Diabetes mellitus (DM) is a metabolic disease caused by the absence or dysfunction of insulin; a hormone secreted by the pancreatic beta cell (β-cell) whenever blood glucose exceeds the normal physiological value. The long-term effects of the disease on the body’s organs are one of the leading causes of death in the world. To alleviate this global burden of DM, a number of studies have been conducted to lower blood glucose levels in patients. For genetic and ethical reasons, humans are far from being appropriate subjects in such investigations and the use of animal models has therefore been the way forward. Streptozotocin (STZ) is a glucosamine-nitrosourea compound that selectively destroys β-cells and has been widely used to induce Type I diabetes in several animal species. Recent literature has shown that a non-diabetic dose of STZ, combined with a high-fat diet (HFD), can mimic Type II diabetes. Yet, researchers seldom provide data to corroborate the high sensitivity of STZ on these animal models. In addition, there are few reports of potentially fatal effects of the use of STZ as a supplement in obese HFD animals when attempting to induce Type II diabetes. The present review article highlights the parameters that could be at the origin of the extreme sensitivity and vulnerability of obese animals to STZ.
A large number of species have been used in diabetes studies, including primates [1] [2] Rodents have the highest recorded use, especially for studies engaged in testing natural compounds and pharmaceuticals; this is due to their small size, ease of availability, short generation interval and economic considerations [3] . Diabetic animal models have been developed by a number of methods ranging from genetic [4] [5] chemical [6] , spontaneous autoimmune [7] , viral [8] [9] , surgical (pancreatectomy) [9] to diet-associated [3] [10] [11] . The induction method to be considered depends on the type of DM to be developed and the objectives of the research [6] . Diabetes induced by means of chemical methods have been shown to be most effective for various research purposes and provide the most cost effective and easiest DM models [12] . Streptozotocin (STZ), a chemical compound that resembles glucose and selectively accumulates in the pancreatic β-cells via the glucose transporter 2 (GLUT2) is one of the diabetogenic agents of choice in this process [13] [14] [15] .
In the cell, STZ causes a number of synergetic molecular mechanisms leading to β-cell death [16] [17] . Beta cells are more active in the glucose uptake than other cell (hepatocyte) in the body and therefore are more vulnerable to STZ toxicity [18] . Significant depletion of insulin-secreting cells ultimately induces hyperglycaemia.
Until recently, STZ was primarily involved in the induction of Type I DM in non-genetically modified adult animal species [19] . The development of a true Type II diabetic model in which insulin resistance precedes the onset of the disease, remains a challenge. This challenge was partly overcome by Reed [20] who successfully developed a Type II DM rodent model (Sprague Dawley rats) by combining a HFD diet with a single dose of STZ (50 mg/kg body weight). To obtain similar results, minor to major modifications of the Reed’s protocol followed in subsequent years, the most notable being the significant reduction of STZ dose (to 30 - 35 mg/kg body weight) [3] [11] [21] [22] . The reasons these changes have occurred over time while keeping other parameters according to Reed’s work are not clearly explained in the literature.
Animals subjected to different diet regimens express different degree of susceptibility to STZ at a given treatment dose [11] [23] . The HFD induces obesity, insulin resistance [20] [24] [25] [26] and sensitivity to STZ [27] . The molecular mechanisms that justify the hypersensitivity and vulnerability (unpublished work) of obese rodents exposed to a dose of STZ that normally does not induce DM in animals fed a standard diet, is yet to be elucidated. Understanding the pathway that describes how HFD/obesity improves the diabetogenic effect of STZ can shed light on the cause(s) of the inconsistency of the results seen when the drug is used to induce diabetes, and thus help to include new parameters during the protocol design.
Here we review the adverse effects of obesity in non-adipose tissue (islets of Langerhans) and discuss the main models of STZ mechanism in β-cell toxicity. The literature will be used to explore the different factors that underlie the association between the islet microenvironment in HFD animals and the intense action of STZ.
2. Obesity and Insulin Resistance
Obesity has a high prevalence in the world today; and is defined as an excessive accumulation of fat in the body [28] . A person is declared obese when their body mass index (BMI), defined as the ratio of a person’s weight in kilograms to the square of their height in meters is greater than 25 [29] . Traditionally considered as an imbalance between the amount of food consumed, and the body’s energy expenditure, obesity is also strongly associated with the genetic context of an individual’s metabolism [28] .
Scientists engaged in the study of obesity have been challenged to identify factors, molecules and pathways that lead to the development of obesity in the hope that these parameters could be targeted for therapeutic intervention [30] [31] [32] . A gene region, known as fat mass and obesity-related gene (FTO) is found to be strongly associated with obesity; and has been extensively studied since its discovery in 2007 [29] . However, previous studies have not found the mechanism that explains how gene differences in this region lead to obesity [11] . Numerous studies have attempted to link the FTO region with brain areas concerned with appetite or propensity to exercise, but have found that the region acts primarily on adipocyte progenitor cells independently of the brain [11] [33] [34] . Whether obesity is caused by an imbalance between dietary intake and energy expenditure, genetic factors, or a combination of both, it typically leads to the organism’s inability to effectively regulate nutrient metabolism [34] [35] . Normally in healthy humans, while excess fat is stored in the adipose tissue during positive caloric balance, excess glucose accumulates in the liver and muscle tissue in the form of glycogen [36] . Whenever the glycogen store is full, lipogenesis may occur mainly in the liver and sometimes in the adipocytes [35] . To compensate for, and maintain normoglycemia, the β-cell of the pancreas becomes very active especially in individuals with insulin resistance, although the molecular signals inducing this functional adaptation remain unknown [37] [38] . Increased insulin secretion, insulin gene expression, and an increase of the β-cell mass successfully keeps the body healthy for some time, and possibly even for life in some individuals [37] . In individuals with certain genetic predispositions, β-cell compensatory activity fails, leading to a condition known as glucolipotoxicity, the main cause of β-cell dysfunction [11] . The first stage of an individual’s transition from a healthy state to a prediabetic state is characterised by the presence of an impaired fasting glucose, impaired glucose tolerance; or both, and resistance to insulin signalling [39] . Nevertheless, metabolically healthy obese individuals and metabolically lean and diseased individuals are present in the population, indicating that obesity does not automatically cause Type II DM [40] [41] .
Despite the evidence of the major role obesity plays in the development of DM, factors causing the disease syndrome in these individuals are not yet defined in the literature [42] . However, Skovsø, 2014 [42] has demonstrated that obesity is always associated with a dramatic increase in the regulation of many inflammatory genes and specific macrophages in white fat cells. Adipose tissue dysfunction causes ectopic fat to accumulate in non-adipose tissues such as liver, muscle, and pancreas [11] [23] . The accumulation of triglyceride in the pancreatic β-cell causes a chain of biochemical reactions leading to an increase in lipogenesis [43] . The alteration of the chemistry of the internal environment thus created facilitates the development of biological interactions putting the β-cell in a total imbalance [44] . It is estimated that a 50 to 60% reduction in β-cell function is established twelve to several years before the diagnosis of diabetes [44] [45] [46] .
