Pulsatile insulin secretion in elderly patients with diabetes

Insulin pulsation is impaired in type 2 diabetes. GLP-1 increases pulsatile insulin secretion in these patients. We conducted these studies with the hypothesis that GLP-1 would enhance pulsatile insulin secretion and alter glucose metabolism in elderly patients with type 2 diabetes. Experiments were conducted in nine patients (age: 72+/-5 years; BMI: 27+/-3kg/m(2); diabetes duration: 7+/-3 years; HbA(1c): 6.6+/-0.9%). Subjects underwent three glucose clamp studies. The first was a euglycemic clamp to determine individual insulin clearance. In the second, GLP-1 was infused from 0-240min (0.75pM/kg/min) and glucose was maintained at fasting levels. The third was similar except that octreotide (30ng/kg/min) was infused with GLP-1 to suppress pulsatile insulin. Insulin and glucose were given to match levels during the second study. 3-(3)H-glucose was infused to allow calculation of hepatic glucose production and glucose disposal rates. There was no significant difference in measurements of pulsatile insulin secretion or hepatic glucose production and glucose disposal rates between the studies. Because there was no difference in pulsatile insulin between experiments, we could not test the effect of pulsatile insulin on glucose metabolism. Further studies are required to determine the impact of insulin pulses on glucose metabolism.     

Modeling the Parameters Involved in Preparation of PLA Nanoparticles Carrying Hydrophobic Drug Molecules Using Artificial Neural Networks

Purpose

Artificial neural networks (ANNs) are used to optimize a formulation of poly(lactic acid) (PLA) nanoparticles containing hydrophobic drug molecules through a study of the critical parameters affecting nanoparticle size.

Methods

We evaluate the effect of input variables, including concentrations of PLA and Tween 80, amplitude of ultrasound wave, and sonication time on the formation of PLA nanoparticles, which were prepared using a solvent evaporation method. Budesonide was used as a model hydrophobic drug. An ANN model was created using training data and evaluated for prediction capability using validation data.

Results

The ANN model demonstrated that reducing PLA concentration and increasing Tween 80 concentration provided optimum conditions for the preparation of small particle size. Additionally, the simultaneous use of high sonication time and amplitude has an adverse effect on particle diameter.

Conclusion

By defining the effects of each parameter on the size of PLA nanoparticles, this study demonstrated the feasibility of using an ANN model to optimize the conditions for achieving minimum particle size in hydrophobic drug-loaded PLA nanoparticles.     

Insulin resistance in relation to inflammatory gene expression and metabolic features in apparently healthy obese individuals

International Journal of Diabetes in Developing Countries - The present study aimed to investigate the association of insulin resistance (IR) with inflammatory gene expression levels, metabolic...     

Thrombospondin-1: an islet endothelial cell signal of importance for β-cell function

OBJECTIVE

Loss of thrombospondin (TSP)-1 in pancreatic islets has been shown to cause islet hyperplasia. This study tested the hypothesis that endothelial-derived TSP-1 is important for β-cell function.

RESEARCH DESIGN AND METHODS

Islet function was evaluated both in vivo and in vitro. Messenger RNA and protein expression were measured by real-time PCR and Western blot, respectively. The role of endothelial-derived TSP-1 for β-cell function was determined using a transplantation design in which recipient blood vessels either were allowed to grow or not into the transplanted islets.

RESULTS

TSP-1–deficient mice were glucose intolerant, despite having an increased β-cell mass. Moreover, their islets had decreased glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate, as well as increased expression of uncoupling protein-2 and lactate dehydrogenase-A when compared with control islets. Almost all TSP-1 in normal islets were found to be derived from the endothelium. Transplantation of free and encapsulated neonatal wild-type and TSP-1–deficient islets was performed in order to selectively reconstitute with TSP-1–positive or –negative blood vessels in the islets and supported that the β-cell defects occurring in TSP-1–deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells. Treatment of neonatal TSP-1–deficient mice with the transforming growth factor (TGF)β-1–activating sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented the development of decreased glucose tolerance in these mice. Thus, endothelial-derived TSP-1 activates islet TGFβ-1 of importance for β-cells.

