Abbreviations: AUC, area under the curve; AUCR a , area under the curve calculated for glucose R a ; AUCR d , area under the curve calculated for glucose R d ; B1-T4-Ins, N ␣B L-thyroxyl-insulin; CV, coefficient of variation; FPLC, fast protein liquid chromatography; GINF, exogenous glucose infusion; IRI, immunoreactive insulin; MCR, metabolic clearance rate; NEFA, nonesterified free fatty acid; R a , glucose production; R d , glucose disposal; RIA, radioimmunoassay; TBG, thyroxine binding protein; THBP, thyroid hormone binding protein; TSH, thyroid-stimulating hormone.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Novel Hepatoselective Insulin AnalogStudies with a covalently linked thyroxyl-insulin complex in humansOBJECTIVE -To test whether a thyroxyl-insulin analog with restricted access to receptor sites in peripheral tissues displays relative hepatoselectivity in humans.RESEARCH DESIGN AND METHODS -Five normal human subjects received a subcutaneous bolus injection of either N ␣B1 L-thyroxyl-insulin (B1-T4-Ins) or NPH insulin in random order. Insulin kinetics, relative effects on hepatic glucose production, and peripheral glucose uptake were studied using euglycemic clamp and stable isotope [D-6,6-2 H 2 ]glucose) dilution techniques. Blood samples were taken for the determination of total immunoreactive insulin/analog concentrations and for liquid chromatography to assess the protein binding of the analog in the circulation.RESULTS -After subcutaneous administration, B1-T4-Ins was well tolerated and rapidly absorbed. The analog had a long serum half-life and was highly protein bound (ϳ86%). Its duration of action, as judged by the duration of infusion of exogenous glucose to maintain euglycemia, was similar to that of NPH insulin. The effect of the analogs on hepatic glucose production was similar to that of NPH insulin, indicating equivalent hepatic potency. The analog demonstrated less effect on peripheral glucose uptake than NPH insulin (P = 0.025), had no effect on metabolic clearance rate of glucose, and exhibited a reduced capacity to inhibit lipolysis (P Ͻ 0.05).CONCLUSIONS -When injected subcutaneously into normal human subjects, B1-T4-Ins is well tolerated, quickly absorbed, and highly protein bound, resulting in a long plasma halflife. This analog appears to have a hepatoselective action, and, therefore, has the potential to provide more physiological insulin action than the insulin preparations currently used. E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s

Using RT-PCR, the present study investigated the effects of formalin administration on mRNA expression coding for NMDA receptor (NR) subunits and splice variants in rat lumbar spinal cord. Subsequent to formalin injection (5%; subcutaneously) into the hind paw of Sprague-Dawley rats, the animals exhibited the typical biphasic behavioural pain response. Spinal cord (L3-6) was prepared six hours after formalin injection. In controls, NR1-b predominated over NR1-a, and NR1-2 and NR1-4 exceeded over NR1-1 and NR1-3, respectively. Regarding the NR2 subunit expression in controls, NR2B exhibited the highest expression, followed by decreasing proportions of NR2C, NR2A, and NR2D. Formalin treatment did not affect NR1 splice variant expression but significantly increased and decreased the proportion of NR2A and NR2C, respectively. In summary, the present data demonstrate adaptive changes in the NR subunit expression pattern in rat spinal cord due to formalin injection.

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Covalently linked insulin dimers have been prepared by cross-linking two insulin monomers with a flexible suberoyl chain at either the B1 phenylalanine or the B29 lysine residue. Binding potencies of dimers determined by inhibition of binding of 125I-insulin to isolated rat liver plasma membranes or adipocytes were 2.5-7-fold greater than their abilities to stimulate lipogenesis in adipocytes. Rates of liver plasma-membrane-associated degradation of labelled insulin and dimers, measured by gel filtration, were similar at 37 degrees C. Binding and lipogenesis potencies of dimers prepared by substitution of each monomeric half of an asymmetrical dimer with desoctapeptide insulin, an almost inactive derivative, implicated the B1-cross-linked monomeric half as predominantly interacting with the insulin receptor. These results suggest that (1) dimers bind univalently to a bivalent insulin-receptor complex, in which the two individual binding subunits are arranged with anti-parallel symmetry and (2) the mechanism by which insulin binds and initiates its biological responses requires a conformational change within the insulin-receptor complex and/or in the insulin molecule for full biological expression.