Many studies have been conducted to determine the exact mechanism governing the glucolipotoxicity process [35] . Unfortunately, of all these studies, no mechanisms have been identified in attempting to mimic the human biological environment [34] . In addition, palmitic acid (PA) and oleic acid (OA) are fatty acids (FAs) usually used in these studies but at widely varying concentrations, and at least 3 times higher than those found in the blood plasma of lean individuals [47] [48] . Therefore, results obtained from in-vitro studies using FAs should be interpreted with caution. Although apoptosis is induced in-vitro by a high concentration of FAs [48] , to our knowledge, no in-vivo study has clearly demonstrated the direct effect of a high concentration of FAs on β-cell death.
Zucker rats developed by mutation of the glutamate-269 (Glu-269) to proline (Pro) substitution in the extracellular portion of the leptin receptor are well used in the study of Type II DM and considered for the analysis of adverse effects of glucolipotoxicity [49] . As in humans, this animal model becomes diabetic as it ages, but does not depend on exogenous insulin to live [50] . Zucker rats’ β-cells initially compensate for the progression of obesity and associated insulin resistance by increasing insulin secretion, insulin mRNA levels, and insulin content, but can no longer lift this challenge, and animals eventually become hyperglycaemic [35] [50] [51] . Factors such as the metabolism of leptin in the body may be associated with a human genetic predisposition to Type II DM because leptin is important in maintaining the plasma level of triglycerides. The following emphasises the key role of the hormone leptin, in fat metabolism.
3. Role of Leptin in Fatty Acid Metabolism
Leptin, also known as the “obesity hormone”, was discovered in 1994 [50] [51] and considered a potential treatment for exceptional weight loss. Secreted by adipocytes, the role of the hormone is to up-regulate the oxidation of long chains of FAs via the sympathetic nerve-α-adrenergic receptor [52] and, in doing so, prevent non-adipose tissue from accumulating triglycerides [50] [51] [53] (Figure 1). Triglycerides are normally maintained in a very narrow range in these tissues (less than 150 milligrams per decilitre) [54] , making the molecule (triglyceride) the most useful index for overall non-oxidative metabolism [50] [51] [55] . When leptin is absent or its receptor non-functional, excess FAs (up to 1000 ng/islet) [43] in non-adipose tissues enter a toxic metabolic pathway in
which ceramide is produced [56] , followed by cellular lipotoxicity and lipoapoptosis [50] [51] [55] . For example, the accumulation of FAs in heart tissue causes cardiac dysfunction, insulin resistance in the muscle, and lipotoxicity; and in the pancreatic islet, lipoapoptosis occurs (55). Also, the toxic consequences of lipid overload would depend on the duration and the magnitude of the imbalance between the fat input and fat output in a specific tissue [53] .
In congenital human disorders characterised by the absence of adipocytes, the fat storage, and leptin production site, lipotoxicity is severe, and begins early in life [55] . In rodents genetically modified by the leptin receptor mutation, lipotoxicity also occurs very early [57] . However, in diet-induced obesity, non-adipose tissues are overprotected by hyperleptinemia; but only for a limited period of time before tissue resistance to leptin of unknown aetiology develops; the time that, excess fat begins to penetrate the non-adipose tissue and resulting in lipotoxicity.
4. Lipotoxicity
The accumulation of triglyceride is not the direct cause of islet cells destruction in genetically modified obese animals (Zucker rats) [58] (Figure 1). In-vitro studies reveal that ceramide formation is the main step in this process. Ceramide is a condensation of serine and palmitol (FA), a reaction catalysed by pamitol transferase [56] ; the level of which is strongly elevated in prediabetic obese Zucker rat models [59] [60] . The increase in ceramide level enhances the activation of nitric oxide synthase (iNOS), that of the formation of nitric oxide (NO) [61] ; the direct cause of cell apoptosis (discussed later in the review).
In non-genetically modified obese HFD rodents, the glucolipotoxicity hardly develops or never develops in DM, and can be suspended before the death of the β-cells. This suggests that factors mediating the conversion of the prediabetic state to a complete Type II DM in humans may be absent or altered in non-genetically modified rodents. However, a few days of HFD diet are sufficient to transform the internal metabolic milieu of these animals to the threshold of a healthy state with significant insulin resistance but never become diabetic. Thus, to trigger the onset of the final stage of the metabolic syndrome as to mimic the typical human pathophysiology of Type II DM [61] , these animals are usually administered a single non-diabetes inducible dose of STZ (30 - 35 mg/kg body weight) which may be the additional factor to insulin resistance that finally causes the development of Type II DM. It raises the questions as to what is, or are, the cumulating factors that enhance the β-cell death under this condition? These observations aroused our curiosity about the striking difference between the diabetogenic doses of STZ administered to the rats and mice. How does STZ work in the model of HFD-induced obesity?
5. Streptozotocin5.1. Chemical Properties of Streptozotocin
Streptozotocin (STZ) (2-deoxy-2-({[methyl(nitroso) amino] carbonyl} amino)-β-D-glucopyranose) (Zanosar) [16] [62] is a broad-spectrum antibiotic [63] [64] . First identified in 1960 from the soil bacterium Streptomyces Achromogenes, the compound has been used in the treatment of human pancreatic neoplasms [65] and for the induction of diabetes in animals [66] . Very soluble in water, lower alcohols, and ketones [67] , STZ is a white or a pale-yellow crystalline powder resulting from a mixture of α and β stereoisomers [62] . The drug has the chemical formula C8H15N3O7 (Figure 2) with a molecular weight of 265 g/mol [62] . Streptozotocin is also a glucosamine-nitrosourea compound structurally
composed of a molecule of glucose at one end and a methyl group at the other end (Figure 2) [43] The methyl nitrosourea fraction appears to be responsible for the toxicity of STZ while the deoxyglucose fraction recognises the GLUT2 glucose transporter receptor, which is abundant on the plasma membrane of β-cells and thus remains the best target cell of the drug. However, GLUT2 is also found in liver, and kidney cells to a lesser extent. Streptozotocin has a biological half-life of 5 - 15 minutes and is relatively unstable: working solutions should be prepared immediately before injection [68] .
5.2. Dose and Method of Administration of Streptozotocin
Streptozotocin is administered to animals either intraperitoneally (IP) [69] , subcutaneously [70] or intravenously (IV) [23] Regardless of mode of administration, the drug seems to have the same metabolic pathway and does not appear to be dose-dependent. A single high dose (40 - 60 mg/kg body weight or multiple low doses can be used to induce Type I DM in rats) [71] ; a condition that initially creates a partial pancreatic β-cell damage leading to an inflammatory response. The inflammatory process, in turn, trigger further loss of insulin-producing cells followed by a significant reduction of insulin secretion and ultimately hyperglycaemia. In rats, a dose of STZ less than 40 mg/kg body weight may not be effective [3] [23] . While the highest single dose for the induction of diabetes in rat is only 65 mg/kg body weight [3] , up to 200 mg/kg of STZ is administered (Dekel et al., 2009), in mice for the same purpose [16] [23] [72] . In addition, even within a single rodent strain, the dose of STZ administered for diabetes induction depends on many other factors; such as animal sex (male or female) [16] [72] , diet, circadian rhythm [16] . These factors constituted the biggest challenge in terms of transferring a well-established protocol from one strain to another [73] . Unfortunately, there is no detail on the molecular pathway that justifies this inconsistency. A better understanding of the logical flow of this scenario will pave the way for new avenues in diabetic research using animal models, but most importantly, the genetic-environmental condition associated with the selective onset of diabetes in some individuals may be revealed.
