin has consistently been shown to ameliorate cardiac remodeling after ischemia/reperfusion (I/R) injury, as well as in several models of heart failure. Sulfonylurea derivatives are controversial with respect to their direct effects on the cardiovascular system. Thiazolidinediones protect against myocardial I/R injury, but their effects on post-MI remodeling are less clear and clinical studies raised concerns about their cardiovascular safety. Glucagon-like peptide-1 analogs have potential beneficial effects on the cardiovascular system that require further confirmation, whereas the results with dipeptidyl peptidase-4 inhibitors are equivocal. Current clinical guidelines, in the absence of prospective clinical trials that evaluated if certain oral anti-diabetic agents are superior over others, only provide generic recommendations, and do not take into account interesting experimental and mechanistic data. The available experimental evidence indicates that some anti-diabetic agents should be preferred over others if cardio-protective effects are warranted. These experimental clues need to be confirmed by clinical trials. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Diabetes and heart failure are very prevalent, and affect each other's incidence and severity. Novel therapies to reduce post-myocardial infarction (MI) remodeling that progresses into heart failure are urgently needed, especially in diabetic patients. Clinical studies have suggested that some oral anti-diabetic agents like metformin exert cardiovascular protective effects in heart failure patients with diabetes, whereas other agents may be deleterious. In the current review, we provide an overview of the cardio-specific effects of oral anti-diabetic drugs in animal models of acute MI, post-MI remodeling, and heart failure. Metformin has consistently been shown to ameliorate cardiac remodeling after ischemia/reperfusion (I/R) injury, as well as in several models of heart failure. Sulfonylurea derivatives are controversial with respect to their direct effects on the cardiovascular system. Thiazolidinediones protect against myocardial I/R injury, but their effects on post-MI remodeling are less clear and clinical studies raised concerns about their cardiovascular safety. Glucagon-like peptide-1 analogs have potential beneficial effects on the cardiovascular system that require further confirmation, whereas the results with dipeptidyl peptidase-4 inhibitors are equivocal. Current clinical guidelines, in the absence of prospective clinical trials that evaluated if certain oral anti-diabetic agents are superior over others, only provide generic recommendations, and do not take into account interesting experimental and mechanistic data. The available experimental evidence indicates that some anti-diabetic agents should be preferred over others if cardio-protective effects are warranted. These experimental clues need to be confirmed by clinical trials. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Aim Real-life studies are needed to confirm the clinical relevance of findings from randomised controlled trials (RCTs). This study aimed to assess the effectiveness and tolerability of vildagliptin add-on vs. other oral antihyperglycaemic drugs (OADs) added to OAD monotherapy in a real-life setting, and to explore the advantages and limitations of large-scale ‘pragmatic’ trials. Methods EDGE was a prospective, 1-year, worldwide, real-life observational study in which 2957 physicians reported on the effects of second-line OADs in 45,868 patients with T2DM not reaching glycaemic targets with monotherapy. Physicians could add any OAD, and patients entered either vildagliptin or (pooled) comparator cohort. The primary effectiveness and tolerability end-point (PEP) evaluated proportions of patients decreasing HbA1c > 0.3%, without hypoglycaemia, weight gain, peripheral oedema or gastrointestinal side effects. The most clinically relevant secondary end-point (SEP 3) was attainment of end-point HbA1c

Patients with critical illness-induced multiple organ failure suffer from a very high morbidity and mortality, despite major progress in intensive care. The pathogenesis of this condition is complex and incompletely understood. Inadequate tissue perfusion and an overwhelming inflammatory response with pronounced cellular damage have been suggested to play an important role, but interventions targeting these disturbances largely failed to improve patient outcome. Hence, new therapeutic perspectives are urgently needed. Cellular dysfunction, hallmarked by mitochondrial dysfunction and endoplasmic reticulum stress, is increasingly recognized as an important contributor to the development of organ failure in critical illness. Several cellular defense mechanisms are normally activated when the cell is in distress, but may fail or respond insufficiently to critical illness. This insight may open new therapeutic options by stimulating these cellular defense mechanisms. This review summarizes the current understanding of the role of mitochondrial dysfunction and endoplasmic reticulum stress in critical illness-induced multiple organ failure and gives an overview of the corresponding cellular defense mechanisms. Therapeutic perspectives based on these cellular defense mechanisms are discussed. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis - edited by Raghavan Raju. ispartof: Biochimica et Biophysica Acta. Molecular Basis of Disease vol:1863 issue:10 pages:2534-2545 ispartof: location:Netherlands status: published

