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Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males
No full textTo investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals
Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System
Full text linkGlucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state
Dapagliflozin lowers plasma glucose concentration and improves β-cell function
No full textBackground: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals. Research Design and Methods: Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT. Results: Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (ΔG0-120) during OGTT by -33 ± 5 mg/dL, -73 ± 9 mg/dL, and -60 ± 12 mg/dL · min, respectively, compared to 0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 ± 0.005 vs 0.002 ± 0.006; P 0-120/ΔG0-120 ÷ insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects. Conclusion: Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function
Pathogenesis of type 2 diabetes -role of defects in insulin secretion and insulin sensitivity
No full textType 2 diabetes is characterised by defects in insulin sensitivity, insulin secretion and increased endogenous glucose production. The relative contribution of each of these defects remains controversial. In order to characterise the metabolic defects in various stages of glucose tolerance, the insulin sensitivity and insulin secretion was measured in a large population based study in Finland and Sweden (Btonia study) The first aim was to evaluate surrogate markers of insulin sensitivity and insulin secretion in subjects with varying degree of glucose tolerance. The insulinogenic index provides a good surrogate estimate of the early insulin response to iv glucose. In contrast, the HOMA IR and indices from OGTT do not describe insulin sensitivity in the same way as glucose uptake measured during a clamp. The latter measures also suffer from the problem that insulin sensitivity is dependent upon the amount of insulin secreted. The second aim was therefore to validate a method for independent estimates of insulin sensitivity and insulin secretion during the same test; the so called Botnia clamp. The test fulfilled the expectations and provides a useful tool for metabolic studies. The results also underscore the importance of adjusting insulin secretion for insulin sensitivity. A third aim was to characterise the metabolic defects leading to type 2 diabetes. Our cross sectional data show that defects in muscle, liver, and islets occur in parallel and correlate with an increase in abdominal obesity and circulating FFA concentrations. They thus support the hypothesis that peripheral and hepatic insulin resistance as well as β-cell dysfunction in type 2 diabetes could be caused by similar defects. They further demonstrate that these defects are influenced by variations in the calpain 10 gene. A fourth aim was to compare insulin secretion and insulin sensitivity in the prediabetic and diabetic state between subtypes of diabetes. We could demonstrate that carriers of MODY mutations are able to maintain normal glucose tolerance by up regulating insulin sensitivity. The last aim was to evaluate the impact of a family history of common type 2 diabetes and the particular phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives. The data underscore the importance to consider age at onset when selecting patients for genetic studies as the metabolic phenotype of the probands is shared by relatives of probands with early but not of late-onset diabetes. They further emphasize the value of stratifying for a phenotype characterised by abdominal obesity as this also shows a high degree of familiality. Taken together the results demonstrate a linear decrease in peripheral (muscle) glucose uptake, hepatic insulin sensitivity and β cell function which precede onset of type 2 diabetes, and strongly correlate with an increase in abdominal obesity. They though emphasize the importance to consider changes in one variable when describing the change in the other
Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes
Full text linkOBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production
Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals
No full textInsulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) 1H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P 50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible. © 2014 by the American Diabetes Association
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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