5.3. Streptozotocin across the Target Cell Membrane
Once introduced into the body, the STZ molecule approaches the target cells through the bloodstream. The compound is internalised in the target cell via the low-affinity GLUT2 (also called facilitated glucose transporter) [14] [68] [74] . Glucose transporter 2 membrane receptors are bidirectional glucose transporters restricted to cells of organs involved in glucose homeostasis such as hepatocytes and pancreatic β-cells [75] . The receptor distributes glucose molecules between the extracellular and the intracellular space which is rapidly maintained under physiological conditions and in diseases such as diabetes. The transporter is highly expressed in β-cell membranes and also transports fructose [76] and drug molecules such as STZ [75] [77] in the cells. However, unlike glucose that is also transported by other glucose transporters, several studies have shown that STZ’s sole gateway into targeted cells is via the GLUT2 transporter [78] .
Streptozotocin sugar moiety is the chemical structural arrangement that allows the drug to identify the target cell membrane receptor and mediate the transfer into the cytoplasm. The receptor thus remains the STZ susceptibility marker and their level of distribution on the β-cell membrane, the expression and state define the degree of toxicity of the drug that may or may not lead to the onset of diabetes [17] . For example, insulin-secreting cells from humans and the Old World monkey are very resistant to STZ because of the very low level of GLUT2 on their cell membrane (1% to 2% of those found in rats) [79] [80] . Recent reports have shown that human β-cells transplanted to rodents are not destroyed when these animals even receive high doses of STZ [17] [81] . Interestingly, human pancreatic islet cancer cells, on the other hand, express high levels of GLUT2 and STZ thus, has been used for many years as an oncogenic agent in the treatment of islet malignancy [82] [83] . On the other hand, rat RINm5f insulinoma cell lines are very insensitive to STZ toxicity because they do not express GLUT2 glucose transporters [84] . These animal models quickly become sensitive once the expression of the transporter is induced [85] . Therefore, if HFD induces susceptibility to STZ in rodents, the properties of GLUT2 may have improved under such conditions.
On the contrary, the impairment of the expression of GLUT2 [81] and its translocation from the cytoplasm to the cell membrane is the early signs of β-cell functional disturbance in HFD/obese animals [86] . These changes are also observed in diabetic Goto-Kakizaki rats [86] [87] and other genetically modified diabetic rodents such as Zucker and Wistar Kyoto rats that are hyperinsulinemia and hyperglycaemic [87] [88] . A prolonged hyperglycaemic clamp at 200 - 250 mg/dl does not alter the expression of GLUT2 in β-cells from standard rat chow-fed rats [89] . This suggests that even a mild hyperglycaemia in HFD fed animals down-regulates the GLUT2 gene expression independent on the level of plasma insulin. Factors suppressing GLUT2 expression in HFD rats are yet to be defined. Nevertheless, even a reduction of more than 90% of the glucose transporter cannot exert any physiological effect on the glucose metabolism in β-cells [16] and certainly also on STZ action. Glucose transporter 2 is therefore not a contributing factor to the STZ influence. The evidence for the extreme susceptibility of β-cells to STZ in HFD-fed rats appears to depend on their cytoplasmic metabolic byproducts such as nitric oxide (NO) and/or reactive oxygen species (ROS).
5.4. Intracellular Fate of Streptozotocin
Although the exact cytotoxic molecular mechanism of the diabetogenic action of STZ is unclear, the process is well-known to be associated with four major synergistic biochemical pathways via its nitrosourea moiety [90] [91] . Firstly, carbamoylation and alkylation of cellular components, secondly, the release of NO, thirdly, the generation of free radicals, and oxidative stress, and lastly, the inhibition of O-GlcNAcase [19] .
Once inside the cell, STZ is able to decompose spontaneously to form an isocyanate molecule and a methyldiazohydroxide molecule [64] [92] (Figure 3). Methyldiazohydroxide in turn splits to form a highly reactive carbonium ion (CH3+) which is considered a key player in DNA alkylation induced by STZ. Carbonium ions cause cross-linking of interstrand DNA. Streptozotocin DNA methylation is initiated at the position O6 of guanine, a reaction which interferes with hydrogen bonding and allows guanine to mis-pair with thymine. This replacement of molecules causes a point of mutation leading to DNA damage [18] [93] [94] .
DNA damage caused by STZ-mediated alkylation is repaired by an excision repair process, which requires activation of NAD-dependent enzyme-dependent poly (ADP-ribose) synthetase (PARP) [93] . The over activation of PARP depletes the nicotinamide adenosine dinucleotide (NAD), the main source of intracellular energy and Adenosine triphosphate (ATP) stores leading to pancreatic β-cell necrosis [91] [94] . Although STZ also methylates cytoplasmic proteins, the main cause of β-cell necrosis is in the process of methylation of DNA. A treatment with nicotinamide, also an inhibitor of PARP before the induction of STZ in experimental rats prevents the damage of DNA, and thus protects β-cells from STZ toxicity [94] [95] .
The cytoplasmic metabolism of STZ also liberates NO in the targeted cells without the intervention of NO synthase [95] [96] . After two hours of STZ injection, NO release is observed in β-cells of the rat pancreas [16] [97] [98] . Nitric oxide is a free radical discovered in 1772 by Joseph Priestly [95] [96] [99] , and is normally synthesised from the enzymatic oxidation of L-arginine to citrulline [95] [99] . Easily transported through biological lipid membranes [95] [100] , NO is present in various tissue cells of the body, particularly in endothelial cells (ECs) where its main function is to regulate mitochondrial respiration [98] . In the aqueous medium, NO rapidly binds to oxygen (O2) and is converted to nitrite [95] [99] [100] . Nitrite acts as a signaling metabolic molecule in several physiological processes [16] [99] [100] [101] [102] and may also participate in cellular toxicity because of its ability to bind to, and inactivate, mitochondrial iron-containing enzymes such as aconitase, involved in the Krebs cycle [103] .
