Animal Models with Induced Diabetes/Obesity/Hypertension: History
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Animal models with a relevant genetic setup are not the only way to analyze the biological effects of polyphenolic compounds. Pathophysiological changes typical of MetS may also be induced by dietary manipulation or the administration of drugs. The nutritional approaches studied involved administering a single type of diet or a combination of diets to modify metabolic pathways, especially those related to carbohydrate and lipid metabolism, to induce changes that best reflect those observed in people with MetS. To cause hypertension, obesity, hyperglycemia, or dyslipidemia in laboratory animals, they can be fed a diet including large doses of carbohydrates, including fructose and sucrose, or a high-fat diet. 

  • laboratory animal models

1. Animal Models with Induced Diabetes/Obesity/Hypertension

Animal models with a relevant genetic setup are not the only way to analyze the biological effects of polyphenolic compounds. Pathophysiological changes typical of MetS may also be induced by dietary manipulation or the administration of drugs. The nutritional approaches studied involved administering a single type of diet or a combination of diets to modify metabolic pathways, especially those related to carbohydrate and lipid metabolism, to induce changes that best reflect those observed in people with MetS. To cause hypertension, obesity, hyperglycemia, or dyslipidemia in laboratory animals, they can be fed a diet including large doses of carbohydrates, including fructose and sucrose, or a high-fat diet. The percentage content of carbohydrates or fat in a diet necessary to induce relevant effects varies. For example, in one study, the dose of fructose used to cause hypertension, insulin resistance, and glucose intolerance exceeded 60% of caloric intake [94], whereas the administration of 30% sucrose solution to male Wistar rats was sufficient to induce hypertension as well as an increase in body weight, insulin content, and total lipids [95]. The fat content used in the experiments ranged from 20% to 60% of the total energy demand [96,97]. The most commonly used strains in diet-induced models of MetS are Sprague Dawley rats, Wistar rats, C57BL/6 J mice, and Syrian hamsters [49]. MetS can also be induced in laboratory animals using drugs such as glucocorticoids. In medicine, glucocorticoids comprise the primary treatment for various conditions, including autoimmune disorders, dermatological conditions, and cancer. However, they have certain side effects, which determine their usefulness in triggering a cascade of changes leading to the development of MetS in laboratory animals. Glucocorticoids act on different tissues and organs by, e.g., stimulating the differentiation of preadipocytes into mature adipocytes; increasing lipolysis, glucose intolerance, and body weight gain; and disturbing calcium metabolism. Experiments involving animal models use the effects of both exogenous and endogenous glucocorticoids [98,99].
Studies investigating the properties of various polyphenols have used animal models with induced changes characteristic of MetS. These polyphenols include cinnamon compounds and curcumin. Table 1 summarizes the beneficial effects on metabolic changes by propitious polyphenolic compounds gathered in this paper.

2. Cinnamon

Cinnamon is primarily known as a spice obtained from the bark of the Cinnamomum tree. It has numerous medicinal properties. Different parts of the plant are enriched in different chemicals, including eugenol, cinnamaldehyde, camphor, and numerous polyphenols [100]. Cinnamon has been found to present anti-inflammatory, anti-microbial, antiviral, antifungal, antioxidant, cardioprotective, hepato-protective, analgesic, wound-healing, and epithelialization-promoting effects, as well as many other properties [100,101]. Cinnamon compounds also have an important impact on carbohydrate metabolism. The supplementation of a diet with cinnamon reduces insulin resistance due to the tannin content by increasing the expression of PPAR-α and PPAR-γ and stimulating the β-subunits of the insulin receptors of adipocytes [102,103]. In vivo studies on animals seem to confirm that cinnamon compounds also have beneficial effects on MetS. A study on Wistar rats fed a high-fat/high-fructose diet for 12 weeks found that a diet containing 20 g of cinnamon improved insulin sensitivity and reduced peritoneal fat accumulation without achieving a statistically significant reduction in body weight compared with controls. The improved insulin sensitivity is probably mediated mainly by the trimeric and tetrameric type A polyphenols present in cinnamon [104]. The wide range of biological activities of cinnamon was confirmed in a study on male Sprague Dawley rats, in which obesity was induced by a high-fat diet, whereas diabetes was induced by the subcutaneous injection of alloxan. A reduction in body weight and fat mass and a decrease in serum leptin levels were observed in rats whose diet included cinnamon extract. Moreover, the administration of cinnamon extract resulted in normalized levels of liver enzymes and reduced blood glucose levels. Furthermore, it produced a dose-dependent antioxidant effect [105]. The findings of many in vivo studies on animals allow the hypothesis that supplementation with cinnamon also has a beneficial impact on MetS [106].

