Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2018, Article ID 2974304, 15 pages
https://doi.org/10.1155/2018/2974304
Review Article

Calcium Signaling in the Ventricular Myocardium of the Goto-Kakizaki Type 2 Diabetic Rat

1College of Natural and Health Sciences, Zayed University, Abu Dhabi, UAE
2Department of Physiology, College of Medicine & Health Sciences, UAE University, Al Ain, UAE
3Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine
4Department of Basic Medical Sciences, College of Medicine, Qatar University, Doha, Qatar
5School of Forensic & Applied Sciences, University of Central Lancashire, Preston, UK

Correspondence should be addressed to L. Al Kury; ea.ca.uz@yrukla.anil

Received 18 October 2017; Revised 16 January 2018; Accepted 8 March 2018; Published 10 April 2018

Academic Editor: Kim Connelly

Copyright © 2018 L. Al Kury et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The association between diabetes mellitus (DM) and high mortality linked to cardiovascular disease (CVD) is a major concern worldwide. Clinical and preclinical studies have demonstrated a variety of diastolic and systolic dysfunctions in patients with type 2 diabetes mellitus (T2DM) with the severity of abnormalities depending on the patients’ age and duration of diabetes. The cellular basis of hemodynamic dysfunction in a type 2 diabetic heart is still not well understood. The aim of this review is to evaluate our current understanding of contractile dysfunction and disturbances of Ca2+ transport in the Goto-Kakizaki (GK) diabetic rat heart. The GK rat is a widely used nonobese, nonhypertensive genetic model of T2DM which is characterized by insulin resistance, elevated blood glucose, alterations in blood lipid profile, and cardiac dysfunction.

1. Use of the Goto-Kakizaki Diabetic Rat

Diabetes mellitus (DM) is a metabolic disease characterized by abnormal glucose homeostasis and defects in insulin metabolism. Cardiovascular disease (CVD) is the leading cause of death in the diabetic population. However, the molecular mechanisms underlying diabetic cardiomyopathy remain unclear.

Animal models are increasingly being used to elucidate the mechanisms underlying diabetic cardiomyopathy in both type 1 and type 2 diabetes. One of the most widely used animal models of type 2 diabetes mellitus (T2DM) is the Goto-Kakizaki (GK) rat. The GK rat is a polygenic nonobese model of T2DM. This model is generated by selective inbreeding of mildly glucose-intolerant Wistar rats over many generations [1]. At least 17 genes associated with metabolism, signal transduction, receptors, and secreted factors are involved in the pathogenesis of diabetes in the GK rat [2]. The general characteristics of the GK rat include fasting hyperglycemia, impaired insulin secretion in response to glucose both in vivo and in isolated pancreata, raised glycosylated hemoglobin, hepatic and peripheral insulin resistance, altered heart and body weight, and a variety of late complications, including cardiomyopathy, nephropathy, and neuropathy [1, 311]. In contrast to many other non-insulin-dependent rodent models, GK rats are non-obese [1, 12].

Three genetic loci are responsible for coding and transferring diabetic pathology to the fetus, and these include genes that are responsible for a reduction in β-cell mass and reduced insulin secretion [12]. During the prediabetic period (first three weeks after birth), animals have reduced body weight and do not show hyperglycemia. After weaning, many changes occur which include hyperglycemia, impaired glucose-induced insulin secretion (due to defective prenatal β-cell proliferation and reduction in β-cell mass), reduced insulin sensitivity in the liver, and moderate insulin resistance in peripheral tissues [12, 13].

Persistent hyperglycemia over time provokes pancreatic islet inflammation, oxidative stress, fibrosis, and finally β-cell dysfunction. In fact, the pancreatic islets of adult GK rats show decreased β-cell number and insulin content as compared to their age-matched control animals [12].

GK rats have been considered as one of the best nonobese type 2 diabetic animal models. GK rats exhibit valuable characteristics that are more or less common and functionally present in human diabetic patients. This animal model is considered appropriate to examine various pathologic mechanisms of T2DM [12, 14]. As mentioned earlier, reduced β-cell mass and reduced β-cell function are key characteristics found in this animal model [15]. Therefore, it is clear that GK rats form an important resource in preclinical T2DM research [16] in order to study the role of β-cell compensation in the pathogenesis of T2DM.

An earlier study has shown that GK islet fibrosis is accompanied by marked inflammation which is a characteristic that has been reported in islets of type 2 diabetic patients [17]. Other changes that are common between GK rats and human diabetic patients include decreased activity of glucose transporter (GLUT-2), glycerol-3-phosphate dehydrogenase (GPDH), and glucokinase and changes in the lipid profile [12].

As in humans, GK rats also develop renal lesions, structural changes in peripheral nerves, and retinal damage [13]. For example, in adult GK rats, significant morphological alterations in kidneys occur in response to chronic hyperglycemia which are similar to that in human diabetic patients [18, 19]. These morphological changes in kidneys include glomerulosclerosis, proliferation of mesangial cells, atrophy of basement membrane, and tubulointerstitial fibrosis [20].

2. Other Animal Models of Type 2 Diabetes

T2DM is characterized by insulin resistance and the inability of the β-cell to sufficiently compensate, which leads to hyperglycemia [21]. In addition, T2DM is closely associated with obesity which is one of the main pathological causes of insulin resistance [15, 22]. Many animal models are therefore obese as a result of naturally occurring mutations or genetic manipulation and are useful in understanding obesity-induced insulin resistance and its effects. These are divided into monogenic models, polygenic models, and diet-induced models [23]. The general characteristics for these obese models are insulin resistance and impaired glucose tolerance. In other words, these models lack sufficient insulin secretion required to compensate for the insulin resistance as part of the obesity (obesity-induced hyperglycemia) [13, 23].

Lepob/ob mice, Leprdb/db mice, and Zucker diabetic fatty rats are the most commonly used models of monogenic obesity. They have a disrupted leptin signaling pathway, leading to hyperphagia and obesity [13]. Polygenetic animal models, however, provide more accurate models of the human condition [15]. These include KK-AY mice, New Zealand obese (NZO) mice, TallHo/Jng mice, and Otsuka Long Evans Tokushima Fat (OLETF) rat. Obesity can also be induced by feeding the rodent a high-fat diet (diet-induced models). The weight gain in these animals is associated with insulin resistance and abnormal glucose metabolism [12, 13, 23].