The biological action of STZ as a NO donor depends on the amount and duration of NO released [16] [95] . In the presence of a high concentration of NO, as in the case of STZ in the targeted cells, the continuous inactivation of these enzymes (involved in the Krebs cycle) leads to the reduction of intracellular respiration creating a pseudo hypoxia, thus facilitating cell death [16] [81] [95] . Although not the only molecule responsible for β-cell toxicity, NO is said to contribute to DNA damage leading to β-cell death in humans and rodents [21] [81] . It is interesting to note that this process can also be avoided by NO scavengers [21] , unfortunately reduced in β-cells [95] . Nitric oxide acting this way contributes in the cascade of cytoplasmic reactions, leading to the formation of free radicals [81] . Streptozotocin reduces the mitochondrial oxygen consumption which in turn reduces ATP mitochondrial production within the β-cells. The reduction of ATP production leads to the depletion NAD [104] [105] . The excessive dephosphorylisation of ATP produces a large amount of substrate to the activity of xanthine oxidase in pancreatic β-cells, causing the formation of uric acid as a by-product of ATP degradation of superoxide anion. Superoxide anion and NO are free radicals carrying unpaired electrons, which for stability, must react with other unpaired electron molecules (other free radicals). The formation of these anions generates hydrogen peroxide and hydroxyl radicals (ROS) [104] [105] . Thus, pre-treatment of β-cells with xanthine oxidase inhibitor allopurinol limits the toxic effect of STZ on β-cells [104] [105] . Free radical production at the early stages of STZ-induced diabetic rats causes oxidative stress [106] [107] .
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
Cite this paper
Eleonore, N., Van Wijk, R. and Ngouakam, H. (2023) Evaluation of the Key Mechanism Justifying the High Sensitivity of Obese Rodents to Streptozotocin (STZ). Journal of Biosciences and Medicines, 11, 376-394. https://doi.org/10.4236/jbm.2023.1112028
ReferencesThomas, F.T., Ricordi, C., Contreras, J.L., Hubbard, W.J., Jiang, X.L., Eckhoff, D.E., Cartner, S., Bilbao, G., Neville Jr., D.M. and Thomas, J.M. (1999) Reversal of Naturally Occurring Diabetes in Primates by Unmodified Islet Xenografts without Chronic Immunosuppression. Transplantation, 67, 846-854. https://doi.org/10.1097/00007890-199903270-00011Dufrane, D., Goebbels, R.M. and Gianello, P. (2010) Alginate Macroencapsulation of Pig Islets Allows Correction of Streptozotocin-Induced Diabetes in Primates up to 6 Months without Immunosuppression. Transplantation, 90, 1054-1062. https://doi.org/10.1097/TP.0b013e3181f6e267Srinivasan, K. and Ramarao, P. (2007) Animal Models in Type 2 Diabetes Research: an Overview. Indian Journal of Medical Research, 125, 451-472.Drel, V.R., Pacher, P., Stavniichuk, R., Xu, W., Zhang, J., Kuchmerovska, T., Slusher, B. and Obrosova, I.G. (2011) Poly (ADP-Ribose) Polymerase Inhibition Counteracts Renal Hypertrophy and Multiple Manifestations of Peripheral Neuropathy in Diabetic Akita Mice. International Journal of Molecular Medicine, 28, 629-635.Zhou, C., Pridgen, B., King, N., Xu, J. and Breslow, J.L. (2011) Hyperglycemic Ins2AkitaLdlr-/- Mice Show Severely Elevated Lipid Levels and Increased Atherosclerosis: A Model of Type 1 Diabetic Macrovascular Disease. Journal of Lipid Research, 52, 1483-1493. https://doi.org/10.1194/jlr.M014092King, A.J. (2012) The Use of Animal Models in Diabetes Research. British Journal of Pharmacology, 166, 877-894. https://doi.org/10.1111/j.1476-5381.2012.01911.xWei, L., Lu, Y., He, S., Jin, X., Zeng, L., Zhang, S. and Deng, S. (2011) Induction of Diabetes with Signs of Autoimmunity in Primates by the Injection of Multiple-Low-Dose Streptozotocin. Biochemical and Biophysical Research Communications, 412, 373-378. https://doi.org/10.1016/j.bbrc.2011.07.105Yoon, J.W., London, W.T., Curfman, B.L., Brown, R.L. and Notkins, A.L. (1986) Coxsackie Virus B4 Produces Transient Diabetes in Nonhuman Primates. Diabetes, 35, 712-716. https://doi.org/10.2337/diab.35.6.712Brendle, T.A. (2010) Preventing Surgically Induced Diabetes after Total Pancreatectomy via Autologous Islet Cell Reimplantation. AORN Journal, 92, 169-184. https://doi.org/10.1016/j.aorn.2010.04.015Srinivasan, K., Viswanad, B., Asrat, L., Kaul, C.L. and Ramarao, P. (2005) Combination of High-Fat Diet-Fed and Low-Dose Streptozotocin-Treated Rat: A Model for Type 2 Diabetes and Pharmacological Screening. Pharmacological Research, 52, 313-320. https://doi.org/10.1016/j.phrs.2005.05.004Magalhaes, D.A., Kume, W.T., Correia, F.S., Queiroz, T.S., Allebrandt, E.W., Santos, M.P. and Franca, S.A. (2019) High-Fat Diet and Streptozotocin in the Induction of Type 2 Diabetes Mellitus: A New Proposal. Anais da Academia Brasileira de Ciências, 91, e20180314. https://doi.org/10.1590/0001-3765201920180314Tesch, G.H. and Allen, T.J. (2007) Rodent Models of Streptozotocin‐Induced Diabetic Nephropathy (Methods in Renal Research). Nephrology, 12, 261-266. https://doi.org/10.1111/j.1440-1797.2007.00796.xArison, R.N., Ciaccio, E.I., Glitzer, M.S., Cassaro, J.A. and Pruss, M.P. (1967) Light and Electron Microscopy of Lesions in Rats Rendered Diabetic with Streptozotocin. Diabetes, 16, 51-56. https://doi.org/10.2337/diab.16.1.51Lenzen, S. (2008) The Mechanisms of Alloxan- and Streptozotocin-Induced Diabetes. Diabetologia, 51, 216-226. https://doi.org/10.1007/s00125-007-0886-7Thurston, D.E. and Pysz, I. (2021) Chemistry and Pharmacology of Anti-Cancer Drugs. CRC Press, Boca Raton. https://doi.org/10.1201/9781315374727Szkudelski T. ,et al. (2001)The Mechanism of