P>Aims:Studies on macrovascular consequences of glucose control in elderly patients (> 75 years) with type 2 diabetes mellitus (T2DM) are lacking. The present study aimed to investigate the relationship between HbA(1c) and mortality in this specific population.Methods:Between 1998 and 1999, 374 primary care patients with T2DM aged older than 75 years participated in the Zwolle Outpatient Diabetes project Integrating Available Care study, a prospective observational study. Early 2009, data on mortality were collected. Updated means for annually measured HbA(1c) values were calculated after a follow-up time of 10 years. Updated mean HbA(1c) was used as a time-dependent covariate in a Cox proportional hazard model. Main outcome measures were all-cause and cardiovascular disease (CVD) mortality. Analyses were performed in strata according to diabetes duration (= 11 years).Results:In the group with a diabetes duration = 5 years.Conclusion:Poor glycaemic control is related to increased all-cause and CVD mortality in patients > 75 years with T2DM of short duration (Discussion:Because of the observational study design, our results should be interpreted with caution. Nevertheless, they are suggestive that improving glycaemic control may be beneficial in elderly patients with T2DM, especially in those with recently diagnosed T2DM. Randomised-controlled trials are necessary to investigate whether this holds true.

Diabetic nephropathy has become a worldwide epidemic accounting for approximately one-third of all cases of end-stage renal disease. The problem is expected to grow, as the prevalence of diabetes is expected to increase from 285 million patients at present to 438 million patients in the year 2030, with increasing prevalence of diabetes particularly in Asia, and a global prevalence of microalbuminuria of similar to 40%. This will have a major societal impact because of the enormous financial burden of renal replacement therapy and the invalidating character of this disease. Improved management of diabetes is clearly required, including improved glycemic control to avoid initiation of diabetic nephropathy, particularly in high-risk patients. Recently, the benefits of strict glycemic control on micro- and macrovascular complications have been questioned despite the clear association in observational studies between hyperglycemia and complications. It has been suggested that the benefit of lowering glucose is partly offset by side effects to the glucose-lowering medications, such as hypoglycemia, weight gain, and fluid retention. New treatment strategies with fewer side effects are necessary. Such a treatment could be an incretin-based treatment with glucagon-like peptide 1 analogs, with dipeptidyl peptidase-4 inhibitors that have recently been marketed, or with sodium-glucose transporter 2 inhibitors that are being developed in phase III studies. However, studies with renal end points using these agents are lacking. Kidney International (2011) 79 (Suppl 120), S28-S32; doi:10.1038/ki.2010.S13

Aim: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts.Methods: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009.Results: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal.Conclusion: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections. (C) 2010 Elsevier Masson SAS. All rights reserved.

Aim: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. Methods: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. Results: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. Conclusion: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections. (C) 2010 Elsevier Masson SAS. All rights reserved.

