Diabetes Portugal Education and Research Center
Diabetes Portugal Education and Research Center
Martins F.O.,Metabolic Control Group |
Martins F.O.,New University of Lisbon |
Martins F.O.,University of Coimbra |
Delgado T.C.,Metabolic Control Group |
And 9 more authors.
British Journal of Pharmacology | Year: 2016
Background and Purpose Thiazolidinediones (TZD) are known to ameliorate fatty liver in type 2 diabetes. To date, the underlying mechanisms of their hepatic actions remain unclear. Experimental Approach Hepatic triglyceride content and export rates were assessed in 2 week high-sucrose-fed Wistar rats treated with troglitazone and compared with untreated high-sucrose rodent controls. Fractional de novo lipogenesis (DNL) contributions to hepatic triglyceride were quantified by analysis of triglyceride enrichment from deuterated water. Hepatic insulin clearance and NO status during a meal tolerance test were also evaluated. Key Results TZD significantly reduced hepatic triglyceride (P < 0.01) by 48%, decreased DNL contribution to hepatic triglyceride (P < 0.01) and increased postprandial non-esterified fatty acids clearance rates (P < 0.01) in comparison with the high-sucrose rodent control group. During a meal tolerance test, plasma insulin AUC was significantly lower (P < 0.01), while blood glucose and plasma C-peptide levels were not different. Insulin clearance was increased (P < 0.001) by 24% and was associated with a 22% augmentation of hepatic insulin-degrading enzyme activity (P < 0.05). Finally, hepatic NO was decreased by 24% (P < 0.05). Conclusions Overall, TZD show direct actions on liver by reducing hepatic DNL and increasing hepatic insulin clearance. The alterations in hepatic insulin clearance were associated with changes in insulin-degrading enzyme activity, with possible modulation of NO levels. © 2015 The British Pharmacological Society.
Jesus A.R.,University of Lisbon |
Dias C.,University of Lisbon |
Matos A.M.,University of Lisbon |
Matos A.M.,New University of Lisbon |
And 13 more authors.
Journal of Medicinal Chemistry | Year: 2014
8-β-d-Glucopyranosylgenistein (1), the major component of Genista tenera, was synthesized and showed an extensive therapeutical impact in the treatment of STZ-induced diabetic rats, producing normalization of fasting hyperglycemia and amelioration of excessive postprandial glucose excursions and and increasing β-cell sensitivity, insulin secretion, and circulating insulin within 7 days at a dose of 4 (mg/kg bw)/day. Suppression of islet amyloid polypeptide (IAPP) fibril formation by compound 1 was demonstrated by thioflavin T fluorescence and atomic force microscopy. Molecular recognition studies with IAPP and Aβ1-42 employing saturation transfer difference (STD) confirmed the same binding mode for both amyloid peptides as suggested by their deduced epitope. Insights into the preferred conformation in the bound state and conformers' geometry resulting from interaction with Aβ1-42 were also given by STD, trNOESY, and MM calculations. These studies strongly support 8-β-d-glucopyranosylgenistein as a promising molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer's disease. © 2014 American Chemical Society.
Jones J.G.,Metabolic Control Group |
Jones J.G.,Diabetes Portugal Education and Research Center
Diabetologia | Year: 2016
The liver has a central role in the regulation of systemic glucose and lipid fluxes during feeding and fasting and also relies on these substrates for its own energy needs. These parallel requirements are met by coordinated control of carbohydrate and lipid fluxes into and out of the Krebs cycle, which is highly tuned to nutrient availability and heavily regulated by insulin and glucagon. During progression of type 2 diabetes, hepatic carbohydrate and lipid biosynthesis fluxes become elevated, thus contributing to hyperglycaemia and hypertriacylglycerolaemia. Over this interval there are also significant fluctuations in hepatic energy state. To date, it is not known to what extent abnormal glucose and lipid fluxes are causally linked to altered energy states. Recent evidence that the glucose-lowering effects of metformin appear to be mediated by attenuation of hepatic energy generation places an additional spotlight on the interdependence of hepatic biosynthetic and oxidative fluxes. The transition from fasting to feeding results in a significant re-direction of hepatic glucose and lipid fluxes and may also incur a temporary hepatic energy deficit. At present, it is not known to what extent these variables are additionally modified by type 2 diabetes and/or non-alcoholic fatty liver disease. Thus, there is a compelling need to measure fluxes through oxidative, gluconeogenic and lipogenic pathways and determine their relationship with hepatic energy state in both fasting and fed conditions. New magnetic resonance-based technologies allow these variables to be non-invasively studied in animal models and humans. This review summarises a presentation given at the symposium entitled ‘The liver in focus’ at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1, and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x). © 2016, Springer-Verlag Berlin Heidelberg.
Macedo M.P.,New University of Lisbon |
Macedo M.P.,Diabetes Portugal Education and Research Center |
Lima I.S.,New University of Lisbon |
Lima I.S.,Beth Israel Deaconess Medical Center |
And 7 more authors.
Reviews in Endocrine and Metabolic Disorders | Year: 2014
Ingestion of a meal is the greatest challenge faced by glucose homeostasis. The surge of nutrients has to be disposed quickly, as high concentrations in the bloodstream may have pathophysiological effects, and also properly, as misplaced reserves may induce problems in affected tissues. Thus, loss of the ability to adequately dispose of ingested nutrients can be expected to lead to glucose intolerance, and favor the development of pathologies. Achieving interplay of several organs is of upmost importance to maintain effectively postprandial glucose clearance, with the liver being responsible of orchestrating global glycemic control. This dogmatic role of the liver in postprandial insulin sensitivity is tightly associated with the vagus nerve. Herein, we uncover the behaviour of metabolic pathways determined by hepatic parasympathetic function status, in physiology and in pathophysiology. Likewise, the inquiry expands to address the impact of a modern lifestyle, especially one's feeding habits, on the hepatic parasympathetic nerve control of glucose metabolism. © 2013 Springer Science+Business Media.
PubMed | Hospital Pulido Valente, Diabetes Portugal Education and Research Center, Instituto Nacional Of Saude Dr Ricardo Jorge, New University of Lisbon and Instituto Gulbenkian Of Ciencia
Type: Journal Article | Journal: BMJ open diabetes research & care | Year: 2016
This study aimed to estimate the prevalence of diabetes mellitus (DM) in hospitalized patients with community-acquired pneumonia (CAP) and its impact on hospital length of stay and in-hospital mortality.We carried out a retrospective, nationwide register analysis of CAP in adult patients admitted to Portuguese hospitals between 2009 and 2012. Anonymous data from 157291 adult patients with CAP were extracted from the National Hospital Discharge Database and we performed a DM-conditioned analysis stratified by age, sex and year of hospitalization.The 74175 CAP episodes that matched the inclusion criteria showed a high burden of DM that tended to increase over time, from 23.7% in 2009 to 28.1% in 2012. Interestingly, patients with CAP had high DM prevalence in the context of the national DM prevalence. Episodes of CAP in patients with DM had on average 0.8days longer hospital stay as compared to patients without DM (p<0.0001), totaling a surplus of 15370days of stay attributable to DM in 19212 admissions. In-hospital mortality was also significantly higher in patients with CAP who have DM (15.2%) versus those who have DM (13.5%) (p=0.002).Our analysis revealed that DM prevalence was significantly increased within CAP hospital admissions, reinforcing other studies findings that suggest that DM is a risk factor for CAP. Since patients with CAP who have DM have longer hospitalization time and higher mortality rates, these results hold informative value for patient guidance and healthcare strategies.