Alloxan and Streptozotocin Action in B Cells of the Rat Pancreas Physiological Research 50, 537-546.Yang, H. and Wright Jr., J.R. (2002) Human β Cells Are Exceedingly Resistant to Streptozotocin in Vivo. Endocrinology, 143, 2491-2495. https://doi.org/10.1210/endo.143.7.8901Elsner, M., Guldbakke, B., Tiedge, M., Munday, R. and Lenzen, S. (2000) Relative Importance of Transport and Alkylation for Pancreatic Beta-Cell Toxicity of Streptozotocin. Diabetologia, 43, 1528-1533. https://doi.org/10.1007/s001250051564Busineni, J.G., Dwarakanath, V. and Chikka Swamy, B.K. (2015) Streptozotocin—A Diabetogenic Agent in Animal Models. International Journal of Pharmacy and Pharmaceutical Sciences, 3, 253-269.Reed, M.J., Meszaros, K., Entes, L.J., Claypool, M.D., Pinkett, J.G., Gadbois, T.M. and Reaven, G.M. (2000) A New Rat Model of Type 2 Diabetes: The Fat-Fed, Streptozotocin-Treated Rat. Metabolism-Clinical and Experimental, 49, 1390-1394. https://doi.org/10.1053/meta.2000.17721Spinas, G.A. (1999) The Dual Role of Nitric Oxide in Islet Β-Cells. Physiology, 14, 49-54. https://doi.org/10.1152/physiologyonline.1999.14.2.49Qian, C., Zhu, C., Yu, W., Jiang, X. and Zhang, F. (2015) High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes in Rats Impacts Osteogenesis and Wnt Signaling in Bone Marrow Stromal Cells. PLOS ONE, 10, e0136390. https://doi.org/10.1371/journal.pone.0136390Deeds, M.C., Anderson, J.M., Armstrong, A.S., Gastineau, D.A., Hiddinga, H.J., Jahangir, A. and Kudva, Y.C. (2011) Single Dose Streptozotocin-Induced Diabetes: Considerations for Study Design in Islet Transplantation Models. Laboratory Animals, 45, 131-140. https://doi.org/10.1258/la.2010.010090Tanaka, S., Hayashi, T., Toyoda, T., Hamada, T., Shimizu, Y., Hirata, M. and Nakao, K. (2007) High-Fat Diet Impairs the Effects of a Single Bout of Endurance Exercise on Glucose Transport and Insulin Sensitivity in Rat Skeletal Muscle. Metabolism, 56, 1719-1728. https://doi.org/10.1016/j.metabol.2007.07.017Flanagan, A.M., Brown, J.L., Santiago, C.A., Aad, P.Y., Spicer, L.J. and Spicer, M.T. (2008) High-Fat Diets Promote Insulin Resistance through Cytokine Gene Expression in Growing Female Rats. The Journal of Nutritional Biochemistry, 19, 505-513. https://doi.org/10.1016/j.jnutbio.2007.06.005Liu, Z., Wang, N., Ma, Y. and Wen, D. (2019) Hydroxytyrosol Improves Obesity and Insulin Resistance by Modulating Gut Microbiota in High-Fat Diet-Induced Obese Mice. Frontiers in Microbiology, 10, Article 390. https://doi.org/10.3389/fmicb.2019.00390Zhou, J., Zhou, S., Tang, J., Zhang, K., Guang, L., Huang, Y. and Li, D. (2009) Protective Effect of Berberine on Beta Cells in Streptozotocin- and High-Carbohydrate/High-Fat Diet-Induced Diabetic Rats. European Journal of Pharmacology, 606, 262-268. https://doi.org/10.1016/j.ejphar.2008.12.056Kopelman, P. (2007) Health Risks Associated with Overweight and Obesity. Obesity Reviews, 8, 13-17. https://doi.org/10.1111/j.1467-789X.2007.00311.xFawcett, K.A. and Barroso, I. (2010) The Genetics of Obesity: FTO Leads the Way. Trends in Genetics, 26, 266-274. https://doi.org/10.1016/j.tig.2010.02.006Dina, C., Meyre, D., Gallina, S., Durand, E., Korner, A., Jacobson, P. and Froguel, P. (2007) Variation in FTO Contributes to Childhood Obesity and Severe Adult Obesity. Nature Genetics, 39, 724-726. https://doi.org/10.1038/ng2048Scuteri, A., Sanna, S., Chen, W.M., Uda, M., Albai, G., Strait, J. and Abecasis, G.R. (2007) Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits. PLOS Genetics, 3, e115. https://doi.org/10.1371/journal.pgen.0030115Claussnitzer, M., Dankel, S.N., Kim, K.H., Quon, G., Meuleman, W., Haugen, C. and Kellis, M. (2015) FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. New England Journal of Medicine, 373, 895-907. https://doi.org/10.1056/NEJMoa1502214McMurray, F., Church, C.D., Larder, R., Nicholson, G., Wells, S., Teboul, L. and Cox, R.D. (2013) Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse. PLOS Genetics, 9, e1003166. https://doi.org/10.1371/journal.pgen.1003166Popa, S. and Mota, M. (2013) Beta-Cell Function and Failure in Type 2 Diabetes. In: Masuo, K., Ed., Type 2 Diabetes, InTech, Croatia, 29-50. https://doi.org/10.5772/56467Poitout, V. and Robertson, R.P. (2008) Glucolipotoxicity: Fuel EXCESS and β-Cell Dysfunction. Endocrine Reviews, 29, 351-366.https://doi.org/10.1210/er.2007-0023Acheson, K.J., Schutz, Y., Bessard, T., Anantharaman, K., Flatt, J.P. and Jequier, E. (1988) Glycogen Storage Capacity and de Novo Lipogenesis during Massive Carbohydrate Overfeeding in Man. The American Journal of Clinical Nutrition, 48, 240-247. https://doi.org/10.1093/ajcn/48.2.240Kahn, S.E. (2003) The Relative Contributions of Insulin Resistance and Beta-Cell Dysfunction to the Pathophysiology of Type 2 Diabetes. Diabetologia, 46, 3-19. https://doi.org/10.1007/s00125-002-1009-0Marchetti, P., Dotta, F., Lauro, D. and Purrello, F. (2008) An Overview of Pancreatic Beta-Cell Defects in Human Type 2 Diabetes: Implications for Treatment. Regulatory Peptides, 146, 4-11. https://doi.org/10.1016/j.regpep.2007.08.017Blüher, M. (2010) The Distinction of Metabolically ‘Healthy’ from ‘Unhealthy’ Obese Individuals. Current Opinion in Lipidology, 21, 38-43. https://doi.org/10.1097/MOL.0b013e3283346cccAlberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2002) Blood Vessels and Endothelial Cells. In: Molecular Biology of the Cell, 4th Edition, Garland Science, New York.Abdesselem, H.B., Madani, A. and Mazloum, N. (2012) Investigating Poly (ADP-Ribose) Polymerase-1 (PARP-1) Activation in Obesity Associated DNA Damage and Pro-Inflammatory Senescence. Qatar Foundation Annual Research Forum, 