van Bruggen R, Gorter K, Stolk R, Klungel O and Rutten G. Clinical inertia in general practice: widespread and related to the outcome of diabetes care. Family Practice 2009; 26: 428–436. Background and aims. Clinical inertia is considered a major barrier to better care. We assessed its prevalence, predictors and associations with the intermediate outcomes of diabetes care. Materials and methods. Baseline and follow-up data of a Dutch randomized controlled trial on the implementation of a locally adapted guideline were used. The study involved 30 general practices and 1283 patients. Treatment targets differed between study groups [HbA1c < 8.0% and blood pressure (BP) < 140/85% versus HbA1c < 8.5% and BP < 150/85]. Clinical inertia was defined as the failure to intensify therapy when indicated. A complete medication profile of all participating patients was obtained. Results. In the intervention and control group, the percentages of patients with poor diabetes or lipid control who did not receive treatment intensification were 45% and 90%, approximately. More control group patients with BP levels above target were confronted with inertia (72.7% versus 63.3%, P < 0.05). In poorly controlled hypertensive patients, inertia was associated with the height of systolic BP at baseline [adjusted odds ratio (OR) 0.98, 95% confidence interval (CI) 0.98–0.99] and the frequency of BP control (adjusted OR 0.89, 95% CI 0.81–0.99). If a practice nurse managed these patients, clinical inertia was less common (adjusted OR 0.12, 95% CI 0.02–0.91). In both study groups, cholesterol decreased significantly more in patients who received proper treatment intensification. Conclusion. GPs were more inclined to control blood glucose levels than BP or cholesterol levels. Inertia in response to poorly controlled high BP was less common if nurses assisted GPs.

Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients.

Background. Acute hyperglycemia is associated with adverse outcome in critically ill patients. Glucose control with insulin improves outcome in surgical intensive care unit (SICU) patients, but the effect in trauma patients is unknown. We investigated hyperglycemia and outcome in SICU patients with and without trauma. Methods: A 12-year retrospective study,was performed at a 12-bed SICU. We collected the reason for admission, Injury Severity Scores (ISS), and 30-day mortality rates. Glucose measurements were used to calculate the hyperglycemic index (HGI), a measure indicative of overall hyperglycemia during the entire SICU stay. Results: In all, 5234 nontrauma and 865 trauma patients were studied. Trauma patients were younger, more frequently male, and had both lower median admission glucose (123 versus 133 mg/dL) and HGI levels (8.9 vs. 18.4 mg/dL) than nontrauma patients (p

Background. Acute hyperglycemia is associated with adverse outcome in critically ill patients. Glucose control with insulin improves outcome in surgical intensive care unit (SICU) patients, but the effect in trauma patients is unknown. We investigated hyperglycemia and outcome in SICU patients with and without trauma.Methods: A 12-year retrospective study,was performed at a 12-bed SICU. We collected the reason for admission, Injury Severity Scores (ISS), and 30-day mortality rates. Glucose measurements were used to calculate the hyperglycemic index (HGI), a measure indicative of overall hyperglycemia during the entire SICU stay.Results: In all, 5234 nontrauma and 865 trauma patients were studied. Trauma patients were younger, more frequently male, and had both lower median admission glucose (123 versus 133 mg/dL) and HGI levels (8.9 vs. 18.4 mg/dL) than nontrauma patients (p Conclusions: The relation of hyperglycemia and mortality is more pronounced in trauma patients than in SICU patients admitted for other reasons. The different behavior of hyperglycemia in these patients underscores the need for evaluation of intensive insulin therapy in these patients.

Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC. Background The changes induced on endothelial cells by a long-term exposure to high glucose, a situation that mimics the hyperglycemia of diabetics, have not yet been determined. We compared short- and long-term effects of elevated glucose on macrovascular and microvascular endothelial cells. Methods Endothelial cells were grown in high-glucose media for 24 hours and for 8 weeks. Cell proliferation was evaluated by cell counting, apoptosis and expression of adhesion molecules by flow cytometry; nitric oxide (NO) by measuring the concentration of nitrite/nitrate in the cell supernatant; α2(IV) collagen mRNA and protein by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The adhesion of peripheral blood mononuclear cells (PBMCs) to endothelial cells was evaluated by adhesion assay. In some experiments, endothelial cells were preincubated with anti-vascular cell adhesion molecule-1 (VCAM-1) and anti-receptor for advanced glycation end product (RAGE) blocking antibodies. Results At 24 hours, but not at 8 weeks, high glucose increased endothelial cell proliferation and apoptosis. High glucose did not modify NO synthesis at 24 hours and 8 weeks. Collagen production and expression were increased only after eight weeks. VCAM-1 but not intercellular adhesion molecule-1 was up-regulated after 8 weeks, a change not observed after 24 hours. The adhesion of PBMCs was significantly increased at eight weeks and was completely abrogated by anti-VCAM-1 and by anti-RAGE antibodies. After 24 hours, there was a modest increase of PBMC adhesion that was not blunted by anti-RAGE antibodies. Conclusions Increased adhesion of PBMCs, caused by up-regulation of VCAM-1 with a mechanism involving advanced glycation end product (AGE) adducts, and augmented collagen deposition are critical effects of long-term high glucose on endothelial cells, and may eventually promote the atherosclerotic process.

