Abstract
Purpose
Assessment of the antidiabetic effect of cinnamon bark extract in histologic damages and some hematologic parameters in Alloxan® induced diabetic female albino rats.
Method
Thirty female albino rats weighing 150–230 g were divided into five groups (n = 6): normal (G1) and diabetic groups (intraperitoneally Alloxan®-injected) including diabetic control (G2), Getformin @ 0.25 (G3), CE @ 0.10 (G4), and CE @ 0.20 g/kg b.wt. (G5) for 49 days. Blood glucose level and weight were measured on weekly interval for the period of seven weeks (49th day). Blood samples were collected for hematologic analysis. Tissue samples from uterus, liver and kidneys were processed by routine paraffine technique. Histologic sections of uterus were studied to measure endometrial glands area and thickness of endo- and myometrium. Liver and kidneys were evaluated for diabetes-induced degenerative changes and antidiabetic effect of cinnamon extract (CE). One-way analysis of variance followed by Tukey test were used to compare the group means for each parameter.
Results
Statistical analysis revealed significant (P < 0.05) deleterious effects of diabetes on all parameters studied, however, CE recovered hematological parameters significantly (P < 0.05) as seen in G3 and G5 groups which showed significant (P < 0.05) improvement in uterus, liver and kidneys’ histology. G4 significantly (P < 0.05) reduced the blood glucose at the 4th week which was maintained in subsequent weeks while G3 and G5 had significantly (P < 0.05) lowered the blood glucose from 1st week, although highly significant (P < 0.01) effect was observed during last two weeks of the study.
Conclusion
Anti-diabetic activity of cinnamon extract was found significant in Alloxan® induced hyperglycemic rats in dose-dependent manners. CE has potential to restore diabetes induced hematological disturbances and histological damages in uterus, liver and kidney due to the presence of cinnamic acid, anhydride tannin and methyl-hydroxy chalcone polymer. Hence, CE can be recommended for the management of glucose homeostasis to avoid diabetes-associated disturbances in female rats.
Keywords: Diabetes, Cinnamon, Internal organs, Hematology, Histology
Introduction
Elevated blood glucose level marks the onset of a metabolic disease called diabetes mellitus (DM) which results from autoimmune disease condition (type I DM) or malfunctioning of insulin receptors on target cells (type II DM) [1, 2]. The changing lifestyle and obesity lead to drastic increase in DM prevalence. The recent estimation surveys reveal that 171 million people suffered from this disease in 2000 and this figure is thought to reach 360 million in 2030 [3]. The whole metabolic processes involving carbohydrates, proteins and fats, are disturbed by hyperglycemia [4, 5]. DM causes long-term complications in different vital internal organs. Although female reproductive problems associated with DM and its underline mechanism is not completely understood but chronic DM in females reported to cause severe disturbances like hypogonadism and low fertility [6]. Earlier investigations confirmed the DM led to atrophy of myo- and endometrium, uterine weight declining and altered normal physiological functions of uterus. [7].
Synthetic drugs are not safe to be used during pregnancy and damage the liver and kidneys [5]. Recent investigations are more inclined towards exploring the medicinal properties of herbal remedies for glycemic control. Most of these showed little or no impact on glycemic activity during studies, although some medicinal plants possess anti-diabetic properties [8]. Useful chemicals are extracted from the medicinal plants to manufacture medicines [9] (Fig. 1).
Fig. 1.
Comparison of Mean ± (SE) values of blood glucose level (mg/ dl) and body weight (grams) in different trial groups (G1-G5) on weekly basis except the week 0. G 1: Negative control/normal group, G 2: Positive control/Diabetic group, G 3: Diabetic treated with Getformin 0.25 g/ kg b. wt, G 4: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.10 g/kg b. wt., Gr 5: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt. Blocks having * and ** in a week are statistically different at P < 0.05 and P < 0.01 from other groups having no * or **
Cinnamon has been used as a spice and herbal medicine for centuries in Asian countries [10]. Cinnamon is one of the commonly used natural products to combat diabetes. There are two major types of cinnamon: Cinnamomum zeylanicum (commonly called true or common cinnamon) and Cinnamomum cassia (commonly called as cassia). Active compounds in Cinnamomum cassia are cinnamic acid, Cinnamaldehyde, tannin and methyl-hydroxy chalcone polymer (MHCP) which reported to have stimulatory effect on glucose transportation in cell and inhibitory on pancreatic amylase [11–13]. The chemical structure of important antidiabetic agents in cinnamon are given in the Fig. 2.