In contrast to the animal models mentioned above, the GK rat is a non-obese animal model of T2DM. It is characterized by reduced β-cell mass and/or β-cell function [24]. The GK rat is glucose intolerant and displays defective glucose-induced insulin secretion. Furthermore, the development of insulin resistance does not seem to be the main initiator of hyperglycemia. Instead, the defective glucose metabolism is regarded to be due to reduced β-cell mass [25] and/or function [26]. Adult GK rats show a 60% decrease in their total pancreatic β-cell mass. Blood glucose is elevated only after the first 3-4 weeks of animal’s age, and blood glucose rises significantly after a glucose challenge [13, 27]. The GK model is characterized by early hyperglycemia, hyperinsulinemia, and insulin resistance, [1, 12]. Other examples of non-obese animal models of T2DM are the C57BL/6 (Akita) mutant mouse, the Cohen diabetic rats, and the spontaneously diabetic Torri (SDT) rats [13].

3. Blood Chemistry in the Goto-Kakizaki Diabetic Rat

Blood insulin, glucose, and lipid profiles in the GK rats compared to controls are summarized in Tables 1, 2, and 3, respectively. Blood insulin is either unaltered [2834] or increased [29, 34, 35] in the GK rats (Table 1). Fasting blood glucose and nonfasting blood glucose are slightly increased [10, 11, 2848] and urine glucose is increased [30] in the GK rat. Following a glucose challenge, in the fasted state, blood glucose is significantly elevated at 30, 60, and 120 min [29, 3740, 44, 46, 4850] in the GK rat indicating end organ resistance to the action of insulin (Table 2). Blood cholesterol is increased [29, 35, 43, 44] whilst high-density lipoprotein cholesterol may be either unaltered [31] or increased [44] and low-density lipoprotein cholesterol is unaltered [31, 44] in the GK rat compared to controls. Blood free fatty acids are either unaltered [11, 31] or increased [38, 45] in the GK rats compared to controls. Triglycerides are either increased [38, 4345] or unaltered [2, 30, 45] in the GK rats compared to controls (Table 3). Part of the variability in blood chemistry may be attributed to the age of the animals and dietary regime. In summary, the GK rat displays hyperglycemia, insulin resistance, and disturbances in lipid profile.

Table 1: Blood insulin in the GK rat.
Table 2: Glucose profile in the GK rat.
Table 3: Lipid profile in the GK rat.

4. Body and Heart Weight in the Goto-Kakizaki Diabetic Rat

Body weight and heart weight measures in GK rats compared to controls are summarized in Tables 4 and 5, respectively. Body weight is either unaltered [31, 34, 36, 3941, 46, 50], decreased [2, 10, 11, 2830, 32, 35, 38, 4246], or increased [34, 47, 48] in the GK rat (Table 4). Heart weight is generally increased [29, 40, 41, 48, 49] but may also be decreased [10, 43] or unaltered [11, 39]; left ventricular weight is either decreased [43, 45] or increased [32]; left ventricular thickness is increased [40] or unaltered [36]; right ventricular weight is either unaltered [45] or decreased [45] in GK rats compared to controls. Heart-weight-to-body-weight ratio is increased [10, 11, 29, 30, 32, 33, 36, 40, 50] but may also be unaltered [31, 41, 48]; heart-weight-to-femur-length ratio is increased [44]; left-ventricle-to-body-weight ratio is increased [36, 43, 45, 51]; right-ventricle-to-body-weight ratio is unaltered [45]; biventricular-weight-to-body-weight and biventricular-weight-to-tibial-length ratios are increased [28, 45] (Table 5). In summary, the various heart to body ratio measures and the structural changes observed in the heart of this nonobese, nonhypertensive animal model provide evidence for regional cardiac hypertrophy.

Table 4: Body weight of the GK rat.
Table 5: Heart weight and other heart-related measurements in the GK rat.

Earlier studies have reported that chronic mild hyperglycemia produces molecular and structural correlates of hypertrophic myopathy in GK rats [40]. Several mechanisms whereby hyperglycemia may induce left ventricle remodeling have been proposed. One of these mechanisms is the increased activity of profibrotic and prohypertrophic cytokine transforming growth factor-β1 (TGF-β1) in the ventricular tissue [52]. TGF-β1 reproduces most of the hallmarks seen in structural remodeling. Specifically, TGF-β1 induces expression levels of extracellular matrix (ECM) constituents by cardiac fibroblasts (i.e., fibrillar collagen, fibronectin, and proteoglycans), self-amplifies its own expression in both cardiac myocytes and fibroblast [53, 54], and stimulates the proliferation of fibroblasts and their phenotypic conversion to myofibroblasts [55, 56]. D’Souza et al. have shown that the increased activity of TGF-β1 and phosphorylation of protein kinase B (PKB)/Akt and its downstream effectors mediate the hypertrophic effects of TGF-β1 in the prediabetic GK left ventricle [36]. The hypertrophic events were also sustained in the aging GK myocardium [40]. Earlier studies have suggested that enhanced activity of myocardial Na+/H+ exchanger plays a role in the molecular mechanisms involved in cardiac hypertrophy. It is likely that the activation of the Akt pathway mediates the hypertrophic effect of myocardial Na+/H+ exchanger in the GK rat model of T2DM [28]. Interestingly, several studies have shown that female rat hearts are more hypertrophied than male hearts [10, 32, 57].

5. In Vivo Hemodynamic Function in the Goto-Kakizaki Rat Heart

In vivo hemodynamic function and related measures in GK rats compared to controls are summarized in Table 6. Heart rate is either unaltered [28, 3033, 37, 45, 58] or reduced [2, 34, 46] in the GK rat. Systolic blood pressure is unaltered [28, 30, 31, 33, 58] or increased [32, 34, 37, 58]; whilst diastolic blood pressure is increased [30, 34], mean arterial pressure is unaltered [35], increased [37], or reduced [30] in GK rat. Rate for pressure development (+dP/dt) and decline (–dP/dt) in left ventricle is unaltered [30, 45] in the GK rat. Ejection fraction is reduced [28, 51], increased [44], or unaltered [30, 33]; fractional shortening is reduced [32, 51] or unaltered [2, 33, 45]; cardiac output is unaltered [33] or decreased [51] in the GK rat. Coronary blood flow is increased [29] or reduced [2] in GK rats compared to controls. In summary, the GK rat heart may display a variety of abnormal hemodynamic characteristics including alterations in heart rate, blood pressure, blood pumping capability, and altered coronary blood flow.

Table 6: In vivo hemodynamic function in the GK rat.

6. Hemodynamic Function in the Isolated Perfused Goto-Kakizaki Rat Heart

Heart rate in the isolated perfused heart is lower in comparison to the heart rate in vivo in GK and control hearts (Table 7). Isolated perfused heart rate is unaltered [10, 11, 31, 50] in GK rats. Left ventricle +dP/dt and –dP/dt are either unaltered [10, 31, 59] or reduced [51] in the GK rat. Coronary flow is either reduced [11, 31] or unaltered [10] in GK rats compared to controls. Collectively, the GK rat heart displays a variety of abnormal hemodynamic characteristics, including altered rate of development and relaxation of ventricular contraction and altered coronary flow compared to controls.

