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First, we analyzed the binding characteristics of insulin glargine and its metabolites M1, M2, and IM to IR-A and IR-B. Using plasma membranes from CHO cells that overexpress the receptor isoforms, the IC 50 value for competition of unlabeled ligand with a constant concentration of radioactively labeled human insulin were determined as a measure of affinity. The results are shown in Table 1 with representative competition curves given in Figure 2 A and B . Both IR isoforms bound human insulin with high affinity that did not significantly (p = 0.23) differ between IR-A (IC 50  = 0.49 nmol/L) and IR-B (IC 50  = 0.57 nmol/L). In contrast, IR-A displayed a considerably higher affinity for IGF-1 (2.7-fold) and IGF-2 (7.5-fold) than IR-B, but the affinity of IR-A and IR-B for IGF-1 were approximately 130- and 300-fold, respectively, less potent than those for human insulin. Both isoforms bound IGF-2 with higher affinity than IGF-1 but with lower affinity than human insulin. These data are consistent with results published previously [35] [39] and demonstrated the validity of our experimental system.

Figure 2. Binding and signaling of insulin glargine and its metabolites to the human insulin receptor isoform A and B.

Binding of the insulin analogs to the human IR-A ( A ) or IR-B ( B ) was analyzed in a competitive binding assay using SPA technology. The binding of a constant concentration of [ 125 I]insulin to plasma membranes from CHO cells overexpressing either IR-A or IR-B was measured in presence of increasing concentrations of unlabeled competing ligand after incubation at room temperature for 12 h. All data has been corrected for non-specific binding and are expressed as percentage of [ 125 I]insulin in absence of competing ligand. To analyze the insulin-stimulated activation and subsequent autophosphorylation of the insulin receptor CHO cells overexpressing the human IR-A ( C ) or IR-B ( D ) were stimulated for 15 min at 37°C with increasing concentrations of peptides, then the cells were fixed with 3.7% PFA and the amount of phosphotyrosines was analyzed via In-Cell Western. The data represent mean values ± SEM of at least 3 individual experiments measured in quadruplicate.

https://doi.org/10.1371/journal.pone.0009540.g002

Table 1. Summarized data for insulin and glargine metabolites.

https://doi.org/10.1371/journal.pone.0009540.t001

Insulin glargine and its metabolites IM, M1, and M2 showed no difference in their respective binding affinities to the two IR isoforms and were only 40–50% less active than human insulin. In contrast, [Asp B10 ]insulin showed significant isoform selectivity, being 3.5-fold more active towards IR-A (p<0.01), and was 8.2- and 2.7-fold more potent in binding to IR-A and IR-B, respectively, relative to human insulin.

Morphine and SB Reduce Infarct Size in Vivo.

Improvement in Oxidative Phosphorylation of Cardiac Mitochondria Isolated from Rats Treated with Morphine and SB. Table 1 showed that the respiratory control ratio of mitochondria isolated after 35 min of ischemia and a 2-h reperfusion in the control group was decreased by 58%. This was related to the decrease in state 3 (ADP-stimulated) respiration rate because state 4 (substrate) respiration rate was unaffected. Thus, ischemia-reperfusion did not disrupt the integrity of the inner membrane of isolated mitochondria. When the oxygen consumption was increased by the presence of the uncoupling agent, carbonyl cyanide 4-trifluoromethoxyphenylhydrazone (FCCP), which removed the contribution of the phosphorylation system, ischemia-reperfusion decreased the extent by which FCCP stimulated state 4 respiration rate, indicating a limitation of the activity of the electron transport chain ( Table 1 ).

Improvement in Oxidative Phosphorylation of Cardiac Mitochondria Isolated from Rats Treated with Morphine and SB.
View this table:
TABLE 1

Respiratory parameters of mitochondria issued from the myocardial area at risk of rats subjected to 35 min of ischemia (I) and either 10 (R) or 120 min (R) of reperfusion after treatments with vehicle (control), morphine (0.3 mg/kg), or SB (0.6 mg/kg)

Mitochondria (0.4 mg/ml) were incubated with 5 mM pyruvate and 5 mM malate at 25°C, and then the respiratory rates were measured. O consumption was expressed as O nanomole per minute per milligrams of proteins. Each value represents the mean ± S.E.M. of six independent experiments performed in triplicate.

Fig. 1.

Effect of morphine and SB on myocardial infarct size expressed as a percentage of the AAR in regional ischemic (35 min), reperfused (2 h), and anesthetized rats. = number of treated rats per group; *, < 0.05 versus control.