2012, BMP77. https://doi.org/10.5339/qfarf.2012.BMP77Skovso, S. (2014) Modeling Type 2 Diabetes in Rats Using High Fat Diet and Streptozotocin. Journal of Diabetes Investigation, 5, 349-358. https://doi.org/10.1111/jdi.12235Benito-Vicente, A., Jebari-Benslaiman, S., Galicia-Garcia, U., Larrea-Sebal, A., Uribe, K.B. and Martin, C. (2021) Molecular Mechanisms of Lipotoxicity-Induced Pancreatic β-Cell Dysfunction. International Review of Cell and Molecular Biology, 359, 357-402. https://doi.org/10.1016/bs.ircmb.2021.02.013Levy, J., Atkinson, A.B., Bell, P.M., McCance, D.R. and Hadden, D.R. (1998) Beta-Cell Deterioration Determines the Onset and Rate of Progression of Secondary Dietary Failure in Type 2 Diabetes Mellitus: The 10-Year Follow-Up of the Belfast Diet Study. Diabetic Medicine, 15, 290-296. https://doi.org/10.1002/(SICI)1096-9136(199804)15:4<290::AID-DIA570>3.0.CO;2-MChen, C., Hosokawa, H., Bumbalo, L.M. and Leahy, J.L. (1994) Mechanism of Compensatory Hyperinsulinemia in Normoglycemic Insulin-Resistant Spontaneously Hypertensive Rats. Augmented Enzymatic Activity of Glucokinase in Beta-Cells. The Journal of Clinical Investigation, 94, 399-404. https://doi.org/10.1172/JCI117335Liu, Y.Q., Jetton, T.L. and Leahy, J.L. (2002) β-Cell Adaptation to Insulin Resistance: Increased Pyruvate Carboxylase and Malate-Pyruvate Shuttle Activity in Islets of Nondiabetic Zucker Fatty Rats. Journal of Biological Chemistry, 277, 39163-39168. https://doi.org/10.1074/jbc.M207157200Kliewer, S.A., Sundseth, S.S., Jones, S.A., Brown, P.J., Wisely, G.B., Koble, C.S. and Lehmann, J.M. (1997) Fatty Acids and Eicosanoids Regulate Gene Expression through Direct Interactions with Peroxisome Proliferator-Activated Receptors α and γ. Proceedings of the National Academy of Sciences of the United States of America, 94, 4318-4323. https://doi.org/10.1073/pnas.94.9.4318Plotz, T., Krümmel, B., Laporte, A., Pingitore, A., Persaud, S.J., Jorns, A. and Lenzen, S. (2017) The Monounsaturated Fatty Acid Oleate Is the Major Physiological Toxic Free Fatty Acid for Human Beta Cells. Nutrition and Diabetes, 7, Article No. 305. https://doi.org/10.1038/s41387-017-0005-xGuberski, D.L., Butler, L., Manzi, S.M., Stubbs, M. and Like, A.A. (1993) The BBZ/Wor Rat: Clinical Characteristics of the Diabetic Syndrome. Diabetologia, 36, 912-919. https://doi.org/10.1007/BF02374472Fortuno, A., Rodriguez, A., Gomez-Ambrosi, J., Frühbeck, G. and Diez-Martinez, J. (2003) Adipose Tissue as an Endocrine Organ: Role of Leptin and Adiponectin in the Pathogenesis of Cardiovascular Diseases. Journal of Physiology and Biochemistry, 59, 51-60. https://doi.org/10.1007/BF03179868Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J.M. (1994) Positional Cloning of the Mouse Obese Gene and Its Human Homologue. Nature, 372, 425-432. https://doi.org/10.1038/372425a0Haynes, W.G., Morgan, D.A., Walsh, S., Mark, A.L. and Sivitz, W.I. (1997) Receptor-Mediated Regional Sympathetic Nerve Activation by Leptin. The Journal of Clinical Investigation, 100, 270-278. https://doi.org/10.1172/JCI119532Zhou, Y.T., Shimabukuro, M., Koyama, K., Lee, Y., Wang, M.Y., Trieu, F. and Unger, R.H. (1997) Induction by Leptin of Uncoupling Protein-2 and Enzymes of Fatty Acid Oxidation. Proceedings of the National Academy of Sciences of the United States of America, 94, 6386-6390. https://doi.org/10.1073/pnas.94.12.6386Miller, M., Seidler, A., Moalemi, A. and Pearson, T.A. (1998) Normal Triglyceride Levels and Coronary Artery Disease Events: The Baltimore Coronary Observational Long-Term Study. Journal of the American College of Cardiology, 31, 1252-1257. https://doi.org/10.1016/S0735-1097(98)00083-7Unger, R.H. and Zhou, Y.T. (2001) Lipotoxicity of Beta-Cells in Obesity and in Other Causes of Fatty Acid Spillover. Diabetes, 50, S118. https://doi.org/10.2337/diabetes.50.2007.S118Shimabukuro, M., Zhou, Y.T., Levi, M. and Unger, R.H. (1998) Fatty Acid-Induced β cell Apoptosis: A Link between Obesity and Diabetes. Proceedings of the National Academy of Sciences of the United States of America, 95, 2498-2502. https://doi.org/10.1073/pnas.95.5.2498Sahin, K., Onderci, M., Tuzcu, M., Ustundag, B., Cikim, G., Ozercan, I.H. and Komorowski, J.R. (2007) Effect of Chromium on Carbohydrate and Lipid Metabolism in a Rat Model of Type 2 Diabetes Mellitus: The Fat-Fed, Streptozotocin-Treated Rat. Metabolism, 56, 1233-1240. https://doi.org/10.1016/j.metabol.2007.04.021Lee, Y., Hiros, H., Zhou, Y. T., Esser, V., McGarry, J.D. and Unger, R.H. (1997) Increased Lipogenic Capacity of the Islets of Obese Rats: A Role in the Pathogenesis of NIDDM. Diabetes, 46, 408-413. https://doi.org/10.2337/diab.46.3.408Pautz, A., Franzen, R., Dorsch, S., Boddinghaus, B., Briner, V.A., Pfeilschifter, J. and Huwiler, A. (2002) Cross-Talk between Nitric Oxide and Superoxide Determines Ceramide Formation and Apoptosis in Glomerular Cells. Kidney International, 61, 790-796. https://doi.org/10.1046/j.1523-1755.2002.00222.xZhang, D.X., Zou, A.P. and Li, P.L. (2003) Ceramide-Induced Activation of NADPH Oxidase and Endothelial Dysfunction in Small Coronary Arteries. American Journal of Physiology-Heart and Circulatory Physiology, 284, H605-H612. https://doi.org/10.1152/ajpheart.00697.2002Burcelin, R., Kande, J., Ricquier, D. and Girard, J. (1993) Changes in Uncoupling Protein and GLUT4 Glucose Transporter Expressions in Interscapular Brown Adipose Tissue of Diabetic Rats: Relative Roles of Hyperglycaemia and Hypoinsulinaemia. Biochemical Journal, 291, 109-113. https://doi.org/10.1042/bj2910109Dolan, M.E. (1997) Inhibition of DNA Repairs as a Means of Increasing the Antitumor Activity of DNA Reactive Agents. Advanced Drug Delivery Reviews, 26, 