Table 7: Isolated heart hemodynamic function in the GK rat.

7. Contraction in Ventricular Myocytes from the Goto-Kakizaki Rat Heart

Characteristics of shortening in myocytes from GK rats compared to controls are shown in Table 8. Myocyte diameter, surface area, cross-sectional area, and cell capacitance were increased [28, 30, 33, 36, 40, 51], and resting cell length may be unaltered [10, 39, 41, 50] or increased [47] in myocytes from the GK rat. In electrically stimulated myocytes, the time-to-peak (TPK) shortening was prolonged [39, 41, 47] or unaltered [48, 50] and the time-to-half (THALF) relaxation of shortening may be unaltered [41, 47, 48] or shortened [50] or lengthened [39] in myocytes from the GK rat. Amplitude of shortening may be unaltered [10, 41, 48, 50] or increased [39] in myocytes from the GK rat. In summary, ventricular myocytes from the GK rat heart tend to be larger in size and have prolonged time course and generally similar amplitude of contraction compared to myocytes from the control heart.

Table 8: Myocyte contraction from the GK rat heart.

During the process of excitation-contraction coupling (ECC), the arrival of an action potential causes depolarization of the cardiac myocyte plasma membrane. This depolarization opens voltage-gated L-type Ca2+ channels in the plasma membrane. The entry of small amounts of Ca2+ through these channels triggers a large release of Ca2+ from the sarcoplasmic reticulum (SR) via activation of the ryanodine receptor (RyR), by the process termed calcium-induced calcium release (CICR). The transient rise in intracellular Ca2+ (Ca2+ transient) results in the binding of Ca2+ to troponin C which initiates and regulates the process of cardiac muscle cell contraction. During the process of relaxation, Ca2+ is pumped back into the SR via the SR Ca2+-ATPase (SERCA2) and extruded from the cell, primarily via the Na+/Ca2+ exchanger (NCX) [60, 61]. Changes in the kinetics of shortening observed in myocytes of GK rats may be attributed, at least in part, to alternations in ventricular myocardial stiffness. Earlier studies have demonstrated increased collagen deposition and increased ventricular stiffness in different experimental models of T2DM, which in turn were associated with altered kinetics of myocardial contraction [62, 63]. The observed disturbance in myocyte shortening may also be attributed to the alternation in the profile of expression of mRNA encoding various proteins involved in excitation-contraction coupling [48].

8. Intracellular Ca2+ in Ventricular Myocytes from the Goto-Kakizaki Rat Heart

Characteristics of intracellular Ca2+ in myocytes from GK rats compared to controls are shown in Table 9. Resting intracellular Ca2+ is unaltered [10, 41, 47, 48] or increased [28]; TPK Ca2+ transient is unaltered [39, 41, 48, 50] or prolonged [47]; THALF decay of the Ca2+ transient is unaltered [39, 47, 48, 50] or shortened [41]; and the amplitude of the Ca2+ transient is unaltered [10, 41, 48], increased [47, 50], or decreased [39] in myocytes from the GK rat. In whole-cell patch clamp experiments, the amplitude, inactivation, and restitution of L-type Ca2+ current are unaltered [48] in myocytes from GK rats compared to controls.

Table 9: Myocyte calcium from the GK rat heart.

Since intracellular Ca2+ in cardiac cells is maintained by Ca2+ influx (through L-type Ca2+ channels; the primary trigger for SR Ca2+ release) and efflux (through NCX; the major pathway for Ca2+ efflux from the cell) [64], as well as Ca2+ release (via the ryanodine receptors) and uptake by both SR (through SERCA2) and mitochondria, it is possible that the observed differences in these results may be attributed to differential changes in Ca2+ transport activities in these organelles. Furthermore, the observed alterations in intracellular Ca2+ may also be due to differences in the stage and severity of diabetes [65, 66].

It is well known that alterations in SR Ca2+ uptake and release mechanisms would impair cardiac cell function. Several studies have reported changes in cardiac SR Ca2+ transport during the development of chronic diabetes [6771]. For example, Ganguly et al. reported that a decrease in Ca2+ uptake activity by SR was associated with a decrease in SERCA2a activity [68]. Furthermore, Golfman et al. showed that SR ATP-dependent Ca2+ uptake activity was markedly decreased in the diabetic rat heart [72]. Yu et al. reported a reduction in both SR Ca2+ content and ryanodine binding sites in diabetic hearts, indicating that the SR functions of storage and release of Ca2+ were depressed [73]. It should be noted that prolonged depression of the SR Ca2+ uptake activity in chronic diabetes may contribute to the occurrence of intracellular Ca2+ overload [65].

In our recently published data, L-type Ca2+ current and Ca2+ transients were simultaneously measured in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of GK rats [74]. Consistent with previous findings [48], the amplitude of L-type Ca2+ current, over a wide range of test potentials, was unaltered in ENDO and EPI myocytes from the left ventricle of GK rat. However, the amplitude of the Ca2+ transients was reduced and by similar extents, in ENDO and EPI myocytes from the GK rat heart. The THALF decay of the Ca2+ transients was reduced in EPI and ENDO myocytes from GK rats compared to controls. Interestingly, while a reduction in the amplitude of L-type Ca+ current has been reported in earlier studies on a diabetic heart [75, 76], it does not necessarily explain the reduced Ca2+ transients. This is because many reports show no change in L-type Ca2+ current despite the reduction in both contractions and Ca2+ transients [48, 74, 7779]. Instead, reduction of Ca2+ transients and the consequent contractile dysfunction may be due to depletion of SR Ca2+, which may result from RYR-dependent Ca2+ leak, an increased Ca2+ extrusion through NCX, or a reduced function of SERCA [61, 80]. Further experiments will be required to investigate the role of SR in Ca2+ transport in myocytes from the GK rat. Sheikh et al. [81] demonstrated that cardiac endothelial cells from diabetic rats treated with NCX inhibitor have higher intracellular Ca2+ transient peaks as compared to controls. This finding supports the idea that altered activity of sarcolemmal NCX during Ca2+ efflux contributes to the decrease in Ca2+ transient-observed GK myocytes. Previous experiments in ventricular myocytes from the streptozotocin-induced diabetic rats have reported reduced caffeine-evoked Ca2+ transients [8291], SERCA2 activity, and Ca2+ uptake [83, 88, 9294] and decreased SR Ca2+ channel (ryanodine receptor) activity [87, 95] suggesting decreased SR Ca2+ content, Ca2+ uptake, and Ca2+ release mechanisms in ventricular myocytes from the streptozotocin-induced diabetic rat.

