Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes:a randomized double-blind placebo-controlled 102-week trial

Aims: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. Methods: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. Results: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. Conclusions: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

Speech and non-speech stimuli in the prediction of early reading skills:the influence of processing demands and response-type

Purpose: Both phonological (speech) and auditory (non-speech) stimuli have been shown to predict early reading skills. However, previous studies have failed to control for the level of processing required by tasks administered across the two levels of stimuli. For example, phonological tasks typically tap explicit awareness e.g., phoneme deletion, while auditory tasks usually measure implicit awareness e.g., frequency discrimination. Therefore, the stronger predictive power of speech tasks may be due to their higher processing demands, rather than the nature of the stimuli. Method: The present study uses novel tasks that control for level of processing (isolation, repetition and deletion) across speech (phonemes and nonwords) and non-speech (tones) stimuli. 800 beginning readers at the onset of literacy tuition (mean age 4 years and 7 months) were assessed on the above tasks as well as word reading and letter-knowledge in the first part of a three time-point longitudinal study. Results: Time 1 results reveal a significantly higher association between letter-sound knowledge and all of the speech compared to non-speech tasks. Performance was better for phoneme than tone stimuli, and worse for deletion than isolation and repetition across all stimuli. Conclusions: Results are consistent with phonological accounts of reading and suggest that level of processing required by the task is less important than stimuli type in predicting the earliest stage of reading.

What drives the prediction of early reading? An analysis of stimulus and response-type

Purpose: Phonological accounts of reading implicate three aspects of phonological awareness tasks that underlie the relationship with reading; a) the language-based nature of the stimuli (words or nonwords), b) the verbal nature of the response, and c) the complexity of the stimuli (words can be segmented into units of speech). Yet, it is uncertain which task characteristics are most important as they are typically confounded. By systematically varying response-type and stimulus complexity across speech and non-speech stimuli, the current study seeks to isolate the characteristics of phonological awareness tasks that drive the prediction of early reading. Method: Four sets of tasks were created; tone stimuli (simple non-speech) requiring a non-verbal response, phonemes (simple speech) requiring a non-verbal response, phonemes requiring a verbal response, and nonwords (complex speech) requiring a verbal response. Tasks were administered to 570 2nd grade children along with standardized tests of reading and non-verbal IQ. Results: Three structural equation models comparing matched sets of tasks were built. Each model consisted of two 'task' factors with a direct link to a reading factor. The following factors predicted unique variance in reading: a) simple speech and non-speech stimuli, b) simple speech requiring a verbal response but not simple speech requiring a non-verbal-response, and c) complex and simple speech stimuli. Conclusions: Results suggest that the prediction of reading by phonological tasks is driven by the verbal nature of the response and not the complexity or 'speechness' of the stimuli. Findings highlight the importance of phonological output processes to early reading.

Deconstructing phonological tasks:the contribution of stimulus and response type to the prediction of early decoding skills

Abstract Phonological tasks are highly predictive of reading development but their complexity obscures the underlying mechanisms driving this association. There are three key components hypothesised to drive the relationship between phonological tasks and reading; (a) the linguistic nature of the stimuli, (b) the phonological complexity of the stimuli, and (c) the production of a verbal response. We isolated the contribution of the stimulus and response components separately through the creation of latent variables to represent specially designed tasks that were matched for procedure. These tasks were administered to 570 6 to 7-year-old children along with standardised tests of regular word and non-word reading. A structural equation model, where tasks were grouped according to stimulus, revealed that the linguistic nature and the phonological complexity of the stimulus predicted unique variance in decoding, over and above matched comparison tasks without these components. An alternative model, grouped according to response mode, showed that the production of a verbal response was a unique predictor of decoding beyond matched tasks without a verbal response. In summary, we found that multiple factors contributed to reading development, supporting multivariate models over those that prioritize single factors. More broadly, we demonstrate the value of combining matched task designs with latent variable modelling to deconstruct the components of complex tasks.

Future glucose-lowering drugs for type 2 diabetes

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.