Aims This 52-week, randomized, multinational, open-label, parallel-group, non-inferiority trial investigated the efficacy and safety of basalbolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 216 years with Type 1 diabetes mellitus. Methods Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks. Results After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA1c [mean difference insulin detemirNPH: 1.30 mmol/mol, 95% CI 1.32 to 3.92 (0.12%, 95% CI 0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI 1.26 to 4.08 (0.13%, 95% CI 0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject-year of exposure of 24-h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.600.97, P = 0.028 and 0.62, 95% CI 0.470.84, P = 0.002, respectively). Weight standard deviation (sd) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: 0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups. Conclusions Insulin detemir was non-inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 216 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin. Diabet. Med. 30, 216-225 (2013)

Diabetic nephropathy has become a worldwide epidemic accounting for approximately one-third of all cases of end-stage renal disease. The problem is expected to grow, as the prevalence of diabetes is expected to increase from 285 million patients at present to 438 million patients in the year 2030, with increasing prevalence of diabetes particularly in Asia, and a global prevalence of microalbuminuria of similar to 40%. This will have a major societal impact because of the enormous financial burden of renal replacement therapy and the invalidating character of this disease. Improved management of diabetes is clearly required, including improved glycemic control to avoid initiation of diabetic nephropathy, particularly in high-risk patients. Recently, the benefits of strict glycemic control on micro- and macrovascular complications have been questioned despite the clear association in observational studies between hyperglycemia and complications. It has been suggested that the benefit of lowering glucose is partly offset by side effects to the glucose-lowering medications, such as hypoglycemia, weight gain, and fluid retention. New treatment strategies with fewer side effects are necessary. Such a treatment could be an incretin-based treatment with glucagon-like peptide 1 analogs, with dipeptidyl peptidase-4 inhibitors that have recently been marketed, or with sodium-glucose transporter 2 inhibitors that are being developed in phase III studies. However, studies with renal end points using these agents are lacking. Kidney International (2011) 79 (Suppl 120), S28-S32; doi:10.1038/ki.2010.S13

Clinical guidelines have the potential to increase health gains, but also to cause harm. In this opinion article we state some misgivings about the application of the Portuguese National Health Directorate's guideline type 2 diabetes therapy: metformin in primary care. We seek to highlight guideline wording that may allow for multiple interpretations (alternatives to monotherapy with metformin, hierarchy of drugs to be associated with metformin, and metformin contraindications). Furthermore, we argue that it seems that choosing a glycemic target of 6.5% in a normative document to be applied in the general population may have unforeseen consequences. publishersversion published

Exogenous insulin administration is the basic way to face the widespread disease of Diabetes Mellitus. To this aim, closed-loop approaches, though theoretically realizable according to the control theory results and to the recent technology concerning continuous glucose measurements and affordable insulin infusion pumps, require a careful and thorough testing ground on a virtual environment before arranging an in-vivo clinical setting of experiments. In this work, a model-based control law for the plasma glycemia, recently published by the same authors, is evaluated by closing the loop on a virtual patient, whose model equations are different from the ones used to synthesize the control law. That means: a minimal model of the glucose-insulin system to design the insulin therapy, and a different, more detailed, comprehensive model to test in silico the control scheme. Uncertainties on the blood glucose measurements, as well as malfunctioning on the insulin delivery devices are considered, according to the standard technology, in order to obtain an effective benchmark for the closed-loop control and to show in fact the robustness of the proposed approach.