Under pathological conditions, such as chronic diabetes, the mitochondria are able to accumulate large amounts of Ca2+, which serves as a protective mechanism during cardiac dysfunction and intracellular Ca2+ overload. Therefore, altered mitochondrial uptake of Ca2+ during diabetes may contribute to the reported decreased Ca2+ transients. Although the mitochondria contribute to Ca2+ signaling, their exact role in diabetic cardiomyopathy remains to be investigated.

Recent investigations, using animal models, suggest that mitochondrial dysfunction may also play a critical role in the pathogenesis of diabetic cardiomyopathy [65, 71]. Potential mechanisms that contribute to mitochondrial impairment in diabetes include altered energy metabolism [9699] oxidative stress [100102], altered mitochondrial dynamics and biogenesis [103, 104], cell death [105, 106], and impaired mitochondrial Ca2+ handling [107, 108].

It should be noted that the main function of the mitochondria in the heart is to produce energy in the form of ATP, which is required for cardiac contractile activity. However, mitochondria are known to serve as Ca2+ sinks in the cell by acting as a local buffering system, removing Ca2+ and modulating cytosolic Ca2+concentrations [65, 109]. In addition to controlling their intraorganelle Ca2+ concentration, mitochondria dynamically interact with the cytosol and intracellular Ca2+ handling machineries to shape the cellular Ca2+ signaling network [65]. Recent evidence suggests that there is a dynamic exchange of Ca2+ between the mitochondria and the cytosol and that mitochondrial Ca2+ uptake increases mitochondrial ATP production [110]. Therefore, mitochondria can play an important role in preventing and/or delaying the occurrence of intracellular Ca2+ overload in cardiomyocytes under different pathological conditions. For example, during the development of cardiac dysfunction and intracellular Ca2+ overload in chronic diabetes, mitochondria are believed to continue accumulating Ca2+, thereby serving as a protective mechanism [65, 71]. However, when the intramitochondrial Ca2+ concentration exceeds its buffering capacity, irreversible swelling occurs leading to mitochondrial dysfunction. As a result, energy production as well as energy stores are depleted. Collectively, these defects may contribute to the development of cardiac dysfunction in diabetic cardiomyopathy [109].

Evidence of deficits in mitochondrial Ca2+ handling has been demonstrated in animal models of both type 1 and type 2 diabetes. For example, in streptozotocin- (STZ-) induced diabetic rats, hyperglycemia was associated with lower rates of mitochondrial Ca2+ uptake [107]. This reduction can be explained by the increased opening of the mitochondrial permeability transition pore (MPTP), resulting in the release of accumulated Ca2+. In STZ-induced diabetic rats, Oliveira et al. observed that Ca2+ uptake was similar in control versus diabetic hearts; however, mitochondria in diabetic hearts were unable to retain the accumulated Ca2+. This effect was not observed in the presence of cyclosporin, an MPTP inhibitor [108]. In type 2 diabetic ob/ob mice, reduced intracellular Ca2+ release upon electrical stimulation, slowed intracellular Ca2+ decay rate, and impaired mitochondrial Ca2+ handling were observed [111, 112]. Similarly, Belke et al. observed a reduction in Ca2+ levels and a reduction in the rate of Ca2+ decay in isolated cardiomyocytes from db/db animals, suggesting impaired mitochondrial Ca2+ uptake [113]. Taken together, these studies support the notion that mitochondrial Ca2+ handling is impaired in diabetic myocardium, resulting in compromised energy metabolism and thus reduced contractility.

9. Conclusion

Although diabetic cardiomyopathy is a frequent and important complication of DM, its physiological bases are still not completely understood. The GK type 2 diabetic heart displays a variety of abnormal hemodynamic characteristics in vivo and in the isolated perfused heart. Hyperglycemia is usually associated with alterations in heart rate, blood pressure, blood pumping capability, and/or coronary blood flow. Contractile function, in terms of amplitude and kinetics of shortening, is frequently disturbed in the GK type 2 diabetic heart. Several mechanisms may contribute to cardiac dysfunction including mitochondrial dysfunction, myocardial fibrosis, hypertrophy, and apoptosis. Many studies show no change in L-type Ca2+ current despite the reduction in both contractions and Ca2+ transient. Instead, reduction of Ca2+ transients and the consequent contractile dysfunction may be attributed to both depletion of SR Ca2+, which may result from RyR-dependent Ca2+ leak, an increased Ca2+ extrusion through NCX, or a reduced function of SERCA (Figure 1). Understanding the molecular mechanism(s) of altered Ca2+ signaling will provide opportunities for the development of new treatments to improve heart function in T2DM patients.

Figure 1: Schematic diagram showing the summary of some of the proposed mechanisms involved in the alterations in Ca2+ signaling in cardiac myocyte from the GK diabetic heart. (1) No change/or decrease in L-type Ca2+ channel activity, (2) increase in Na+/Ca2+ exchange current, (3) decrease in SR Ca2+ content, (4) decrease in SR Ca2+ uptake, and (5) increase in Ca2+ release through RYR. SR: sarcoplasmic reticulum; RYR: ryanodine receptor; SERCA: sarcoplasmic reticulum Ca2+-ATPase; NCX: Na+/Ca2+ exchanger; —: no effect; ↑: increased activity; ↓: decreased activity (adapted from Eisner, 2013).

Abbreviations

DM:Diabetes mellitus
CVDs:Cardiovascular diseases
T2DM:Type 2 diabetes mellitus
GK:Goto-Kakizaki
GLUT-2:Glucose transporter
GPDH:Glycerol-3-phosphate dehydrogenase
NZO:New Zealand obese
OLETF:Otsuka Long Evans Tokushima Fat
SDT:Spontaneously diabetic Torri
TGF-β1:Transforming growth factor-β1
ECM:Extracellular matrix
PKB:Protein kinase B
ECC:Excitation-contraction coupling
SR:Sarcoplasmic reticulum
RyR:Ryanodine receptor
CICR:Calcium-induced calcium release
SERCA2:SR Ca2+-ATPase2
NCX:Na+/Ca2+ exchanger
ENDO:Endocardial
EPI:Epicardial.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Acknowledgments

The research reported in this article was supported by grants from the College of Medicine and Health Sciences, United Arab Emirates University, Al Ain; United Arab Emirates University, Al Ain; Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences, Dubai; and Zayed University, Abu Dhabi.

