To evaluate the effects of Diprivan and Intralipid on the insulin response, Diprivan and Intralipid were added to the perfusate 3 minutes before insulin administration. In accordance with previous reports in rat hearts,26,27 insulin administration was accompanied with mild negative inotropic effects (Table 2). Intralipid reduced glucose uptake in both healthy and diabetic hearts by 25% and 61% of insulin response on average, respectively (Fig. 1A). Likewise, Diprivan reduced glucose uptake to a greater extent in both healthy and diabetic hearts by 48% and 109% of the insulin response, respectively (Fig. 1A). The reduced glucose uptake in Diprivan-treated healthy hearts and Diprivan-treated and Intralipid-treated diabetic hearts was due to a reduction in glycolytic flux rates (Fig. 1B). In insulin-stimulated healthy hearts, the treatment with both fat emulsions decreased total glycogen content (Fig. 1C), with the most profound effect occurring in the Intralipid group (h-INS versus h-INS/IL post hoc; P = 0.008). Conversely, glycogen levels increased in diabetic hearts (Fig. 1C), again with the largest effect occurring in the Intralipid group (ff-INS versus ff-INS/IL post hoc; P = 0.043). Consistent with reduced oxidative capacity in diabetic hearts, as measured by citrate synthase activity (Table 1), glucose was diverted from substrate oxidation to glycogen storage when exposed to fat emulsions. Together, these data show that Diprivan and Intralipid promote insulin resistance, predominantly in diabetic hearts.
GLUT4 protein content was reduced in insulin-stimulated diabetic hearts (Panel A in Supplemental Digital Content 4, which shows differences in protein expression and phosphorylation of insulin-stimulated healthy and diabetic hearts, http://links.lww.com/AA/B35), but membrane translocation was largely maintained (data not shown). When comparing the effect of Diprivan and Intralipid on GLUT4 trafficking to the sarcolemma in the healthy hearts, there was a clear propofol-specific impairment (Fig. 2A). GLUT4 translocation to the membrane was also reduced in Diprivan-treated and Intralipid-treated diabetic hearts (Fig. 2A). This was consistent with reduced glycolysis and glucose uptake, as measured with the radioactive tracer in the respective groups. The analysis of the glycolytic metabolites further revealed that only Diprivan reduced phosphofructokinase-1 activity in diabetic but not in healthy hearts (Supplemental Digital Content 5, a table showing glycolytic metabolites, http://links.lww.com/AA/B36). In terms of IRS-1 phosphorylation at Ser1100(h1101), there was also an evident propofol-specific effect in both healthy and diabetic hearts (Fig. 2B). Phosphorylation of IRS-1 at Ser307(h312) was already increased in diabetic hearts independent of any treatment (Fig. 2C, and Panel B in Supplemental Digital Content, http://links.lww.com/AA/B35). Phosphorylation of Tyr608(h612) of IRS-1 was similar between healthy and diabetic hearts and not affected by either treatments (Fig. 2D). There was no difference in the expression of IRS-1 between healthy and diabetic hearts (data not shown). Overall, propofol impairs GLUT4 trafficking and specifically increases serine phosphorylation of IRS-1. Intralipid impairs GLUT4 trafficking only in type-2 diabetic hearts.