Aim: Injections administered by patients are one of the mainstays of diabetes management. Proper injection technique is vital to avoiding intramuscular injections, ensuring appropriate delivery to the subcutaneous tissues and avoiding common complications such as lipohypertrophy. Yet few formal guidelines have been published summarizing all that is known about best practice. We propose new injection guidelines which are thoroughly evidence-based, written and vetted by a large group of international injection experts. Methods: A systematic literature study was conducted for all peer-reviewed studies and publications which bear on injections in diabetes. An international group of experts met regularly over a two-year period to review this literature and draft the recommendations. These were then presented for review and revision to 127 experts from 27 countries at the TITAN workshop in September, 2009. Results: Of 292 articles reviewed, 157 were found to meet the criteria of relevance to the recommendations. Each recommendation was graded by the weight it should have in daily practice and by its degree of support in the medical literature. The topics covered include The Role of the Professional, Psychological Challenges, Education, Site Care, Storage, Suspension and Priming, Injecting Process, Proper Use of Pens and Syringes, Insulin analogues, Human and Pre-mixed Insulins, GLP-1 analogs, Needle Length, Skin Folds, Lipohypertrophy, Rotation, Bleeding and Bruising, Pregnancy, Safety and Disposal. Conclusion: These injecting recommendations provide practical guidance and fill an important gap in diabetes management. If followed, they should help ensure comfortable, effective and largely complication-free injections. (C) 2010 Elsevier Masson SAS. All rights reserved.

This paper investigates the problem of plasma glucose regulation by means of intra-venous insulin administration. A model-based approach is followed, according to a discrete-time framework, since the available standard technology provides sampled glucose measurements and piece-wise constant insulin delivery devices. The digital control scheme is designed on the basis of an approximated sampled model, whose continuous-time original version is available in the recent literature, and has been shown to very well resemble real data on healthy subjects as well as on diabetic patients (both type 1 and type 2 Diabetes Mellitus). In silico simulations show the high performance of the proposed digital control law. ©2010 IEEE.

Background and Aims Non-adherence is considered a major barrier to better outcomes of diabetes care. A relationship has been established between polypharmacy and patients' adherence. This study aims to investigate the occurrence of polypharmacy and non-adherence in general practice, their mutual relationship and the association between adherence and the intermediate outcomes of diabetes care.Materials and Methods We used the baseline and follow-up data of a randomised controlled trial (RCT) that compared usual care with care in accordance with a locally adapted national guideline. This study took place in the Netherlands and involved 30 general practices and 1283 patients. We obtained a complete medication profile of all participants and calculated the number of prescribed drugs and the adherence indices (AI) for oral blood glucose, blood pressure and cholesterol lowering drugs. Patients with an adherence index Results Approximately 80% of the participating patients demonstrated an adherence index >= 0.8 for oral blood glucose, blood pressure and cholesterol lowering drugs. In the intervention group, increase of drug prescriptions exceeded that of controls (1.1 +/- 2.0 vs. 0.6 +/- 1.5, p Conclusion During the intervention the mean number of drug prescriptions increased in both the study groups. This did not result in a lower adherence to blood glucose and cholesterol lowering medications. Given the relationship between the number of medications and patients' adherence to blood pressure lowering drugs, it may be wise to discuss adherence before prescribing multiple drug regimens. Copyright (C) 2009 John Wiley & Sons, Ltd.

Background. Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone.Methods. The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study, which will include three categories of high-risk patients with type 2 diabetes (aged >= 35 years): those with either urinary albumin/creatinine ratio (UACR) >= 200 mg/g; microalbuminuria (UACR) >= 20 = 30 = 30 Conclusion. ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.

Background A growing body of evidence suggests that earlier diagnosis and treatment of diabetes may be beneficial; however, definitive evidence is lacking. Aim To evaluate the effectiveness of an intensified multifactorial treatment on cardiovascular risk factors in patients with screen-detected type 2 diabetes. Design of study Randomised controlled trial. Setting Seventy-nine general practices in the southwestern region of the Netherlands. Method In this randomised trial, patients diagnosed with diabetes by screen-detection were assigned to intensified ( n = 255) or routine treatment ( n = 243), and followed over 1 year. Intensified treatment consisted of pharmacological treatment combined with lifestyle education to achieve haemoglobin A1c (HbA1c)

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration. A model-based approach is followed. Only measurements of glycemia are considered. A nonlinear observer for delay differential systems is used for the estimation of insulinemia. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the feedback linearization, which makes use of the observer estimations instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. In silico simulations, which also take into account input saturation, show the very good performance of the proposed control technique.