References

  1. Y. Goto, M. Kakizaki, and N. Masaki, “Spontaneous diabetes produced by selective breeding of normal Wistar rats,” Proceedings of the Japan Academy, vol. 51, pp. 80–85, 1975. View at Google Scholar
  2. S. Devanathan, S. T. Nemanich, A. Kovacs, N. Fettig, R. J. Gropler, and K. I. Shoghi, “Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism,” PLoS One, vol. 8, no. 10, article e78477, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. B. Portha, P. Serradas, D. Bailbe, K. Suzuki, Y. Goto, and M. H. Giroix, “β-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes,” Diabetes, vol. 40, no. 4, pp. 486–491, 1991. View at Publisher · View at Google Scholar
  4. S. Bisbis, D. Bailbe, M. A. Tormo et al., “Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver,” American Journal of Physiology Endocrinology and Metabolism, vol. 265, no. 5, pp. E807–E813, 1993. View at Publisher · View at Google Scholar
  5. C. G. Östenson, A. Khan, S. M. Abdel-Halim et al., “Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat,” Diabetologia, vol. 36, no. 1, pp. 3–8, 1993. View at Publisher · View at Google Scholar · View at Scopus
  6. D. Gauguier, I. Nelson, C. Bernard et al., “Higher maternal than paternal inheritance of diabetes in GK rats,” Diabetes, vol. 43, no. 2, pp. 220–224, 1994. View at Publisher · View at Google Scholar · View at Scopus
  7. S. J. Hughes, K. Suzuki, and Y. Goto, “The role of islet secretory function in the development of diabetes in the GK Wistar rat,” Diabetologia, vol. 37, no. 9, pp. 863–870, 1994. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Villar-Palasi and R. V. Farese, “Impaired skeletal muscle glycogen synthase activation by insulin in the Goto-Kakizaki (G/K) rat,” Diabetologia, vol. 37, no. 9, pp. 885–888, 1994. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. Murakawa, W. Zhang, C. R. Pierson et al., “Impaired glucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy,” Diabetes/Metabolism Research and Reviews, vol. 18, no. 6, pp. 473–483, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. M. M. El Omar, Z. K. Yang, A. O. Phillips, and A. M. Shah, “Cardiac dysfunction in the Goto-Kakizaki rat: a model of type II diabetes mellitus,” Basic Research in Cardiology, vol. 99, no. 2, pp. 133–141, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Desrois, K. Clarke, C. Lan et al., “Upregulation of eNOS and unchanged energy metabolism in increased susceptibility of the aging type 2 diabetic GK rat heart to ischemic injury,” American Journal of Physiology Heart and Circulatory Physiology, vol. 299, no. 5, pp. H1679–H1686, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. M. S. Akash, K. Rehman, and S. Chen, “Goto-Kakizaki rats: its suitability as non-obese diabetic animal model for spontaneous type 2 diabetes mellitus,” Current Diabetes Reviews, vol. 9, no. 5, pp. 387–396, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Chatzigeorgiou, A. Halapas, K. Kalafatakis, and E. Kamper, “The use of animal models in the study of diabetes mellitus,” In Vivo, vol. 23, no. 2, pp. 245–258, 2009. View at Google Scholar
  14. B. Portha, M. H. Giroix, C. Tourrel-Cuzin, H. Le-Stunff, and J. Movassat, “The GK rat: a prototype for the study of non-overweight type 2 diabetes,” in Animal Models in Diabetes Research, H. G. Joost, H. Al-Hasani, and A. Schürmann, Eds., vol. 933 of Methods in Molecular Biology, pp. 125–159, Humana Press, Totowa, NJ, USA, 2012. View at Publisher · View at Google Scholar
  15. A. J. King, “The use of animal models in diabetes research,” British Journal of Pharmacology, vol. 166, no. 3, pp. 877–894, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. P. Masiello, “Animal models of type 2 diabetes with reduced pancreatic beta-cell mass,” The International Journal of Biochemistry & Cell Biology, vol. 38, no. 5-6, pp. 873–893, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. F. Homo-Delarche, S. Calderari, J. C. Irminger et al., “Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat,” Diabetes, vol. 55, no. 6, pp. 1625–1633, 2006. View at Publisher · View at Google Scholar · View at Scopus
  18. S. M. Mauer, M. W. Steffes, E. N. Ellis, D. E. Sutherland, D. M. Brown, and F. C. Goetz, “Structural-functional relationships in diabetic nephropathy,” The Journal of Clinical Investigation, vol. 74, no. 4, pp. 1143–1155, 1984. View at Publisher · View at Google Scholar · View at Scopus
  19. A. O. Phillips, K. Baboolal, S. Riley et al., “Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non–insulin-dependent diabetes mellitus,” American Journal of Kidney Diseases, vol. 37, no. 2, pp. 400–410, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. N. Sato, K. Komatsu, and H. Kurumatani, “Late onset of diabetic nephropathy in spontaneously diabetic GK rats,” American Journal of Nephrology, vol. 23, no. 5, pp. 334–342, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Prentki and C. J. Nolan, “Islet β cell failure in type 2 diabetes,” The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1802–1812, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. B. B. Kahn and J. S. Flier, “Obesity and insulin resistance,” The Journal of Clinical Investigation, vol. 106, no. 4, pp. 473–481, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. A. King and J. Bowe, “Animal models for diabetes: understanding the pathogenesis and finding new treatments,” Biochemical Pharmacology, vol. 99, pp. 1–10, 2016. View at Publisher · View at Google Scholar · View at Scopus
  24. Y. Goto, M. Kakizaki, and N. Masaki, “Production of spontaneous diabetic rats by repetition of selective breeding,” The Tohoku Journal of Experimental Medicine, vol. 119, no. 1, pp. 85–90, 1976. View at Publisher · View at Google Scholar · View at Scopus
  25. B. Portha, M. H. Giroix, P. Serradas et al., “Beta-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony,” vol. 50, Supplement 1, pp. S89–S93, 2001. View at Publisher · View at Google Scholar
  26. C. G. Ostenson and S. Efendic, “Islet gene expression and function in type 2 diabetes; studies in the Goto-Kakizaki rat and humans,” Diabetes, Obesity and Metabolism, vol. 9, Supplement 2, pp. 180–186, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. F. Miralles and B. Portha, “Early development of beta-cells is impaired in the GK rat model of type 2 diabetes,” Diabetes, vol. 50, Supplement 1, pp. S84–S88, 2001. View at Publisher · View at Google Scholar