By comparing the pattern of metabolic kinase phosphorylation between Diprivan and Intralipid treatment in insulin-stimulated healthy hearts, we observed that propofol specifically increased Akt phosphorylation at Ser473 and Thr308 (Fig. 3, A and B). Diprivan and Intralipid similarly enhanced GSK3β phosphorylation (Fig. 3C), but neither treatment had any effect on AMPK phosphorylation (Fig. 3D) nor any of the stress kinases tested (Fig. 4). However, in diabetic hearts, neither Diprivan nor Intralipid affected Akt phosphorylation at Ser473 or Thr308. GSK3β and AMPK phosphorylation were similarly enhanced by both Diprivan and Intralipid treatment in diabetic hearts (Fig. 3, C and D). Diprivan and Intralipid treatment further activated ERK1/2 exclusively in diabetic hearts (Fig. 4A). Only Diprivan activated p38MAPK and S6K1 in diabetic hearts (Fig. 4, B and C). Expression of JNK was increased in diabetic hearts (Panel C in Supplemental Digital Content 3, http://links.lww.com/AA/B34), but there was no difference in phosphorylation in response to Diprivan or Intralipid treatment (Fig. 4D). Membrane and total tissue expression of the novel PKCθ was increased in diabetic hearts (Panel D in Supplemental Digital Content 3, http://links.lww.com/AA/B34). Only Diprivan significantly increased PKCθ translocation to the membrane in healthy hearts (Fig. 5A). The conventional PKCβII was activated only in Diprivan-treated healthy and diabetic hearts (Fig. 5B). PKC activation by Diprivan only clearly indicates a propofol-specific effect. There was no increase in total expression of Akt, GSK3β, AMPK, ERK1/2, p38MAPK, S6K1, and PKCβII in diabetic hearts compared with healthy hearts (data not shown). Likewise, there was no change in phosphorylation of Akt, GSK3β, AMPK, ERK1/2, p38MAPK, and S6K1.
To determine whether diabetic hearts exposed to Diprivan or Intralipid showed changes in concentrations of potentially toxic lipid species, we examined the concentrations of phospholipids and sphingolipids in cardiac tissue extracts using mass spectrometry. These measurements showed accumulation of the phospholipids phosphatidylglycerol and phosphatidylethanolamine in Diprivan-treated and Intralipid-treated diabetic hearts (Table 3). Unexpectedly, only Diprivan but not Intralipid reduced ceramide levels in diabetic hearts. In healthy hearts, both Diprivan and Intralipid reduced phosphatidylethanolamine, the most abundant sphingoid base C18-sphingosine, and its saturated counterpart C18-sphinganine (Table 3). Diprivan was more effective than Intralipid in increasing C18-sphingosines and sphingadienes in diabetic hearts.
Our study shows the following salient findings. First, insulin-stimulated glucose uptake was reduced in Diprivan-treated healthy hearts, and the reduction in glucose uptake under Intralipid treatment almost reached statistical significance (P = 0.078). However, only Diprivan abolished the action of insulin on glycolytic flux. This was accompanied by impaired GLUT4 trafficking to the sarcolemma. Conversely, healthy hearts responded to insulin in the presence of Intralipid and increased glycolytic flux, implying that Intralipid alone only marginally affects insulin sensitivity.28 Possibly, the release of intracellular glucose stores from glycogen due to unsaturated fatty acid–induced activation of glycogen phosphorylase34 caused the reduction in glucose uptake without changing GLUT4 trafficking. Glycerol, another constituent of Intralipid, may have further contributed to pyruvate formation and thus reduced glucose uptake.35 Together, these results indicate that propofol itself acutely promotes insulin resistance in healthy hearts. This conclusion is also supported by our observation that Diprivan, but not Intralipid, caused marked activation and membrane translocation of PKCθ and PKCβII as well as the phosphorylation at Ser1100(h1101) of the IRS protein IRS-1, a key player in insulin signaling.36,37 More recently, insulin resistance and feedback inhibition of insulin signaling were found to be mediated by serine/threonine phosphorylation of IRS-1.36,37 There are as many as 50 serine phosphorylation sites of IRS-1 and most of them negatively modulate insulin effects, whereas multiple (so far at least 8) tyrosine phosphorylation sites of IRS-1 have opposite effects.37 Ser1100(h1101) of IRS-1 is a target of PKCθ,38 the importance of which in insulin signaling is further supported by studies showing the lack of insulin resistance to dietary challenge in PKCθ-knockout mice.39,40 Overexpression of PKCβII in mouse skeletal muscle induces insulin resistance.41 Both PKC isoforms further inhibit insulin receptor tyrosine kinase by serine phosphorylation.42 Interestingly, healthy hearts exposed to Diprivan showed increased Akt phosphorylation at Ser473 and Thr308, consistent with full Akt activation. It appears that Akt signaling in Diprivan-treated healthy hearts is dysfunctional. However, it inhibits phosphatases,43 and it has been reported that sustained phosphorylation of Akt mediates insulin-induced feedback inhibition44 and thus contributes to cardiac insulin resistance.45