De behandeling van diabetes bestaat grotendeels uit zelfzorg. Patienten moeten dagelijks en waarschijnlijk levenslang hun medicatie, voeding en lichamelijke activiteit op elkaar afstemmen. Ze moeten constant alert zijn op tekenen van ontregeling van bloedglucosewaarden of beginnende complicaties. Diabetes heeft dan ook een grote emotionele impact, met als gevolg veelvoorkomende psychologische problemen varierend van aanpassingsproblemen tot angststoornissen en depressie.

Background. Acute hyperglycemia is associated with adverse outcome in critically ill patients. Glucose control with insulin improves outcome in surgical intensive care unit (SICU) patients, but the effect in trauma patients is unknown. We investigated hyperglycemia and outcome in SICU patients with and without trauma. Methods: A 12-year retrospective study,was performed at a 12-bed SICU. We collected the reason for admission, Injury Severity Scores (ISS), and 30-day mortality rates. Glucose measurements were used to calculate the hyperglycemic index (HGI), a measure indicative of overall hyperglycemia during the entire SICU stay. Results: In all, 5234 nontrauma and 865 trauma patients were studied. Trauma patients were younger, more frequently male, and had both lower median admission glucose (123 versus 133 mg/dL) and HGI levels (8.9 vs. 18.4 mg/dL) than nontrauma patients (p

Introduction Tight glycaemic control is an important issue in the management of intensive care unit (ICU) patients. The glycaemic goals described by Van Den Berghe and colleagues in their landmark study of intensive insulin therapy appear difficult to achieve in a real life ICU setting. Most clinicians and nurses are concerned about a potentially increased frequency of severe hypoglycaemic episodes with more stringent glycaemic control. One of the steps we took before we implemented a glucose regulation protocol was to review published trials employing insulin/ glucose algorithms in critically ill patients.Methods We conducted a search of the PubMed, Embase and Cochrane databases using the following terms: 'glucose', 'insulin', 'protocol', 'algorithm', 'nomogram', 'scheme', ' critically ill' and ' intensive care'. Our search was limited to clinical trials conducted in humans. The aim of the papers selected was required to be glycaemic control in critically ill patients; the blood glucose target was required to be 10 mmol/l or under ( or use of a protocol that resulted in a mean blood glucose = 10 mmol/l). The studies were categorized according to patient type, desired range of blood glucose values, method of insulin administration, frequency of blood glucose control, time taken to achieve the desired range for glucose, proportion of patients with glucose in the desired range, mean blood glucose and frequency of hypoglycaemic episodes.Results A total of twenty-four reports satisfied our inclusion criteria. Most recent studies ( nine) were conducted in an ICU; nine others were conducted in a perioperative setting and six were conducted in patients with acute myocardial infarction or stroke. Studies conducted before 2001 did not include normoglycaemia among their aims, which changed after publication of the study by Van Den Berghe and coworkers in 2001; glycaemic goals became tighter, with a target range between 4 and 8 mmol/l in most studies.Conclusion Studies using a dynamic scale protocol combining a tight glucose target and the last two blood glucose values to determine the insulin infusion rate yielded the best results in terms of glycaemic control and reported low frequencies of hypoglycaemic episodes.