  28. A. Darmellah, D. Baetz, F. Prunier, S. Tamareille, C. Rucker-Martin, and D. Feuvray, “Enhanced activity of the myocardial Na+/H+ exchanger contributes to left ventricular hypertrophy in the Goto–Kakizaki rat model of type 2 diabetes: critical role of Akt,” Diabetologia, vol. 50, no. 6, pp. 1335–1344, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Sarkozy, G. Szucs, V. Fekete et al., “Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats,” Cardiovascular Diabetology, vol. 15, no. 1, p. 110, 2016. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Korkmaz-Icoz, A. Lehner, S. Li et al., “Mild type 2 diabetes mellitus reduces the susceptibility of the heart to ischemia/reperfusion injury: identification of underlying gene expression changes,” Journal of Diabetes Research, vol. 2015, Article ID 396414, 16 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  31. E. Liepinsh, R. Vilskersts, L. Zvejniece et al., “Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats,” British Journal of Pharmacology, vol. 157, no. 8, pp. 1549–1556, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. T. Gronholm, Z. J. Cheng, E. Palojoki et al., “Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto–Kakizaki rats,” European Journal of Pharmacology, vol. 519, no. 3, pp. 267–276, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. E. Vahtola, M. Louhelainen, H. Forsten et al., “Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat,” Cardiovascular Diabetology, vol. 9, no. 1, p. 5, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. K. Witte, K. Jacke, R. Stahrenberg et al., “Dysfunction of soluble guanylyl cyclase in aorta and kidney of Goto–Kakizaki rats: influence of age and diabetic state,” Nitric Oxide, vol. 6, no. 1, pp. 85–95, 2002. View at Publisher · View at Google Scholar · View at Scopus
  35. S. B. Kristiansen, B. Løfgren, N. B. Støttrup et al., “Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes,” Diabetologia, vol. 47, no. 10, pp. 1716–1721, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. A. D’Souza, F. C. Howarth, J. Yanni et al., “Left ventricle structural remodelling in the prediabetic Goto–Kakizaki rat,” Experimental Physiology, vol. 96, no. 9, pp. 875–888, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. Z. J. Cheng, T. Vaskonen, I. Tikkanen et al., “Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats,” Hypertension, vol. 37, no. 2, pp. 433–439, 2001. View at Publisher · View at Google Scholar
  38. J. Crisostomo, P. Matafome, D. Santos-Silva et al., “Methylglyoxal chronic administration promotes diabetes-like cardiac ischaemia disease in Wistar normal rats,” Nutrition, Metabolism & Cardiovascular Diseases, vol. 23, no. 12, pp. 1223–1230, 2013. View at Publisher · View at Google Scholar · View at Scopus
  39. F. C. Howarth and M. A. Qureshi, “Myofilament sensitivity to Ca2+ in ventricular myocytes from the Goto–Kakizaki diabetic rat,” Molecular and Cellular Biochemistry, vol. 315, no. 1-2, pp. 69–74, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. A. D’Souza, F. C. Howarth, J. Yanni et al., “Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat,” Heart Failure Reviews, vol. 19, no. 1, pp. 65–74, 2014. View at Publisher · View at Google Scholar · View at Scopus
  41. K. A. Salem, T. E. Adrian, M. A. Qureshi, K. Parekh, M. Oz, and F. C. Howarth, “Shortening and intracellular Ca2+ in ventricular myocytes and expression of genes encoding cardiac muscle proteins in early onset type 2 diabetic Goto–Kakizaki rats,” Experimental Physiology, vol. 97, no. 12, pp. 1281–1291, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Jurysta, C. Nicaise, M. H. Giroix, S. Cetik, W. J. Malaisse, and A. Sener, “Comparison of GLUT1, GLUT2, GLUT4 and SGLT1 mRNA expression in the salivary glands and six other organs of control, streptozotocin-induced and Goto-Kakizaki diabetic rats,” Cellular Physiology and Biochemistry, vol. 31, no. 1, pp. 37–43, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Radosinska, L. H. Kurahara, K. Hiraishi et al., “Modulation of cardiac connexin-43 by omega-3 fatty acid ethyl-ester supplementation demonstrated in spontaneously diabetic rats,” Physiological Research, vol. 64, no. 6, pp. 795–806, 2015. View at Google Scholar
  44. B. Picatoste, E. Ramírez, A. Caro-Vadillo et al., “Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms,” PLoS One, vol. 8, no. 10, article e78330, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. M. P. Chandler, E. E. Morgan, T. A. McElfresh et al., “Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats,” American Journal of Physiology Heart and Circulatory Physiology, vol. 293, no. 3, pp. H1609–H1616, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. F. C. Howarth, M. Jacobson, M. Shafiullah, and E. ADEGHATE, “Long-term effects of type 2 diabetes mellitus on heart rhythm in the Goto–Kakizaki rat,” Experimental Physiology, vol. 93, no. 3, pp. 362–369, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. E. M. Gaber, P. Jayaprakash, M. A. Qureshi et al., “Effects of a sucrose-enriched diet on the pattern of gene expression, contraction and Ca2+ transport in Goto–Kakizaki type 2 diabetic rat heart,” Experimental Physiology, vol. 99, no. 6, pp. 881–893, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. K. A. Salem, M. A. Qureshi, V. Sydorenko et al., “Effects of exercise training on excitation–contraction coupling and related mRNA expression in hearts of Goto-Kakizaki type 2 diabetic rats,” Molecular and Cellular Biochemistry, vol. 380, no. 1-2, pp. 83–96, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. D. L. Santos, C. M. Palmeira, R. Seica et al., “Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat,” Molecular and Cellular Biochemistry, vol. 246, no. 1-2, pp. 163–170, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. F. C. Howarth, M. Shafiullah, and M. A. Qureshi, “Chronic effects of type 2 diabetes mellitus on cardiac muscle contraction in the Goto-Kakizaki rat,” Experimental Physiology, vol. 92, no. 6, pp. 1029–1036, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. X. Yu, Q. Zhang, W. Cui et al., “Low molecular weight fucoidan alleviates cardiac dysfunction in diabetic Goto-Kakizaki rats by reducing oxidative stress and cardiomyocyte apoptosis,” Journal of Diabetes Research, vol. 2014, Article ID 420929, 13 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  52. R. Ramos-Mondragon, C. A. Galindo, and G. Avila, “Role of TGF-β on cardiac structural and electrical remodeling,” Vascular Health and Risk Management, vol. 4, no. 6, pp. 1289–1300, 2008. View at Publisher · View at Google Scholar
  53. A. Desmouliere, A. Geinoz, F. Gabbiani, and G. Gabbiani, “Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts,” Journal of Cell Biology, vol. 122, no. 1, pp. 103–111, 1993. View at Publisher · View at Google Scholar
  54. C. S. Long, “Autocrine and paracrine regulation of myocardial cell growth in vitro the TGFβ paradigm,” Trends in Cardiovascular Medicine, vol. 6, no. 7, pp. 217–226, 1996. View at Publisher · View at Google Scholar · View at Scopus
  55. A. P. Sappino, I. Masouye, J. H. Saurat, and G. Gabbiani, “Smooth muscle differentiation in scleroderma fibroblastic cells,” The American Journal of Pathology, vol. 137, no. 3, pp. 585–591, 1990. View at Google Scholar