Second, both Diprivan and Intralipid abolished the action of insulin on glycolytic flux in early diabetic hearts and impaired GLUT4 trafficking to the sarcolemma. In addition, Diprivan decreased phosphofructokinase-1 activity in these hearts. The reduced insulin sensitivity in diabetic hearts exposed to Diprivan and Intralipid was closely linked to increased phosphorylation of AMPK and stress kinases (ERK1/2 and p38MAPK). Insulin inhibits cardiac AMPK, and hearts perfused in the absence of insulin have been reported to show higher AMPK phosphorylation than hearts perfused in the presence of insulin.46 In fact, phosphorylation of AMPK at Ser485 or Ser491 is responsible for the effect of high insulin concentrations to blunt AMPK activation (Thr172 site) in the heart.47 Our data are thus consistent with the concept that activation of AMPK ensures adequate cardiac energy production when glucose utilization is compromised.48 AMPK also inhibits insulin signalling by phosphorylating IRS-1 at Ser789(h794).49 Diprivan-mediated and Intralipid-mediated insulin resistance and AMPK activation may have also lead to the observed accumulation of glycogen in diabetic hearts.50 Consistent with this interpretation, glycogen synthase kinase-3β phosphorylation was increased in Diprivan-treated and Intralipid-treated diabetic hearts leading to the activation of glycogen synthase. Finally, increased ERK1/2 and p38MAPK activities also inhibit IRS-1 by phosphorylation at Ser612 (ERK1/2)37,51 and Ser636 (p38MAPK),52 respectively. In diabetic hearts, only Diprivan treatment activated PKCβII and the proinflammatory S6K1, which also promotes Ser1100(h1101) phosphorylation of IRS-1,53 again implying distinct diabetogenic effects of propofol itself.
Third, our study shows for the first time that administration of Diprivan and Intralipid leads to accumulation of potentially diabetogenic lipids in the heart. A recent study found that prediabetes and type-2 diabetes are associated with increased plasma levels of phosphatidylethanolamine, phosphatidylglycerol, and ceramides.54 Lysophosphatidylcholine, another phospholipid, is reportedly an efficient effector of fatty acid–induced insulin resistance.55 Lysophosphatidylcholine activates JNK, which phosphorylates IRS-1 at Ser307(h312). Moreover, the increased levels of phosphatidylethanolamine detected in our study in the diabetic myocardium exposed to Diprivan and Intralipid may exert strong proinflammatory effects when oxidized or glycated.56 Recent studies also linked increased plasma sphingolipid levels to impaired insulin signaling.22
Taken together, our data suggest that propofol and Intralipid activate key kinases involved in serine/threonine phosphorylation of IRS-1 and thereby reduce insulin signaling (Fig. 6). Increased serine phosphorylation of IRS-1 reduces GLUT4 trafficking either downstream via reduced phosphoinositide 3-kinase activation45,57,58 or upstream via inhibition of insulin receptor tyrosine kinase activity,59 which initiates small GTPase (TC10)–mediated phosphoinositide 3-kinase–independent GLUT4 exocytosis.57
Because insulin resistance is tightly associated with increased morbidity and mortality,4–6 it is possible that further impairment of insulin signaling by Diprivan or Intralipid treatment in at-risk patients with diabetes may worsen clinical outcomes. A meta-analysis in surgical and critically ill patients reported higher complication rates in subgroups of patients treated with lipid-based parenteral nutrition compared with patients receiving lipid-free formulations.60 Hence, future studies in at-risk patients are necessary to address the relevance of our experimental observations in the clinical setting.
In conclusion, our experiments show that Diprivan and Intralipid reduce glucose uptake predominantly in diabetic hearts. The loss of metabolic flexibility is triggered by alterations in insulin signaling and GLUT4 trafficking and accompanied by accumulation of potentially diabetogenic lipids.
T. Hornemann and A. Zhakupova are grateful to the Center of Integrated Human Physiology (ZIHP) and the “radiz”–Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich.
a Available at: http://rsbweb.nih.gov/ij/. Accessed December 1, 2008.
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