The vascular endothelium controls vasomotor tone and microvascular flow and regulates trafficking of nutrients and biologically active molecules. When endothelial activation is excessive, compromised microcirculation and subsequent cellular hypoxia contribute to the risk of organ failure. We hypothesized that strict blood glucose control with insulin during critical illness protects the endothelium, mediating prevention of organ failure and death. In this preplanned subanalysis of a large, randomized controlled study, intensive insulin therapy lowered circulating levels of ICAM-1 and tended to reduce E-selectin levels in patients with prolonged critical illness, which reflects reduced endothelial activation. This effect was not brought about by altered levels of endothelial stimuli, such as cytokines or VEGF, or by upregulation of eNOS. In contrast, prevention of hyperglycemia by intensive insulin therapy suppressed iNOS gene expression in postmortem liver and skeletal muscle, possibly in part via reduced NF-kappaB activation, and lowered the elevated circulating NO levels in both survivors and nonsurvivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with intensive insulin therapy. In conclusion, maintaining normoglycemia with intensive insulin therapy during critical illness protects the endothelium, likely in part via inhibition of excessive iNOS-induced NO release, and thereby contributes to prevention of organ failure and death. ispartof: Journal Of Clinical Investigation vol:115 issue:8 pages:2277-2286 ispartof: location:United States status: published

This study aimed to determine effects of a Multidisciplinary Intensive Education Programme (MIEP) based on the empowerment approach for diabetic patients with prolonged self-management difficulties. In 89 participants, glycaemic control (HbA1c), health related quality of life (HR-QoL) and indicators of empowerment were measured before MIEP (10 days in 10 weeks, follow-up after 6 and 12 weeks) and at 12 weeks follow-up. The participants were compared with 231 average outpatients who were measured once. Overall, participants improved their glycaemic control, mental health, satisfaction with treatment and became more empowered. Subgroup analyses revealed that especially patients with poor baseline control improved their HbA1c. At baseline, participants with poor mental health scored worse on all other HR-QoL subscales too and were less empowered compared to the satisfactory mental health group. The poor mental health participants improved in most of these aspects. MIEP has beneficial effects in HbA1c, HR-QoL, and empowerment, especially in patients with poor status at baseline.

To compare efficacy and tolerability of combination treatment with metformin and sulfonylurea with each of these drugs alone in the treatment of type 2 diabetes, 88 type 2 diabetic subjects (hemoglobin A1c [HbA1c] levels, 8.0%+/-1.0%; age, 57.3+/-7.1 years; body mass index [BMI]. 27.0+/-2.6 kg/m2; diabetes duration, 9.8+/-8.2 years; means +/- SD) were randomly assigned to double-blind treatment with metformin (500 to 3,000 mg/d), glibenclamide (5 to 15 mg/d), or their combination (metformin 400 to 2,400 mg/d + glibenclamide 2.5 to 15 mg/d) for 6 months. Thereafter, groups were crossed over for the following 6 months. Thus, each patient received metformin or glibenclamide alone, and the combination treatment. Doses were titrated to obtain HbA1c levels < or = 6.0% and fasting plasma glucose levels less than 140 mg/dL. Eighty patients concluded both treatment periods and were included in the analysis of treatment efficacy. In patients receiving metformin or glibenclamide alone, the maximal dose was reached in 21 and 25 patients, respectively; 8 and 15 of these subjects, respectively, required the maximal dose when they were on the combination treatment. During the study, 4 (10.0%) subjects receiving metformin, 7 (17.1%) receiving glibenclamide, and 31 (39.2%) receiving the combination treatment reached HbA1c levels < or = 6.0%. Moreover, when efficacy of the combination treatment on glycemic control was compared with that of single-drug therapies in each individual patient, the combination was significantly more effective than either metformin or glibenclamide (HbA1c after treatment, 6.1%+/-1.1% v 7.3%+/-1.4%, and 6.5%+/-0.7% v 7.6%+/-1.5%, respectively, both P