Spatial correlations between beta-amyloid (Abeta) deposits and blood vessels in early-onset Alzheimer's disease

In cases of late-onset Alzheimer’s disease (AD), there is a spatial correlation between the classsic ‘cored’ type of Beta-amyloid (Abeta) deposit and the large vertically penetrating arterioles in the cerebral cortex suggesting that blood vessels are involved in the pathogenesis of the classic deposits. In this chapter, the spatial correlations between the diffuse, primitive, and classic Abeta deposits and blood vessels were studied in 10 cases of early-onset AD in the age range 40 – 65 years. Sections of frontal cortex were immunostained with antibodies against Abeta?and with collagen IV to reveal the Abeta deposits and blood vessel profiles. In the early-onset cases as a whole, all types of Abeta? deposit and blood vessel profiles were distributed in clusters. There was a positive spatial correlation between the clusters of the diffuse Abeta deposits and the larger (>10µm) and smaller diameter (<10?m) blood vessel profiles in one and three cases respectively. The primitive and classic Abeta deposits were spatially correlated with larger and smaller blood vessels both in three and four cases respectively. Spatial correlations between the Abeta deposits and blood vessels may be more prevalent in cases expressing amyloid precursor protein (APP) than presenilin 1 (PSEN1) mutations. Apolipoprotein E (Apo E) genotype of the patient did not appear to influence the spatial correlation with blood vessel profiles. The data suggest that the larger diameter blood vessels are less important in the pathogenesis of the classic Abeta deposits in early-onset compared with late-onset AD.

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage.

Management of type 2 diabetes:new and future developments in treatment

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11ß-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

Neuronal convergence in early contrast vision: binocular summation is followed by response nonlinearity and area summation

We assessed summation of contrast across eyes and area at detection threshold ( C t). Stimuli were sine-wave gratings (2.5 c/deg) spatially modulated by cosine- and anticosine-phase raised plaids (0.5 c/deg components oriented at ±45°). When presented dichoptically the signal regions were interdigitated across eyes but produced a smooth continuous grating following their linear binocular sum. The average summation ratio ( C t1/([ C t1+2]) for this stimulus pair was 1.64 (4.3 dB). This was only slightly less than the binocular summation found for the same patch type presented to both eyes, and the area summation found for the two different patch types presented to the same eye. We considered 192 model architectures containing each of the following four elements in all possible orders: (i) linear summation or a MAX operator across eyes, (ii) linear summation or a MAX operator across area, (iii) linear or accelerating contrast transduction, and (iv) additive Gaussian, stochastic noise. Formal equivalences reduced this to 62 different models. The most successful four-element model was: linear summation across eyes followed by nonlinear contrast transduction, linear summation across area, and late noise. Model performance was enhanced when additional nonlinearities were placed before binocular summation and after area summation. The implications for models of probability summation and uncertainty are discussed.

Are there two distinct populations of cored senile plaques in senile dementia of the Alzheimer type?

The relationship between plaque diameter (PD) and core diameter (CD) was studied in four brains from each of four SDAT brains. The regions studied were parahippocampal gyrus (PHG), hippocampus, frontal and inferior temporal lobes. The largest diameters of 100 cored classical plaques and their cores were measured. CD was positively correlated with PD (Pearson's 'r' 0.4 - 0.95) in all region studied. Significant linear regressions of CD on PD with positive slopes (0.10 - 0.65) were found. Two distinct types of regression were found. Type A had a steep slope and a negative intercept on the ordinate whereas Type B had a shallow slope and a positive intercept. Both types can be found within the same brain but Type A or B predominate in a particular tissue. The data suggest that core development may occur either early or late in the development of the plaque. The two types of plaque may thus have different aetiologies. Such an interpretation is consistent with current ideas of plaque formation.

Comparative risk of microalbuminuria and proteinuria in UK residents of south Asian and white European ethnic background with type 2 diabetes:a report from UKADS

Objective - This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus. Research design and methods - A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross-sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed. Main outcome measures - Prevalences of microalbuminuria and overt proteinuria. Results - Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, X2?=?15.85, 2df, P?=?0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P?=?0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years’ duration, OR?=?1.40 (0.63, 3.08). Limitations - Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio. Conclusions - There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity.

Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response

CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication.

Avandamet:Combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2-diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes. © 2004 Blackwell Publishing Ltd.

Innovative biomarkers for predicting type 2 diabetes mellitus:relevance to dietary management of frailty in older adults

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a “healthy” diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.