Fig. 3.
Histological examination of uterus: G1 (normal group) showed normal histological parameters of endometrium (uterine epithelial height (EP), endometrium glands (GL) and myometrium (inner circular (IC), outer longitudinal (OL) smooth muscles thickness (μm) while diabetic group (G2) showing decreased thickness of these parameters. Getformin treated group (G3) and cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt treated group (G5) showed significant improvements in the uterine parameters due to presence of the Polyphenolic compounds in CE (rutin, catechin, quercetin and kaempferol) and tannic acid (Hematoxylin and Eosin (H&E) at 100X)
Methyl-hydoxychalone polymer (MHCP) in C. zeylanicum and C. cassia successfully mimics the effect of insulin [12]. This study was aimed to evaluate antidiabetic effect of cinnamon on hematologic and histologic parameters of selected organs in alloxan® induced diabetic female albino rats.
Materials and methods
Animals
All procedures performed in this study involving rats were in accordance with the research ethical standards of the University of Agriculture, Faisalabad, Pakistan. Thirty female albino rats weighing 150–230 g were subjected for this study. Adult female albino rats were purchased from local market. These rats were acclimatized for two weeks in the animal house of Institute of Microbiology, University of Agriculture, Faisalabad, under optimum room environment in a light/dark cycle of 12-h and were fed with food and water ad libitum.
Cinnamon extraction (CE)
After cleaning and air-drying the cinnamon bark, a very fine powder was made. The extraction was carried out with 70:30 water-ethanol solutions and the solution was kept at room temperature (26 ± 2 °C) for 24 h. The residues were removed by filtering. In order to eliminate some quantity of water and ethanol, evaporation of filtrate was carried out under reduced pressure in a rotary evaporator.
Diabetes induction
Alloxan® was administered intraperitoneally to induce diabetes at a rate of 150 mg/kg body weight in overnight fasting rats except the normal rats which were given only normal saline. To confirm the diabetes induction, 3 days after the drug administration blood glucose level was measured using glucometer (Certeza® GL-110). The rats having fasting blood glucose level above 200 mg/dL were considered diabetic.
Experiment
The experimental animals were arranged into the following groups (n = 6):
Group 1: Negative control/normal group
Group 2: Positive control/Diabetic group
Group 3: Diabetic treated with Getformin 0.25 g/ kg b. wt
Group 4: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.10 g/kg b. wt.
Group 5: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt.
The treatment was given orally with the help of nasogastric tube to rats on daily basis for the period of 49 days.
Blood sampling
Weekly fasting blood glucose level was measured from blood taken from tail vein by glucometer (Certeza® GL-110). On the 49th day, prior to humane euthanasia, a 2 ml blood sample was collected from the heart in EDTA containing vacutainer for hematology. Hematological parameters including Red and White cell count and hemoglobin by automated cell counter machine (Medionic®).
Tissue sampling
At the end of trial (49th day), animals were euthanized and samples of uterus, liver and kidney collected. After washing with the normal saline, the tissue samples immediately transferred into fixative solutions. Liver and kidneys were fixed in buffered formalin whereas uterus was fixed in Bouin’s solution. All tissue samples were processed by Paraffin embedding technique, followed by sectioning at 5.0 μm thickness and staining with hematoxylin and eosin stain. Stained slides of uteri were examined for different histological layers while degenrative changes were assessed in liver and kidneys slides.
Histometric analysis
Automated image analysis system Image J® was used to measure the area of endometrial glands and myometrium thickness (μm). All slides were examined under microscope at 100X. The observations also included regarding the degenerative changes in hepatocytes and vacuolar changes in tubules of kidneys.
Statistical analysis
One-way analysis of variance (ANOVA) was used to calculate the means of each parameters. Tukey’s Honestly Significant Test (THS) was used to compare the group means as post ANOVA interface at 5% level of significance.
Results
Hematologic parameters
Mean values of blood parameters studied white blood cells (WBCs), red blood cells (RBCs), mean corpuscular volume (MCV) and hemoglobin concentration (Hb) decreased significantly (P < 0.05) in untreated diabetic group (Group 2) as compared to normal (Group 1) (Table 1). These diabetic induced values are significantly improved by the Getformin and Cinnamon Extract (CE) treatment at the dose rate of 0.20 g/ kg b.wt. treatments in Group 3 and Groups 5, respectively. Group 4 which was given CE @ 0.10 g/ kg b. wt showed no significant improvements in these values.
Table 1.