Morphine and SB improved oxidative phosphorylation as demonstrated by increases in both respiratory control ratio and ADP/O values. This was due to the partial restoration of state 3 respiration rate promoted by the increase in the activity of the electron transport chain, which is evidenced in the presence of FCCP ( Table 1 ). Indeed, morphine and SB restored (+87 and +76%, respectively) the FCCP-accelerated state 4 respiration rate altered by ischemia-reperfusion. The improvement of oxidative phosphorylation parameters was also observed when cardiac mitochondria were isolated after 2-h reperfusion ( Table 1 ).

Cardiac Mitochondria Isolated from Morphine- or SB-Treated Rats Are Less Sensitive to mPTP Opening. As shown in Fig. 2 , the amount of Ca 2+ required to trigger mPTP opening in sham-operated rats reached 94 ± 7 nmol/mg mitochondrial proteins. Control ischemia-reperfusion significantly reduced the capacity of mitochondria to retain Ca 2+ before mPTP opening, regardless of the duration of reperfusion (29.5 ± 6 and 27.8 ± 7 nmol/mg proteins for 10-min and 2-h reperfusion, respectively). Morphine significantly increased the resistance to mPTP opening to Ca 2+ during reperfusion (59.7 ± 8.2 and 54.9 ± 6.8 nmol/mg protein for 10-min and 2-h reperfusion, respectively), whereas it did not modify this sensitivity when the drug was administrated to sham-operated rats (97.5 ± 3.9 nmol/mg protein). Like morphine, SB also significantly increased the resistance to mPTP opening to Ca 2+ during reperfusion (66.5 ± 3.5 and 66.4 ± 8.7 nmol/mg protein for 10-min and 2-h reperfusion, respectively).

View larger version:
Figure 1

The proposed role of adiponectin in renal pathophysiology and the interplay between adiponectin and renal injury. AMPK, AMP-activated protein kinase; ADIPOR1, adiponectin receptor 1. A full colour version of this figure is available at http://dx.doi.org/10.1530/JOE-13-0578

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In steady-state subjects, in whom plasma adiponectin levels do not change over time, urinary adiponectin excretion rate (as assessed by the ratio urinary adiponectin:urinary creatinine) equates with adiponectin production rate in adipose tissue – hepatic adiponectin excretion rate. The urinary adiponectin excretion rate has been reported to be positively correlated with UAE and negatively with GFR ( SOPHIA WEBSTER 10MM SERAPHINA LEATHER amp; SUEDE FLATS 0JBCL
, Fujita et al . 2006 , Saint LaurentLeather High Trainers hBjI6
). The positive relationship between urinary adiponectin excretion rate and UAE has been shown to strengthen with increasing UAE; this association has been found to exist mainly in patients with macroalbuminuria (UAE >300 mg/24 h) or microalbuminuria (UAE between 30 and 300 mg/24 h) and less consistently in subjects with normoalbuminuria ( Koshimura et al . 2004 , Fujita et al . 2006 , Jorsal et al . 2013 ). Thus, in patients with increased UAE or decreased GFR, the adiponectin production rate – hepatic adiponectin excretion rate – appears to be increased. This elevation could be attributed to an increased rate of adiponectin production, because adiponectin expression and adiponectin protein content in visceral as well as subcutaneous adipose tissue were found to be increased in patients with end-stage renal disease ( Martinez Cantarin et al . 2013 ). Studies investigating the possible modulation of hepatic adiponectin excretion rate in patients with renal disease are lacking, and thus further studies investigating this issue are needed. Taking into account the renoprotective properties of adiponectin mentioned earlier, a plausible explanation for the upregulation of adipose tissue adiponectin production in patients with albuminuria or decreased GFR is that adiponectin production in adipose tissue and secretion into the bloodstream is enhanced via an as yet unknown mechanism to mitigate renal injury. Consistently, Scarosso Italo Nero Nubuck fzyzz
found that adiponectin accumulated in the glomeruli and interstitium of the remnant kidney of WT mice to counteract for the subtotal nephrectomy-induced renal injury. In addition, serum adiponectin levels have been found to be positively correlated with urinary levels of markers of renal tubulointerstitial injury in diabetics, such as N -acetylglucosaminidase and MCP1 ( Fujita et al . 2006 ). Moreover, exposure of proximal tubular cells to recombinant adiponectin has been reported to result in decreased MCP1 secretion ( Shen et al . 2008 ).

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Morishita, J., Matsusaka, T., Goshima, G., Nakamura, T., Tatebe, H. and Yanagida, M.

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