CONCLUSIONS

Our study indicates a novel role for endothelial cells as functional paracrine support for pancreatic β-cells.The vasculature traditionally has been regarded mainly as a transport system that mediates metabolic exchange between tissues and blood. However, aside from its transport functions, blood-vessel cells have, in recent years, been recognized to be able to interact with and differentiate adjacent parenchymal cells through paracrine signals during development (1–3). Moreover, they seem to be able to provide mitotic signals during adulthood (4).To date, there have been few studies (5–7) on whether endothelial cells may directly affect parenchymal function. Islets of Langerhans in the adult have a uniquely dense network of capillaries maintained by constant exposure to vascular endothelial growth factor (VEGF)-A secreted from adjacent β-cells (8,9). The high number of islet capillaries results in each β-cell being located directly adjacent to at least one endothelial cell (10), thereby enabling a direct interaction with endothelium-derived factors. The importance of islet endothelial factors in the control of β-cell proliferation recently has been studied, and both endothelium-derived hepatocyte growth factor (11) and the vascular membrane component laminin (7) seem to be important in this context.In the current study, we investigated products of purified and isolated islet endothelial cells and thereby found the glycoprotein thrombospondin (TSP)-1 to be highly expressed in the endothelium of islets. TSP-1 is mainly known for its antiangiogenic properties (12) but also may alter the morphology of pancreatic islets and functions as a major activator of transforming growth factor (TGF)β-1 (13). Because TGFβ-1 is known to modulate β-cell function (14,15), we tested the hypothesis that endothelial cell–derived TSP-1 is important to maintain β-cell function postnatally.     

Immobilization of Candida rugosa lipase for resolution of racimic ibuprofen

AimDue to lipases’ regio-selectivity and ability to catalyze different reactions such as hydrolysis, esterification, and transesterification, the enzyme is attractive in biotransformation technology. Besides, another technology, namely enzyme immobilization, has attracted scientists/technologists’ attention to employ immobilized lipase in such a field. Thus lipase of Candida rugosa was immobilized onto silica nanoparticles through adsorption. Furthermore, the immobilized biocatalyst was characterized and used to esterify ibuprofen enantioselectively.MethodsTo characterize immobilized lipase onto silica nanoparticles scanning electron microscopy (SEM) and dynamic light scattering (DLS) were used.ResultsThe catalytic properties of both immobilized and free lipases such as optima pH and temperature were not different. According to the results, the immobilized lipase on silica nanoparticles showed 45% and 96% conversion (C) and enantioselectivity (ee_s), respectively. In comparison to free lipase, the immobilized enzyme came with better catalytic activity.ConclusionSilica nanoparticles as one of the most promising materials for the immobilization of lipase in enantioselective esterification of ibuprofen, were introduced in this work.Graphical abstract     

Rational design of peptide derivatives for inhibition of MyD88‐mediated toll‐like receptor signaling in human peripheral blood mononuclear cells and epithelial cells exposed to Francisella tularensis

Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88‐mediated toll‐like receptor (TLR) signaling by Francisella tularensis. Fifty‐three tripeptide derivatives were synthesized to mimic a key BB‐loop region involved in toll‐like/interleukin‐1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF‐α, IFN‐γ, IL‐6, and IL‐1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F. tularensis. From 53 compounds synthesized and tested, ten compounds were identified as effective inhibitors of F. tularensisLPS‐induced cytokines. Compound stability testing in the presence of human liver microsomes and human serum resulted in the identification of tripeptide derivative 7 that was a potent, stable, and drug‐like small molecule. Target corroboration using a cell‐based reporter assay and competition experiments with MyD88 TIR domain protein supported that the effect of 7 was through MyD88 TIR domain interactions. Compound 7 also attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis at a multiplicity of infection of 1:5. Small molecules that target TIR domain interactions in MyD88‐dependent TLR signaling represent a promising strategy toward host‐directed adjunctive therapeutics for inflammation associated with biothreat agent‐induced sepsis.