Mean ± SE values of hematological and uterine histometric parameters in different trial groups at the end of trial (49 days)
| Groups | Hematological Parameters | Uterine Parameters | |||||
|---|---|---|---|---|---|---|---|
| WBCs (109/ Liter) | RBCs (1012/ Liter) | MCV (fl) | Hb (g/ dl) | Endometrium glands area (μm2) | Endometrium thickness (μm) | Myometrium thickness (μm) | |
| Group 1 | 15.11 ± 0.76 A | 9.42 ± 0.76 A | 51.00 ± 2.00 A | 14.77 ± 0.67 A | 40.26 ± 5.59A | 213.33 ± 05.80A | 692.4 ± 22.00A |
| Group 2 | 8.26 ± 0.93 C | 4.87 ± 0.52 C | 43.67 ± 2.52 AB | 10.40 ± 0.44 B | 21.66 ± 3.93B | 147.46 ± 03.60C | 301.06 ± 14.63C |
| Group 3 | 12.25 ± 0.62 B | 7.68 ± 0.52 B | 48.00 ± 1.00 B | 13.97 ± 0.60 A | 39.12 ± 6.66A | 213.39 ± 16.13A | 558.0 ± 23.30B |
| Group 4 | 8.91 ± 0.73 C | 5.59 ± 0.31 C | 45.33 ± 0.58 AB | 11.87 ± 0.55 B | 26.54 ± 5.85AB | 179.51 ± 11.60B | 362.3 ± 33.60C |
| Group 5 | 11.13 ± 0.31B | 7.05 ± 0.18 B | 46.33 ± 2.52 B | 13.43 ± 0.47 A | 38.54 ± 6.15A | 203.85 ± 05.45AB | 507.0 ± 22.80B |
Mean having different alphabet superscripts in a column are statistically different at P < 0.05:
Means having superscript A are significantly (P < 0.05) different from means having superscript B, C, BC; Means having superscript B are significantly (P < 0.05) different from means having superscript A, C, AC; Means having superscript C are significantly (P < 0.05) different from means having superscript A, B, AB; Means having superscript AB are significantly (P < 0.05) different from means having superscript C, CD in a column
Group 1: Negative control/normal group, Group 2: Positive control/Diabetic group, Group 3: Diabetic treated with Getformin 0.25 g/ kg b. wt, Group 4: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.10 g/kg b. wt., Group 5: Diabetic treated with cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt. WBCs: White Blood cells. RBCs: Red blood cells, MCV: Mean Corpuscular Volume, Hb: Hemoglobin
Histologic and Histometric parameters
Uterus
Values of uterine parameters including endometrial glands area, endo- and myometrial thickness are presented in Table 1. Diabetic conditions led to a decline in values of these parameters in Group 2 in contrast to normal rats. Treatment of CE extract and Getformin significantly (P < 0.05) shifted uterine changes towards normal at the dose rate of 0.20 and 0.25 g/ kg b. wt while CE @ 0.10 g/ kg b. wt remained unaltered in diabetes (Group 4) as shown in Table 1 & Fig. 3.
Fig. 4.
Histological examination of liver of different groups: Hepatic micrograph of normal rats (G1) showed normal pattern of hepatocytes (H) and sinusoidal cords (S) around the central vein (CV). Diabetic group (G2) liver showed: hemorrhage in the central vein (HA), hepatic vein (HV), bile duct (BD) and distorted radial arrangement of hepatocytes. Improvements in hepatocytes (H) and sinusoidal cords (S) arrangement around central vein (CV) are found in the Diabetic rats treated with Getformin (G3) and cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt (G5). The restoration of histology of liver may be credited to presence of hydroxycinnamaldehyde identified in C. cassia bark exhibited an inhibitory effect on the production of nitric oxide by inhibiting the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), indicating that this substance can potentially be used as an anti-inflammatory (Hematoxylin and Eosin (H&E) at 100X)
Liver
Noticeable necrosis of liver cells with scattered arrangement of the hepatocytes and sinusoidal cords were seen in diabetic group (G2). The CE treated group (Group 5) showed less hemorrhage of central vein and distorted pattern of hepatocytes, compared to Getformin results. Group 4, treated with CE @ 0.10 g/ kg b. wt. depicted relatively less improvement in the hepatic tissue damaged sections (Fig. 4).
Fig. 5.
