J Diabetes Res. 2016;2016:8178936. doi: 10.1155/2016/8178936.

The Actions of Lyophilized Apple Peel on the Electrical Activity and Organization of the Ventricular Syncytium of the Hearts of Diabetic Rats.

Martínez-Ladrón de Guevara E1, Pérez-Hernández N2, Villalobos-López MÁ3, Pérez-Ishiwara DG2, Salas-Benito JS2, Martínez Martínez A1, Hernández-García V1.
  • 1Institute of Biomedical Sciences, Autonomous University of Ciudad Juárez, 32310 Ciudad Juárez, CHIH, Mexico.
  • 2National School of Medicine and Homeopathy, National Polytechnic Institute, 07320 Mexico City, DF, Mexico.
  • 3Centre for Research in Applied Biotechnology, National Polytechnic Institute, 90700 Tepetitla, TLAX, Mexico.



This study was designed to examine the effects of lyophilized red delicious apple peel (RDP) on the action potentials (APs) and the input resistance-threshold current relationship. The experiments were performed on isolated papillary heart muscles from healthy male rats, healthy male rats treated with RDP, diabetic male rats, and diabetic male rats treated with RDP. The preparation was superfused with oxygenated Tyrode’s solution at 37°C. The stimulation and the recording of the APs, the input resistance, and the threshold current were made using conventional electrophysiological methods. The RDP presented no significant effect in normal rats. Equivalent doses in diabetic rats reduced the APD and ARP. The relationship between input resistance and threshold current established an inverse correlation. The results indicate the following: (1) The functional structure of the cardiac ventricular syncytium in healthy rats is heterogeneous, in terms of input resistance and threshold current. Diabetes further accentuates the heterogeneity. (2) As a consequence, conduction block occurs and increases the possibility of reentrant arrhythmias. (3) These modifications in the ventricular syncytium, coupled with the increase in the ARP, are the adequate substrate so that, with diabetes, the heart becomes more arrhythmogenic. (4) RDP decreases the APD, the ARP, and most syncytium irregularity caused by diabetes.

PMID: 26839897




Apple daily consumption has been associated with multiple health benefits, particularly on the cardiovascular system. These benefits are attributable to the polyphenols, which are more abundant in the apple peel. Therefore, the principal objective of our work was to evaluate if the lyophilized red delicious apple peel (RDP) had a quantifiable action, from an electrophysiological point of view, on experimental type 1 diabetes well establish and widely used by scientists interested on the study of this pathology.

For this purpose, and considering that we needed to obtain reliable experimental evidence from the action of apple peel, personally we perform the following actions in order to avoid, as much as possible, any alteration of the biological active compounds contained in the apple:

1) Lyophilization of the red delicious apple peel (RDP) (Figure 1A)

2) Pulverization of the RDP (Figure 1B)

3) Provide the daily oral dose of 150 mg/kg of RDP to each rat (Figure 1C)

4) Ensure the quality of life of the rats (healthy, diabetic with or without RDP) (Figure 1D).




Under normal conditions the generation, the propagation and the duration of action potentials (APs) in the heart is performed by the interaction of their passive and active properties [1]:

1) The passive properties are determined by:  the cellular structural geometry, the morphology, the cellular dimensions, the amount and spatial distribution of the gap junctions (nexus) that interconnect the cardiac myocytes (structure and functional organization of the ventricular syncytium)

2) The active properties depend on: the distribution, the amount, conductance and kinetic characteristics of the different ionic channels (INa+, Ito, IK, IKir, IKr, IKur,IKs,Ica2+,INa/Ca,), transporters and exchangers express on the sarcolemma of the cardiac myocytes.

Thus, interactions between these proprieties during the propagation of the action potentials confer the ability to the heart to performance like a functional syncytium.



Diabetes Mellitus (DM) is a syndrome characterized by chronic hyperglycemia and alterations of the metabolism of carbohydrates, lipids and proteins produced by total deficiency of insulin (type 1) or impaired action of insulin (type 2) [2].

