Phlorizin increased myocardial injury after ischemia-reperfusion.

<p>(A) CPK profiles in the effluent collected during the reperfusion period. (B) Area under the curve (AUC) was calculated from the CPK profile shown in (A). (phlorizin-perfused hearts, n = 11; control hearts, n = 10). (C) Micrograph showing representative TTC staining of cardiac sections obtained from the control (top row) and phlorizin-perfused hearts (bottom row). (D) Effects on quantitated cumulative infarct area size in the phlorizin-perfused hearts (n = 9) compared with that observed in the control group (n = 8). %MI, myocardial infarct area/ventricular area. *P<0.05 and **P<0.01 versus control.</p

Phlorizin reduced tissue ATP content in the heart, associated with decreased glucose uptake and glycolytic flux during IRI.

<p>(A) Ischemic contracture was observed as a sigmoid increase in end-diastolic pressure, the onset and extent of which was recorded. The definitions of the individual parameters are shown. (B) The tissue ATP content in the hearts measured at the indicated time points (Ischemia 0 minutes: n = 4 each, Ischemia 5 minutes: n = 4 each, Ischemia 20 minutes: phlorizin-perfused; n = 4, control; n = 7, Reperfusion 10 minutes: phlorizin-perfused; n = 7, control; n = 8, Reperfusion 40 minutes: phlorizin-perfused; n = 7, control; n = 8). *P<0.05 versus control. (C) Glucose uptake in the hearts perfused with or without phlorizin under the pre-ischemic baseline condition (n = 6 each) and post-ischemic condition measured at 10-minute reperfusion following 20-minute global ischemia (phlorizin-perfused; n = 7, control; n = 6). **P<0.01 versus the control hearts at baseline; ^†P<0.01 versus the phlorizin-perfused hearts at baseline; ^$P<0.05 versus the control hearts at post-ischemia. (D) Glycogen content in the perfused hearts under the baseline condition prior to global ischemia (n = 4 each). (E) Lactate output profiles in the effluent collected during the reperfusion period (n = 10 each). *P<0.05 versus control. (F) AUC was calculated from the lactate output profiles shown in (E) (n = 10 each). *P<0.05 versus control.</p

SGLT1 is highly expressed in human hearts.

<p>(A) Results of the immunohistochemical analysis of the SGLT1 expression in the various parts of the myocardium (in each panel: left, HE staining; right, immunostaining with an SGLT1 antibody) obtained from the human autopsied hearts (x40). Representative data from five independent patients are shown. Bars: 20 μm. (B) Immunohistochemical analysis of the SGLT1 expression using the same antibody in the brush border membrane of the human small intestine (left panel, x10, bar: 100 μm) and proximal tubule straight segment in the deep cortex and medullary rays (Cortico-medullary junction) of human kidneys (mid panel, x10, bar: 100 μm; right panel, x2, bar: 1mm) obtained from intraoperative samples shown as positive controls. (C) Representative immunoblots of SGLT1 in the membrane fraction from the indicated regions in the human autopsied hearts from four independent patients are shown. Total lysates extracted from the human autopsied small intestine and kidneys were immunoblotted as positive controls. Immunoblots of Na⁺/K⁺ ATPase from the same membrane are shown as a loading control for the membrane fraction.</p

Possible increase in insulin resistance and concealed glucose-coupled potassium-lowering mechanisms during acute coronary syndrome documented by covariance structure analysis

<div><p>Objective</p><p>Although glucose-insulin-potassium (GIK) therapy ought to be beneficial for ischemic heart disease in general, variable outcomes in many clinical trials of GIK in acute coronary syndrome (ACS) had a controversial impact. This study was designed to examine whether “insulin resistance” is involved in ACS and to clarify other potential intrinsic compensatory mechanisms for GIK tolerance through highly statistical procedure.</p><p>Methods and results</p><p>We compared the degree of insulin resistance during ACS attack and remission phase after treatment in individual patients (n = 104). During ACS, homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly increased (P<0.001), while serum potassium levels were transiently decreased (degree of which was indicated by ΔK) (P<0.001). This finding provides a renewed paradox, as ΔK, a surrogate marker of intrinsic GIK cascade activation, probably reflects the validated glucose metabolism during ischemic attack. Indeed, multiple regression analysis revealed that plasma glucose level during ACS was positively correlated with ΔK (P = 0.026), whereas HOMA-IR had no impact on ΔK. This positive correlation between ΔK and glucose was confirmed by covariance structure analysis with a strong impact (β: 0.398, P = 0.015). Intriguingly, a higher incidence of myocardial infarction relative to unstable angina pectoris, as well as a longer hospitalization period were observed in patients with larger ΔK, indicating that ΔK also reflects disease severity of ACS.</p><p>Conclusions</p><p>Insulin resistance most likely increases during ACS; however, ΔK was positively correlated with plasma glucose level, which overwhelmed insulin resistance condition. The present study with covariance structure analysis suggests that there are potential endogenous glucose-coupled potassium lowering mechanisms, other than insulin, regulating glucose metabolism during ACS.</p></div