  56. G. A. Walker, K. S. Masters, D. N. Shah, K. S. Anseth, and L. A. Leinwand, “Valvular myofibroblast activation by transforming growth factor-β: implications for pathological extracellular matrix remodeling in heart valve disease,” Circulation Research, vol. 95, no. 3, pp. 253–260, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Desrois, R. J. Sidell, D. Gauguier, C. L. Davey, G. K. Radda, and K. Clarke, “Gender differences in hypertrophy, insulin resistance and ischemic injury in the aging type 2 diabetic rat heart,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 2, pp. 547–555, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. H. Yang, M. D. Nyby, Y. Ao et al., “Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats,” Hypertension Research, vol. 35, no. 2, pp. 157–165, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. A. F. Ceylan-Isik, K. H. LaCour, and J. Ren, “Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus,” Journal of Applied Physiology, vol. 100, no. 5, pp. 1638–1646, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. F. Brette, J. Leroy, J. Y. Le Guennec, and L. Salle, “Ca2+ currents in cardiac myocytes: old story, new insights,” Progress in Biophysics and Molecular Biology, vol. 91, no. 1-2, pp. 1–82, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. D. M. Bers, “Cardiac excitation-contraction coupling,” Nature, vol. 415, no. 6868, pp. 198–205, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Patel, A. Iyer, and L. Brown, “Evaluation of the chronic complications of diabetes in a high fructose diet in rats,” Indian Journal of Biochemistry and Biophysics, vol. 46, no. 1, pp. 66–72, 2009. View at Google Scholar
  63. C. Rickman, A. Iyer, V. Chan, and L. Brown, “Green tea attenuates cardiovascular remodeling and metabolic symptoms in high carbohydrate-fed rats,” Current Pharmaceutical Biotechnology, vol. 11, no. 8, pp. 881–886, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. Y. Hattori, N. Matsuda, J. Kimura et al., “Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload,” The Journal of Physiology, vol. 527, no. 1, pp. 85–94, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. N. S. Dhalla, S. Rangi, S. Zieroth, and Y. J. Xu, “Alterations in sarcoplasmic reticulum and mitochondrial functions in diabetic cardiomyopathy,” Experimental & Clinical Cardiology, vol. 17, no. 3, pp. 115–120, 2012. View at Google Scholar
  66. N. S. Dhalla, P. K. Das, and G. P. Sharma, “Subcellular basis of cardiac contractile failure,” Journal of Molecular and Cellular Cardiology, vol. 10, no. 4, pp. 363–385, 1978. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Penpargkul, F. Fein, E. H. Sonnenblick, and J. Scheuer, “Depressed cardiac sarcoplasmic reticular function from diabetic rats,” Journal of Molecular and Cellular Cardiology, vol. 13, no. 3, pp. 303–309, 1981. View at Publisher · View at Google Scholar · View at Scopus
  68. P. K. Ganguly, G. N. Pierce, K. S. Dhalla, and N. S. Dhalla, “Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy,” American Journal of Physiology Endocrinology and Metabolism, vol. 244, no. 6, pp. E528–E535, 1983. View at Publisher · View at Google Scholar
  69. G. D. Lopaschuk, A. G. Tahiliani, R. V. Vadlamudi, S. Katz, and J. H. Mcneill, “Cardiac sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic rats,” American Journal of Physiology Heart and Circulatory Physiology, vol. 245, no. 6, pp. H969–H976, 1983. View at Publisher · View at Google Scholar
  70. N. S. Dhalla, G. N. Pierce, I. R. Innes, and R. E. Beamish, “Pathogenesis of cardiac dysfunction in diabetes mellitus,” The Canadian Journal of Cardiology, vol. 1, no. 4, pp. 263–281, 1985. View at Google Scholar
  71. N. S. Dhalla, X. Liu, V. Panagia, and N. Takeda, “Subcellular remodeling and heart dysfunction in chronic diabetes,” Cardiovascular Research, vol. 40, no. 2, pp. 239–247, 1998. View at Publisher · View at Google Scholar · View at Scopus
  72. L. S. Golfman, N. Takeda, and N. S. Dhalla, “Cardiac membrane Ca2+-transport in alloxan-induced diabetes in rats,” Diabetes Research and Clinical Practice, vol. 31, pp. S73–S77, 1996. View at Publisher · View at Google Scholar · View at Scopus
  73. Z. Yu, G. F. Tibbits, and J. H. Mcneill, “Cellular functions of diabetic cardiomyocytes: contractility, rapid-cooling contracture, and ryanodine binding,” American Journal of Physiology Heart and Circulatory Physiology, vol. 266, no. 5, pp. H2082–H2089, 1994. View at Publisher · View at Google Scholar
  74. L. Al Kury, V. Sydorenko, M. M. A. Smail et al., “Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto–Kakizaki type 2 diabetic rats,” Molecular and Cellular Biochemistry, vol. 9, pp. 10–3269, 2018. View at Google Scholar
  75. L. Pereira, J. Matthes, I. Schuster et al., “Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice,” Diabetes, vol. 55, no. 3, pp. 608–615, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. Lu, Y. P. Jiang, X. H. Xu, L. M. Ballou, I. S. Cohen, and R. Z. Lin, “Decreased L-type Ca2+ current in cardiac myocytes of type 1 diabetic Akita mice due to reduced phosphatidylinositol 3-kinase signaling,” Diabetes, vol. 56, no. 11, pp. 2780–2789, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Kaab, H. B. Nuss, N. Chiamvimonvat et al., “Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure,” Circulation Research, vol. 78, no. 2, pp. 262–273, 1996. View at Publisher · View at Google Scholar · View at Scopus
  78. A. M. Gomez, H. H. Valdivia, H. Cheng et al., “Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure,” Science, vol. 276, no. 5313, pp. 800–806, 1997. View at Publisher · View at Google Scholar · View at Scopus
  79. M. M. Smail, M. A. Qureshi, A. Shmygol et al., “Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle,” Physiological Reports, vol. 4, no. 22, article e13034, 2016. View at Publisher · View at Google Scholar · View at Scopus
  80. X. H. Wehrens, S. E. Lehnart, and A. R. Marks, “Intracellular calcium release and cardiac disease,” Annual Review of Physiology, vol. 67, no. 1, pp. 69–98, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. A. Q. Sheikh, J. R. Hurley, W. Huang et al., “Diabetes alters intracellular calcium transients in cardiac endothelial cells,” PLoS One, vol. 7, no. 5, article e36840, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. D. Lagadic-Gossmann, K. J. Buckler, K. Le Prigent, and D. Feuvray, “Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats,” American Journal of Physiology Heart and Circulatory Physiology, vol. 270, no. 5, pp. H1529–H1537, 1996. View at Publisher · View at Google Scholar
  83. K. M. Choi, Y. Zhong, B. D. Hoit et al., “Defective intracellular Ca2+ signaling contributes to cardiomyopathy in type 1 diabetic rats,” American Journal of Physiology Heart and Circulatory Physiology, vol. 283, no. 4, pp. H1398–H1408, 2002. View at Publisher · View at Google Scholar
  84. J. Z. Yu, G. A. Quamme, and J. H. Mcneill, “Altered [Ca2+]i mobilization in diabetic cardiomyocytes: responses to caffeine, KCl, ouabain, and ATP,” Diabetes Research and Clinical Practice, vol. 30, no. 1, pp. 9–20, 1995. View at Publisher · View at Google Scholar · View at Scopus