The hearts of rats with induced type 1 diabetes show that the increase of the action potential duration (APD) on ventricular myocytes is associated with a decrease of density of the repolarization currents of potassium (active properties), specifically the transitory potassium current (Ito) and the stable state potassium current (IK). Furthermore, the increase of APD provoke by DM is of different magnitude depending from the area of the heart. Thus, the increase of the APs are major in endocardium that epicadium [3,4,5]. These findings indicate that DM induces remodeling of the potassium ionic channels (active proprieties) which affects the electrical activity of the heart. Interestingly, this electrical remodeling of the potassium channels occurs in the first week of the establishment of diabetes [6]. Therefore, the most consistent interpretation is that the increase in the DPA origins a refractory period dispersion, which makes the heart more vulnerable to suffer arrhythmias and increase the probability of sudden death in diabetes [7].



It is well known than in humans with diabetes and rodents with experimental induced type 1 DM, by streptozotocin, the following phenomena appear with time:

1) Cell death, apoptosis and necrosis [8,9]

2) Decrease in conductivity and uncoupling of cardiac myocytes [9]

3) Reduction of the expression of connexin 43 in diabetic rat heart, which is the more abundant protein on the formation of nexus in the ventricular myocardiac tissue [10,11,12,13,14].

In these new conditions, the geometry organization of the ventricular tissues changes and acquires a new organization (remodeling). Consequently, in diabetes occur two important events in the heart:

1) Electric remodeling (active proprieties) is a result of the increase in DPA and the magnitude of the Absolute refractory period

2) Structural and functional remodeling of the ventricular syncytium (passive properties) due to the alteration of the propagations of the AP.

In conclusion, in order to develop an arrhythmogenic heart activity in organisms with diabetes is necessary the alteration not only in the potassium currents, but also in the structural and functional organization of the ventricular syncytium.



Definitely, the action mechanism or mechanisms that take place by the active biological components of the RDP most be carried out by a direct action the potassium ion channels, specifically Ito and IK, which are the currents affected in the diabetes on rats, and also in the mechanisms of the expression of connexin 43. However, at this time we only have questions and need a lot of work in the laboratory so that in the future we can provide evidence to suggest the way which the RDP held its beneficial effects on diabetic organisms.



  1. Fast VG, Kleber AG. Role of wavefront curvature in propagation of cardiac impulse. Cardiovasc Res. (1997); 33(2):258–271.
  2. American diabetes association (ADA). Clinical practice recomendations. Diabetes Care. (2002);25:21-24.
  3. Jourdon P, Feuvray D. Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. J Physiol. (1993);470:411-429.
  4. Wang DW, Kiyosue T, Shigematsu S, Arita M. Abnormalities of K+ and Ca+ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol. (1995);269:1288-1296
  5. Shimoni Y, Rattner JB. Type 1 diabetes leads to cytoskeleton changes that are reflected in insulin action on rat candiac K currents. Am J Physiol Endocrinol Metab. (2001);281(3):575-585.
  6. Shimoni Y, Firek L, Severson D, Giles W.  Short-term Diabetes Alters K+ Currents in Rat Ventricular Myocytes. Circ Res. (1994);74(4):620-628.
  7. Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. (1993);88(6):2953-2961.
  8. Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, Kajstura J. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent myocardial cell death in human diabetes. Lab Invest. (2000);80(4):513-27.
  9. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. Myocardial Cell Death in Human Diabetes. Circ Res. (2000);87:1123-1132.
  10. Lin H, Ogawa K,  Imanaga I, Tribulova N. Alterations of connexin 43 in the diabetic rat heart. Adv Cardiol. (2006);42:243-254.
  11. Mayama T, Matsumura K, Lin H, Ogawa K, Imanaga I. Remodelling of cardiac gap junction connexin 43 and arrhythmogenesis. Exp Clin Cardiol. (2007);12(2):67-76.
  12. Mitasíková M,  Lin H, Soukup T, Imanaga I, Tribulová N. Diabetes and thyroid hormones affect connexin-43 and PKC-epsilon expression in rat heart atria. Physiol Res. (2009);58(2):211-217.
  13. Howarth FC, Nowotny N, Zilahi E, El Haj MA, Lei M. Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart. Mol Cell Biochem. (2007);305(1-2):145-151.
  14. Lin H, Mitasikova M, Dlugosova K, Okruhlicova L, Imanaga I, Ogawa K, Weismann P, Tribulova N. Thyroid hormones suppress epsilon-PKC signalling, down-regulate connexin-43 and increase lethal arrhythmia susceptibility in non-diabetic and diabetic rat hearts. J Physiol Pharmacol. (2008);59(2):271-285.



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