Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 µg·kg-1·h-1, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do2) and consumption (V̇o2) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do2 all significantly decreased with trauma, but renal V̇o2 was unchanged. GLP-1 treatment normalized RBF, GFR, and Do2 without affecting V̇o2. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

Self-assembling hydrogels crosslinked solely by receptor-ligand interactions: tunability, rationalization of physical properties, and 3D cell culture.

We report a novel, noncovalent hydrogel system crosslinked solely by receptor-ligand interactions between biotin and avidin. The simple hydrogel synthesis and functionalization together with the widespread use of biotinylated ligands in biosciences make this versatile system suitable for many applications. The gels possess a range of tunable physical properties, including stiffness, lifetime, and swelling. The erosion rates, unexpectedly fast compared to the kinetic parameters for biotin-avidin, are explored in terms of stretching tensions on the polymers, a concept well-known on the single-molecule level, but largely unexplored in supramolecular systems. As proof of utility, the gels were functionalized with different peptide sequences to control human mesenchymal stromal cell morphology in 3D culture.

SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion.

Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin-related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse ß-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO-1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes.

Cementless acetabular fixation with and without screws: analysis of stability and migration.

The purpose of this study was to compare initial stability and late migration of 775 cementless acetabular components with and without screw fixation. Screw fixation was used in 509 cups and no screws in 266 cups. Average follow-up in the screw fixation group was 6.32 years (range, 2-10 years) and 6.9 years (range, 2-10 years) in the no-screw group. One component (0.2%, osteolysis) in the screw group and one (0.4%, loss of fixation) in the no-screw group required revision. Osteolytic lesions more than 4 cm(2) were noted in 8 (1.6%) screw fixation cups and 2 (0.75%) no-screw fixation cups. No cups in either cohort had radiographic evidence of migration. Screw fixation did not have a favorable or adverse effect on the outcome of acetabular reconstruction.

Unusual Fe9 and Fe18 structural types from the use of 2,6-pyridinedimethanol in Fe(III) cluster chemistry.

The syntheses, crystal structures and magnetochemical characterization are reported for two new Fe(III) complexes [Fe(18)O(6)(OH)(8)(pdm)(10)(pdmH)(4)(H(2)O)(4)](ClO(4))(10) (3) and [Fe(9)O(4)(OH)(2)(O(2)CMe)(10)(pdm)(pdmH)(4)](NO(3)) (4). They were synthesized from the use of the potentially O,N,O tridentate chelate, 2,6-pyridinedimethanol (pdmH(2)), in the presence or absence of carboxylate groups. Octadecanuclear complex 3 was obtained during reactivity studies on previously-reported [Fe(8)O(3)(OEt)(pdm)(4)(pdmH)(4)(EtOH)(2)](ClO(4))(5) (2), the latter undergoing hydrolysis to 3 on recrystallization from undried MeCN. The reaction of pdmH(2) with preformed [Fe(3)O(O(2)CMe)(6)(py)(3)](NO(3)) in CH(2)Cl(2) gave enneanuclear complex 4. Both complexes 3 and 4 are unprecedented structural types. The core of 3 comprises a central [Fe(4)O(6)] defective-dicubane attached on either side to a [Fe(7)O(11)] unit, which can be described as two [Fe(4)(µ(4)-O)] tetrahedra fused at a common Fe atom. The core of 4 can be considered as four vertex-fused triangular [Fe(3)(µ(3)-O)] units. Variable-temperature (T) and -field (H) solid-state dc and ac magnetization (M) studies were carried out on complexes 3 and 4 in the 1.8-300 K range. Analysis of the obtained data revealed that complexes 3 and 4 possess an S = 4 and S = 5/2 ground state spin, respectively.