3. Curcumin

Curcumin is a polyphenolic compound that is naturally present in turmeric rhizomes. It has anti-inflammatory, anti-carcinogenic, and antioxidant properties. Moreover, it shows antibacterial, antiviral, and antifungal effects. Its mechanism of action inhibits the expression of the NF-kB transcription factor, which in turn regulates the expression of numerous proteins involved in the initiation and maintenance of inflammation, which underlies multiple conditions [107]. In a study on male albino Wistar rats, in which a high-fat diet induced diabetes with a dose of streptozotocin, the administration of curcumin for 8 weeks (80 mg/kg BW/day) lowered glucose levels and reduced insulin resistance, dyslipidemia, and lipid peroxidation. Moreover, the administration of curcumin significantly increased the expression of the GLUT-4 gene, which regulates insulin-dependent glucose transport in muscles and adipose tissue, compared with the control group. The regulation of this transporter is altered under pathological conditions, including, among others, type 2 diabetes. The administration of curcumin was found to stimulate the expression of GLUT4, thus normalizing glucose metabolism in the treated group [108]. Curcumin can also be used as a dietary intervention against lipid accumulation and liver fibrosis. It acts via the stimulation of lipogenic gene expression and, in this way, induces lipolysis and inhibits lipogenesis. In groups of Wistar rats administered curcumin at a dose of 100 mg/kg for 4 weeks, lipid imbalance was induced by bile duct ligation. A reduction in hepatic fat accumulation via AMPK upregulation was observed. AMPK is a serine/threonine-protein kinase that is responsible for lipid metabolism. Its dysregulation may lead to the development of hepatic injury. Curcumin seems to improve the expression of AMPK and hepatic redox potential and attenuate lipid peroxidation. A curcumin-treated group also showed protective effects against hepatic fibrosis. The hepatic protection was also associated with a reduction in the lipid level in serum by curcumin [109].
Table 1. The effects of selected polyphenolic compounds with promising bioactive potential on MetS.
Substance Animal Model Dose (Time) Metabolic Effect Mechanism References
Red wine Zucker Fatty rats 20 mg/kg BW
(8 weeks)
↑ FS
↑ CO
↓ serum glucose
↓ LDL cholesterollevel
↓ TG level
↓ peripheral arterial resistance
↓ superoxide anions
↓ thromboxane A2
↓ 8-isoprostane
↑ NO bioavailability
↑ eNOS activity
↓ NADPH oxidase expression
[60]
Green tea Zucker Fatty rats 200 mg/kg BW
(8 weeks)
↓ body weight
↓ visceral fat
↓ hepatic lipogenesis
↓ insulin level
↓ glucose level
↓ lipids level
↑ expression AMPK-Thr172
↑ expression phosphorylated acetyl-CoA carboxylase (ACC)
↑ sterol regulatory element-binding protein 1c (SREBP1c)
[63]
Zucker Fatty rats,
Sprague Dawley rats
15 mg, 20 mg, 40 mg
(7 days, 4 days)
↓ food intake
↓ testosterone level
↓ estradiol level
↓ LH level
↓ leptin level
↓ insulin level
↓ glucose level
↓ IGF-1 level
↓ cholesterol level
↓ TG level
↓ food intake (hypothalamic neuropeptide gene expression alternation?, changes in bilirubin, alkaline phosphatase activity?) [64]
Zucker Fatty rats 200 mg/kg BW
(8 weeks)
↓ body weight
↓ visceral fat
↓ insulin level
↓ glucose level
↓ insulin resistance
modulation of insulin signaling protein in skeletal muscle