Background The increasing prevalence of type 2 diabetes poses both clinical and public health challenges. Cost-effective approaches to prevent progression of the disease in primary care are needed. Evidence suggests that intensive multifactorial interventions including medication and behaviour change can significantly reduce cardiovascular morbidity and mortality among patients with established type 2 diabetes, and that patient education in self-management can improve short-term outcomes. However, existing studies cannot isolate the effects of behavioural interventions promoting self-care from other aspects of intensive primary care management. The ADDITION-Plus trial was designed to address these issues among recently diagnosed patients in primary care over one year. Methods/Design ADDITION-Plus is an explanatory randomised controlled trial of a facilitator-led, theory-based behaviour change intervention tailored to individuals with recently diagnosed type 2 diabetes. 34 practices in the East Anglia region participated. 478 patients with diabetes were individually randomised to receive (i) intensive treatment alone (n = 239), or (ii) intensive treatment plus the facilitator-led individual behaviour change intervention (n = 239). Facilitators taught patients key skills to facilitate change and maintenance of key behaviours (physical activity, dietary change, medication adherence and smoking), including goal setting, action planning, self-monitoring and building habits. The intervention was delivered over one year at the participant's surgery and included a one-hour introductory meeting followed by six 30-minute meetings and four brief telephone calls. Primary endpoints are physical activity energy expenditure (assessed by individually calibrated heart rate monitoring and movement sensing), change in objectively measured dietary intake (plasma vitamin C), medication adherence (plasma drug levels), and smoking status (plasma cotinine levels) at one year. We will undertake an intention-to-treat analysis of the effect of the intervention on these measures, an assessment of cost-effectiveness, and analyse predictors of behaviour change in the cohort. Discussion The ADDITION-Plus trial will establish the medium-term effectiveness and cost-effectiveness of adding an externally facilitated intervention tailored to support change in multiple behaviours among intensively-treated individuals with recently diagnosed type 2 diabetes in primary care. Results will inform policy recommendations concerning the management of patients early in the course of diabetes. Findings will also improve understanding of the factors influencing change in multiple behaviours, and their association with health outcomes. Trial registration ISRCTN: ISRCTN99175498

Introduction A single centre has reported that implementation of an intensive insulin protocol, aiming for tight glycaemic control (blood glucose 4.4 to 6.1 mmol/l), resulted in significant reduction in mortality in longer stay medical and surgical critically ill patients. Our aim was to determine the degree to which tight glycaemic control can be maintained using an intensive insulin therapy protocol with computerized decision support and to identify factors that may be associated with the degree of control. Methods At a general adult 22-bed intensive care unit, we implemented an intensive insulin therapy protocol in mechanically ventilated patients, aiming for a target glucose range of 4.4 to 6.1 mmol/l. The protocol was integrated into the computerized information management system by way of a decision support program. The time spent in each predefined blood glucose band was estimated, assuming a linear trend between measurements. Results Fifty consecutive patients were investigated, involving analysis of 7,209 blood glucose samples, over 9,214 hours. The target tight glycaemic control band (4.4 to 6.1 mmol/l) was achieved for a median of 23.1% of the time that patients were receiving intensive insulin therapy. Nearly half of the time (median 48.5%), blood glucose was within the band 6.2 to 7.99 mmol/l. Univariate analysis revealed that body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score and previous diabetes each explained approximately 10% of the variability in tight glycaemic control. BMI and APACHE II score explained most (27%) of the variability in tight glycaemic control in the multivariate analysis, after adjusting for age and previous diabetes. Conclusion Use of the computerized decision supported intensive insulin therapy protocol did result in achievement of tight glycaemic control for a substantial percentage of each patient's stay, although it did deliver 'normoglycaemia' (4.4 to about 8 mmol/l) for nearly 75% of the time. Tight glycaemic control was difficult to achieve in critically ill patients using this protocol. More sophisticated methods such as continuous blood glucose monitoring with automated insulin and glucose infusion adjustment may be a more effective way to achieve tight glycaemic control. Glycaemia in patients with high BMI and APACHE II scores may be more difficult to control using intensive insulin therapy protocols. Trial registration number 05/Q0505/1.

The paper investigates the problem of the optimal tracking of a desired plasma glucose evolution by means of a continuous intravenous infusion. The model for the glucose-insulin system here adopted, and recently published, belongs to the class of nonlinear single-distributed delay models. The closed-loop control law is performed according to the feedback linearization theory: a state-feedback is designed in order to exactly linearize the model with respect to a suitably defined change of coordinates. Then, the optimal tracking is achieved by minimizing a performance index. The methodology here proposed allows both to decrease and increase the glycemia. Simulations support theoretical results and show the physical reliability of the approach proposed.