  85. N. Yaras, M. Ugur, S. Ozdemir et al., “Effects of diabetes on ryanodine receptor ca release channel (RyR2) and Ca2+ homeostasis in rat heart,” Diabetes, vol. 54, no. 11, pp. 3082–3088, 2005. View at Publisher · View at Google Scholar · View at Scopus
  86. N. Yaras, A. Bilginoglu, G. Vassort, and B. Turan, “Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade,” American Journal of Physiology Heart and Circulatory Physiology, vol. 292, no. 2, pp. H912–H920, 2007. View at Publisher · View at Google Scholar · View at Scopus
  87. C. H. Shao, G. J. Rozanski, K. P. Patel, and K. R. Bidasee, “Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats,” Journal of Molecular and Cellular Cardiology, vol. 42, no. 1, pp. 234–246, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. V. A. Lacombe, S. Viatchenko-Karpinski, D. Terentyev et al., “Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes,” American Journal of Physiology Regulatory, Integrative and Comparative Physiology, vol. 293, no. 5, pp. R1787–R1797, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. C. H. Shao, X. H. Wehrens, T. A. Wyatt et al., “Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation,” Journal of Applied Physiology, vol. 106, no. 4, pp. 1280–1292, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. T. I. Lee, Y. C. Chen, Y. H. Kao, F. C. Hsiao, Y. K. Lin, and Y. J. Chen, “Rosiglitazone induces arrhythmogenesis in diabetic hypertensive rats with calcium handling alteration,” International Journal of Cardiology, vol. 165, no. 2, pp. 299–307, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. A. L. Kranstuber, R. C. Del, B. J. Biesiadecki et al., “Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling,” Frontiers in Physiology, vol. 3, p. 292, 2012. View at Publisher · View at Google Scholar · View at Scopus
  92. N. Afzal, G. N. Pierce, V. Elimban, R. E. Beamish, and N. S. Dhalla, “Influence of verapamil on some subcellular defects in diabetic cardiomyopathy,” American Journal of Physiology Endocrinology and Metabolism, vol. 256, no. 4, pp. E453–E458, 1989. View at Publisher · View at Google Scholar
  93. N. Takeda, I. C. Dixon, T. Hata, V. Elimban, K. R. Shah, and N. S. Dhalla, “Sequence of alterations in subcellular organelles during the development of heart dysfunction in diabetes,” Diabetes Research and Clinical Practice, vol. 30, Supplement 1, pp. S113–S122, 1996. View at Publisher · View at Google Scholar · View at Scopus
  94. F. L. Norby, L. E. Wold, J. Duan, K. K. Hintz, and J. Ren, “IGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes,” American Journal of Physiology Endocrinology and Metabolism, vol. 283, no. 4, pp. E658–E666, 2002. View at Publisher · View at Google Scholar
  95. C. J. Moore, C. H. Shao, R. Nagai, S. Kutty, J. Singh, and K. R. Bidasee, “Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes,” Molecular and Cellular Biochemistry, vol. 376, no. 1-2, pp. 121–135, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. P. K. Mazumder, B. T. O'Neill, M. W. Roberts et al., “Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts,” Diabetes, vol. 53, no. 9, pp. 2366–2374, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. J. Buchanan, P. K. Mazumder, P. Hu et al., “Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity,” Endocrinology, vol. 146, no. 12, pp. 5341–5349, 2005. View at Publisher · View at Google Scholar · View at Scopus
  98. W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk, “Myocardial substrate metabolism in the normal and failing heart,” Physiological Reviews, vol. 85, no. 3, pp. 1093–1129, 2005. View at Publisher · View at Google Scholar · View at Scopus
  99. P. Wang, S. G. Lloyd, H. Zeng, A. Bonen, and J. C. Chatham, “Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats,” American Journal of Physiology Heart and Circulatory Physiology, vol. 288, no. 5, pp. H2102–H2110, 2005. View at Publisher · View at Google Scholar · View at Scopus
  100. X. L. Du, D. Edelstein, L. Rossetti et al., “Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 22, pp. 12222–12226, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. G. Ye, N. S. Metreveli, R. V. Donthi et al., “Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes,” Diabetes, vol. 53, no. 5, pp. 1336–1343, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. X. Shen, S. Zheng, N. S. Metreveli, and P. N. Epstein, “Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy,” Diabetes, vol. 55, no. 3, pp. 798–805, 2006. View at Publisher · View at Google Scholar
  103. S. Boudina and E. D. Abel, “Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes,” Physiology, vol. 21, no. 4, pp. 250–258, 2006. View at Publisher · View at Google Scholar · View at Scopus
  104. J. G. Duncan, J. L. Fong, D. M. Medeiros, B. N. Finck, and D. P. Kelly, “Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-α/PGC-1α gene regulatory pathway,” Circulation, vol. 115, no. 7, pp. 909–917, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. Z. Li, T. Zhang, H. Dai et al., “Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats,” Journal of Clinical Biochemistry and Nutrition, vol. 41, no. 1, pp. 58–67, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. C. L. Williamson, E. R. Dabkowski, W. A. Baseler, T. L. Croston, S. E. Alway, and J. M. Hollander, “Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location,” American Journal of Physiology Heart and Circulatory Physiology, vol. 298, no. 2, pp. H633–H642, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. C. E. Flarsheim, I. L. Grupp, and M. A. Matlib, “Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart,” American Journal of Physiology Heart and Circulatory Physiology, vol. 271, no. 1, pp. H192–H202, 1996. View at Publisher · View at Google Scholar
  108. P. J. Oliveira, R. Seica, P. M. Coxito et al., “Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats,” FEBS Letters, vol. 554, no. 3, pp. 511–514, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. J. G. Duncan, “Mitochondrial dysfunction in diabetic cardiomyopathy,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1813, no. 7, pp. 1351–1359, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. L. S. Jouaville, P. Pinton, C. Bastianutto, G. A. Rutter, and R. Rizzuto, “Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 24, pp. 13807–13812, 1999. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Fauconnier, J. T. Lanner, S. J. Zhang et al., “Insulin and inositol 1, 4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice,” Diabetes, vol. 54, no. 8, pp. 2375–2381, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. F. Dong, X. Zhang, X. Yang et al., “Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice,” Journal of Endocrinology, vol. 188, no. 1, pp. 25–36, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. D. D. Belke, E. A. Swanson, and W. H. Dillmann, “Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart,” Diabetes, vol. 53, no. 12, pp. 3201–3208, 2004. View at Publisher · View at Google Scholar · View at Scopus