↑ expression and translocation of GLUT-4 in skeletal muscle
↓ activation of the inhibitory protein kinase isoform- PKC-θ
[65]
Quercetin Zucker Fatty rats 2 mg/kg BW
10 mg/kg BW
(10 weeks)
↓ dyslipidemia
↓ hypertension
↓ insulin resistance
↓ weight (only dose 10mg/kg BW)
+ anti-inflammatory effect
↑ eNOS expression
↑ adiponectin level in plasma
↓ TNF-alpha production in visceral tissue
[74]
Pomegranate Zucker Diabetic Fatty rats 500 mg/kg BW
(6 weeks)
↓ TG level
↓ lipid droplet content in liver
↑ expression PPAR-α
↑ expression acyl-CoA oxidase
↑ expression CPT1
[80]
Zucker Diabetic Fatty 500 mg/kg BW
(6 weeks)
↓ hyperglycemia
↓ hyperlipidemia
↓ cardiac fibrosis
↓ NF- κB activation in macrophages
↓ expression ET-1
[81]
Zucker Diabetic Fatty 500 mg/kg BW
(6 weeks)
↓ cardiac TG accumulation
↓ TG level
↓ cholesterol level
↑ cardiac expression PPAR-α
↑ cardiac expression CPT-1
↑ cardiac expression ACO
↑ cardiac expression AMPKαK
↓ cardiac expression acetyl-CoA carboxylase (ACC)
[82]
Cocoa Zucker Diabetic Fatty 10% cocoa-rich diet (10 weeks) ↑glucose tolerance
↓ body weight
↓ insulin resistance
↓ glucose level
↓ insulin level
+ nephroprotective effect
↓ renal synthesis PEPCK
↓ renal synthesis G-6-P
↓ expression of glucose transporters (SGLT-2, GLUT-2) in the renal cortex
[84]
Zucker diabetic Fatty 10% cocoa-rich diet (9 weeks) ↓ body weight
↓ lipid accumulation in liver cells
↑ phosphorylated AMPK level in liver
↑ phosphorylated protein kinase B (AKT) level in liver
↓ phosphorylated protein kinase C (PKCζ) level in liver
[85]
Zucker diabetic Fatty 10% cocoa-rich diet (10 weeks) ↑ glucose homeostasis
↑ intestinal integrity
+ modification of gut microbiota
↓ amount of lactate- producing bacteria
↓ expression TNF-α
↓ expression IL-6
[86]
Resveratrol Spontaneously Hypertensive rats dissolved in drinking water (concentration 50 mg/L), ad libitum (10 weeks) ↓ hypertension
↓ oxidative stress
↓ H2O2 content
↓ SOD activity
↓ eNOS uncoupling
↓ NO scavenging
[91]
  Spontaneously Hypertensive rats 2.5 mg/kg BW
(10 weeks)
↓ concentric heart hypertrophy
↓ systolic heart dysfunction
↓ oxidative stress in cardiac muscle tissue [92]
  Spontaneously Hypertensive rats 50 mg/kg BW
(28 days)
↓ SBP ↑ outward voltage-dependent potassium currents (IK)
↓ inward voltage-dependent sodium currents (INa),
↓ inward voltage-dependent calcium currents (ICa)
↓ inward voltage-dependent nicotinic currents (IAch)
[93]
Cinnamon Wistar rats (high-fat/high-fructose diet) 20 g cinnamon-rich/kg of diet (12 weeks) ↓ insulin resistance
↓ peritoneal fat accumulation
↑ peroxisome proliferators-activated receptors activity? [104]
Sprague Dawley rats (high-fat diet + subcutaneous injection of alloxan) 200 mg/kg BW
400 mg/kg BW
(6 weeks)
↑ HDL cholesterol level
↓ body weight
↓ LDL cholesterol level
↓ leptin level
↓ glucose level
↓ liver enzymes levels
+ antioxidant effect
↓ the intestinal absorption of cholesterol?
↓ appetite?
↓ oxidative stress?
[105]
Curcumin Wistar rats (high-fat diet + streptozotocin) 80 mg/kg BW
(8 weeks)
↓ glucose level
↓ insulin resistance
↓ lipid level
↓ lipid peroxidation
↑ expression GLUT-4 [108]
Wistar rats (bile duct ligation) 100 mg/kg BW
(4 weeks)
↓ hepatic fat accumulation
↓ lipid peroxidation
↓ hepatic fibrosis
↑expression AMPK
↑expression CPT-1a
[109]

This entry is adapted from 10.3390/biology11040559

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