105-118. https://doi.org/10.1016/S0169-409X(97)00028-8Weiss R.B. ,et al. (1982)Streptozocin: A Review of Its Pharmacology, Efficacy, and Toxicity Cancer Treatment Reports 66, 427-438.Schott, M., Scherbaum, W.A. and Feldkamp, J. (2000) Drug Therapy of Endocrine Neoplasms. Part II: Malignant Gastrinomas, Insulinomas, Glucagonomas, Carcinoids and Other Tumors. Medizinische Klinik (Munich, Germany: 1983), 95, 81-84. https://doi.org/10.1007/BF03044988Rerup, C. and Tarding, F. (1969) Streptozotocin- and Alloxan-Diabetes in Mice. European Journal of Pharmacology, 7, 89-96. https://doi.org/10.1016/0014-2999(69)90169-1Vivek K.S. ,et al. (2010)Streptozotocin: An Experimental Tool in Diabetes and Alzheimer’s Disease (A-Review) International Journal of Pharmaceutical Research and Development 2, 1-7.Eleazu, C.O., Eleazu, K.C., Chukwuma, S. and Essien, U.N. (2013) Review of the Mechanism of Cell Death Resulting from Streptozotocin Challenge in Experimental Animals, Its Practical Use and Potential Risk to Humans. Journal of Diabetes and Metabolic Disorders, 12, Article No. 60. https://doi.org/10.1186/2251-6581-12-60Sanguinetti, R.E., Ogawa, K., Kurohmaru, M. and Hayashi, Y. (1995) Ultrastructural Changes in Mouse Leydig Cells after Streptozotocin Administration. Experimental Animals, 44, 71-73. https://doi.org/10.1538/expanim.44.71Ahlgren, S.C. and Levine, J.D. (1993) Mechanical Hyperalgesia in Streptozotocin-Diabetic Rats. Neuroscience, 52, 1049-1055. https://doi.org/10.1016/0306-4522(93)90551-PFiordaliso, F., Li, B., Latini, R., Sonnenblick, E.H., Anversa, P., Leri, A. and Kajstura, J. (2000) Myocyte Death in Streptozotocin-Induced Diabetes in Rats Is Angiotensin II-Dependent. Laboratory Investigation, 80, 513-527. https://doi.org/10.1038/labinvest.3780057Katsumata, K. and Katsumata, Y. (1992) Protective Effect of Diltiazem Hydrochloride on the Occurrence of Alloxan- or Streptozotocin-Induced Diabetes in Rats. Hormone and Metabolic Research, 24, 508-510. https://doi.org/10.1055/s-2007-1003376Ito, M., Kondo, Y., Nakatani, A., Hayashi, K. and Naruse, A. (2001) Characterization of Low Dose Streptozotocin-Induced Progressive Diabetes in Mice. Environmental Toxicology and Pharmacology, 9, 71-78. https://doi.org/10.1016/S1382-6689(00)00064-8Nakamura, M., Nagafuchi, S., Yamaguchi, K. and Takaki, R. (1984) The Role of Thymic Immunity And Insulitis in the Development of Streptozocin-Induced Diabetes in Mice. Diabetes, 33, 894-900. https://doi.org/10.2337/diab.33.9.894Leturque, A., Brot-Laroche, E. and Le Gall, M. (2009) GLUT2 Mutations, Translocation, and Receptor Function in Diet Sugar Managing. American Journal of Physiology. Endocrinology and Metabolism, 296, E985-E992. https://doi.org/10.1152/ajpendo.00004.2009Narasimhan, A., Chinnaiyan, M. and Karundevi, B. (2015) Ferulic Acid Regulates Hepatic GLUT2 Gene Expression in High Fat and Fructose-Induced Type-2 Diabetic Adult Male Rat. European Journal of Pharmacology, 761, 391-397. https://doi.org/10.1016/j.ejphar.2015.04.043Kahraman, S., Aydin, C., Elpek, G. O., Dirice, E. and Sanlioglu, A. D. (2015) Diabetes-Resistant NOR Mice Are More Severely Affected by Streptozotocin Compared to the Diabetes-Prone NOD Mice: Correlations with Liver and Kidney GLUT2 Expressions. Journal of Diabetes Research, 2015, Article ID: 450128. https://doi.org/10.1155/2015/450128Ventura-Sobrevilla, J., Boone-Villa, V.D., Aguilar, C.N., Román-Ramos, R., Vega-Avila, E., Campos-Sepúlveda, E. and Alarcón-Aguilar, F. (2011) Effect of Varying Dose and Administration of Streptozotocin on Blood Sugar in Male CD1 Mice. Proceedings of the Western Pharmacology Society, 54, 5-9.Kramer, J., Moeller, E.L., Hachey, A., Mansfield, K.G. and Wachtman, L.M. (2009) Differential Expression of GLUT2 in Pancreatic Islets and Kidneys of New and Old World Nonhuman Primates. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 296, R786-R793. https://doi.org/10.1152/ajpregu.90694.2008Elsner, M., Tiedge, M. and Lenzen, S. (2003) Mechanism Underlying Resistance of Human Pancreatic Beta Cells against Toxicity of Streptozotocin and Alloxan. Diabetologia, 46, 1713-1714. https://doi.org/10.1007/s00125-003-1241-2Eizirik, D.L., Pipeleers, D.G., Ling, Z., Welsh, N., Hellerstrom, C. and Andersson, A. (1994) Major Species Differences Between Humans and Rodents in the Susceptibility to Pancreatic Beta-Cell Injury. Proceedings of the National Academy of Sciences of the United States of America, 91, 9253-9256. https://doi.org/10.1073/pnas.91.20.9253Tyrberg, B., Andersson, A. and Borg, L.H. (2001) Species Differences in Susceptibility of Transplanted and Cultured Pancreatic Islets to the Β-Cell Toxin Alloxan. General and Comparative Endocrinology, 122, 238-251. https://doi.org/10.1006/gcen.2001.7638Tuomilehto, J., Lindstrom, J., Eriksson, J.G., Valle, T.T., Hamalainen, H., Ilanne-Parikka, P. and Uusitupa, M. (2001) Prevention of Type 2 Diabetes Mellitus by Changes in Lifestyle among Subjects with Impaired Glucose Tolerance. New England Journal of Medicine, 344, 1343-1350. https://doi.org/10.1056/NEJM200105033441801Ledoux, S.P. and Wilson, G.L. (1984) Effects of Streptozotocin on a Conal Isolate of Rat Insulinoma Cells. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 804, 387-392. https://doi.org/10.1016/0167-4889(84)90064-8Flatt, P.R., Swanston-Flatt, S.K., Tan, K.S. and Marks, V. (1987) Effects of Cytotoxic Drugs and Inhibitors of Insulin Secretion on a Serially Transplantable Rat Insulinoma and Cultured Rat Insulinoma Cells. General Pharmacology, 18, 293-297. https://doi.org/10.1016/0306-3623(87)90014-0Schnedl, W.J., Ferber, S., Johnson, J.H. and Newgard, C.B. (1994) STZ Transport and Cytotoxicity: Specific Enhancement in GLUT2-Expressing Cells. Diabetes, 43, 1326-1333. https://doi.org/10.2337/diab.43.11.1326Kim, Y.B., Iwashita, S., Tamura, T., Tokuyama, K. and Suzuki, M. (1995) Effect of High-Fat Diet on the Gene Expression of Pancreatic GLUT2 and Glucokinase in Rats. Biochemical and Biophysical Research Communications, 208, 1092-1098. https://doi.org/10.1006/bbrc.1995.1446Ohneda, M., Johnson, J.H., Inman, L.R., Chen, L., Suzuki, K.I., Goto, Y., et al. (1993) GLUT2 Expression and Function in β-Cells of GK Rats with NIDDM: Dissociation between Reductions in Gucose Tansport and Glucose-Stimulated Insulin Secretion. Diabetes, 42, 1065-1072. https://doi.org/10.2337/diab.42.7.1065Johnson, J.H., Ogawa, A., Chen, L., Orci, L., Newgard, C.B., Alam, T. and Unger, R.H. (1990) Underexpression of β Cell High K m Glucose Transporters in Noninsulin-Dependent Diabetes. Science, 250, 546-549. https://doi.org/10.1126/science.2237405Orci, L., Unger, R.H., Ravazzola, M., Ogawa, A., Komiya, I., Baetens, D. and Thorens, B. (1990) Reduced Beta-Cell Glucose Transporter in New Onset Diabetic BB Rats. The Journal of Clinical Investigation, 86, 1615-1622. https://doi.org/10.1172/JCI114883Tal, M.G. (2009) Type 2 Diabetes: Microvascular Ischemia of Pancreatic Iislets? Medical Hypotheses, 73, 357-358. https://doi.org/10.1016/j.mehy.2009.03.034Saini, K.S., Thompson, C., Winterford, C.M., Walker, N.I. and Cameron, D.P. (1996) Streptozotocin at Low Doses Induces Apoptosis and at High Doses Causes Necrosis in a Murine Pancreatic β Cell Line, INS-1. IUBMB Life, 39, 1229-1236. https://doi.org/10.1080/15216549600201422Murata, M., Takahashi, A., Saito, I. and Kawanishi, S. (1999) Site-Specific DNA Methylation and Apoptosis: Induction by Diabetogenic Streptozotocin. Biochemical Pharmacology, 57, 881-887. https://doi.org/10.1016/S0006-2952(98)00370-0Wilson, G.L. and Leiter, E.H. (1990) Streptozotocin Interactions with Pancreatic β Cells and the Induction of Insulin-Dependent Diabetes. In: Dyrberg, T., Ed., The Role of Viruses and the Immune System in Diabetes Mellitus. Current Topics in Microbiology and Immunology, Springer, Berlin, 27-54. https://doi.org/10.1007/978-3-642-75239-1_3Bennett, R.A. and Pegg, A.E. (1981) Alkylation of DNA in Rat Tissues Following Administration of Streptozotocin. Cancer Research, 41, 2786-2790.Pieper, A.A., Brat, D.J., Krug, D.K., Watkins, C.C., Gupta, A., Blackshaw, S. and Snyder, S.H. (1999) Poly(ADP-Ribose) Polymerase-Deficient Mice Are Protected from Streptozotocin-Induced Diabetes. Proceedings of the National Academy of Sciences of the United States of America, 96, 3059-3064. https://doi.org/10.1073/pnas.96.6.3059Kroncke, K.D., Fehsel, K., Sommer, A., Rodriguez, M.L. and Kolb-Bachofen, V. (1995) Nitric Oxide Generation during Cellular Metabolization of the Diabetogenic N-Methyl-N-nitroso-urea Streptozotozin Contributes to Islet Cell DNA Damage. Biological Chemistry Hoppe-Seyler, 376, 179-185. https://doi.org/10.1515/bchm3.1995.376.3.179Malinski, T. (2000) The Vital Role of Nitric Oxide. Oakland Journal, No. 1, 47-57.https://our.oakland.edu/bitstream/handle/10323/7516/01_Malinski.pdf?sequence=1Wada, R. and Yagihashi, S. (2004) Nitric Oxide Generation and Poly (ADP Ribose) Polymerase Activation Precede Beta-Cell Death in Rats with a Single High-Dose Injection of Streptozotocin. Virchows Archiv, 444, 375-382. https://doi.org/10.1007/s00428-003-0967-zMiura, D., Wada, N. and Brunaud, L. (2005) Comparative Genomic Hybridization in Thyroid Neoplasms. In: Clark, O.H., Duh, Q.-Y. and Kebebew, E., Eds., Textbook of Endocrine Surgery, WB Saunders, Philadelphia, PA, 344-354. https://doi.org/10.1016/B978-0-7216-0139-7.50040-5Mori, M. (2007) Regulation of Nitric oxide Synthesis and Apoptosis by Arginase and Arginine Recycling. The Journal of Nutrition, 137, 1616S-1620S. https://doi.org/10.1093/jn/137.6.1616STurk, J., Corbett, J., Ramanadham, S., Bohrer, A. and McDaniel, M.L. (1993) Biochemical Evidence for Nitric Oxide Formation from Streptozotocin in Isolated Pancreatic Islets. Biochemical and Biophysical Research Communications, 197, 1458-1464.https://doi.org/10.1006/bbrc.1993.2641Thorens, B., Weir, G.C., Leahy, J.L., Lodish, H.F. and Bonner-Weir, S. (1990) Reduced Expression of the Liver/Beta-cell Glucose Transporter Isoform in Glucose-Insensitive Pancreatic Beta Cells of Diabetic Rats. Proceedings of the National Academy of Sciences of the United States of America, 87, 6492-6496. https://doi.org/10.1073/pnas.87.17.6492Tousoulis, D., Kampoli, A.-M., Tentolouris, C., Papageorgiou, N. and Stefanadis, C. (2012) The Role of Nitric Oxide on Endothelial Function. Current Vascular Pharmacology, 10, 4-18. https://doi.org/10.2174/157016112798829760Castro, L., Rodriguez, M. and Radi, R. (1994) Aconitase Is Readily Inactivated by Peroxynitrite, but Not by Its Precursor, Nitric Oxide. Journal of Biological Chemistry, 269, 29409-29415. https://doi.org/10.1016/S0021-9258(18)43894-XNukatsuka, M., Yoshimura, Y., Nishida, M. and Kawada, J. (1990) Allopurinol Protects Pancreatic β Cells from the Cytotoxic Effect of Streptozotocin: In Vitro Study. Journal of Pharmacobio-Dynamics, 13, 259-262. https://doi.org/10.1248/bpb1978.13.259Takasu, N., Komiya, I., Asawa, T., Nagasawa, Y. and Yamada, T. (1991) Streptozocin- and Alloxan-Induced H2O2 Generation and DNA Fragmentation in Pancreatic Islets: H2O2 as Mediator for DNA Fragmentation. Diabetes, 40, 1141-1145. https://doi.org/10.2337/diab.40.9.1141Raza, H., Prabu, S.K., John, A. and Avadhani, N.G. (2011) Impaired Mitochondrial Respiratory Functions and Oxidative Stress in Streptozotocin-Induced Diabetic Rats. International Journal of Molecular Sciences, 12, 3133-3147. https://doi.org/10.3390/ijms12053133