Histological examination of kidneys: Renal tissues of diabetic group (G2) showed degenerative changes in the glomeruli (GM) structure with proximal convoluted tubules (PCT) along with reduced urinary space (US) as compared to normal (G1). Tubular Degenerative (TD) changes are observed minimum in the renal sections of Getformin treated group (G3) and cinnamon aqueous-ethanol extract @ 0.20 g/kg b. wt treated group (G5).(Hematoxylin and Eosin (H&E) at 100X)
Kidney
Tubular degeneration and glomerular damage was seen in kidneys’ sections of diabetic group (G2) along with the reduced urinary space as compared to normal kidneys. CE extract @ 0.20 g/ kg b.wt (Group 5) significantly recovered these hyperglycemic induced changes towards normal, however, these improvements are less pronounced in the Group 3 & 4 (Fig. 5).
Fig. 2.
Chemical structure of cinnamaldehyde, cinnamic acid, cinnamyl acetate and procyanidin type-A polymers found in cinnamon that enhance insulin activity (28)
Blood glucose level and weight gain
Induction of diabetes caused significantly (P < 0.05) elevated blood glucose level in the rats (Fig. 1). The treatment given to the diabetic rats remained unaffected in first four weeks of the trial, however, at 5th and 6th-week declining trend of blood glucose level became significant (P < 0.05) in Group 3 and 5. Group 4 showed less reduction in the blood glucose level as compared to other treated group. Induction of hyperglycemic condition in rats resulted in significant (P < 0.05) decrease in the body weight at week 5 and 6. The treatment given to the groups reflected the same pattern as that of blood glucose level (Fig. 1).
Discussion
Diabetes Mellitus (DM) has become the one of the most common metabolic disease disturbing the whole metabolic process, consequence in neuropathy, hypertension, retinopathy, hepatopathy, nephropathy and neurological defects [4, 14].
Alloxan® suppressing the immunity of animals by decreasing number of white blood cells (WBCs) through the production of hydroxyl radicals [15]. Deprived leukocytosis in bone marrow in induced diabetes conditions may relate to this immune-competency [16]. In current study, WBCs significantly (P < 0.05) reduced by diabetes as observed by Usman et al. [3] and Ateeq et al. [17] but cinnamon extract (CE) treatment improved the WBCs count @ 0.20 g/kg b. wt. in diabetes. This potential recovery may be due to the antioxidant compounds (flavonoids, cinnamaldehyde, eugenol, and linalool) that mimics the activity of superoxide dismutase and glutathione, having free radical scavenging properties [18].
Other haematologic parameters (RBCs, MCV, Hb) were also severely affected by diabetes induction. Glycosylation and lipid peroxidation of erythrocytes can be held responsible for this diabetes-induced reduction [16]. In different treatments, CE at the dose rate of 0.20 g/kg b. wt. and Getformin significantly (P < 0.05) raised the RBCs count, hemoglobin conc. and MCV level. Volatile oils (41) identified in bark extract of Cinnamon) cinnamic acid and eugenol reported to have special protective effect against lipid oxidation and glycosylation through enhancing the antioxidant system and removing Cytoxan damage [18, 19].
Chronic DM causes atrophy of myometrium and endothelial cells and thus changes the uterine histology. Diabetes Mellitus induced uterine atrophy of the rat uterus is related with a decrease in the manifestation of neural crest cells, neurons and myofibrils [20]. In current study, DM triggered significant (P < 0.05) decrease in myometrium thickness (outer longitudinal and inner circular muscles) and endometrium (glands area and endometrium thickness) in accordance with Usman et al. [3] but Favaro et al. [7] who reported the time-dependent changes in diabetic uterus and concluded that the short duration (6–7 weeks) doesn’t lead to significant changes in uterine histopathology [6, 7]. The exact mechanism behind this phenomenon is unexplained yet and need more detailed research.
Significant decline in the values of uterine parameters witnessed in diabetes. Reduced or impaired insulin production in hyperglycemia agitate the hormones secreted from the ovarian thecal and stromal cells through the IGF-1. This interrupted and disturbed insulin production may contribute towards uterine cellular alteration (28). Getformin and CE @ 0.20 g/ kg b. wt. showed significant (P < 0.05) improvement in thickness of both endometrium and myometrium. Polyphenolic compounds in CE (rutin, catechin, quercetin and kaempferol) and tannic acid may be the element which recovered uterus histology through tyrosine phosphatase inhibition and enhanced insulin signaling pathway [21].
Alloxan® induced diabetes transformed the normal histology and impaired the cellular structure of liver and kidney [22]. Nonexistence of insulin and hyperglycemic induced oxidative stress may be considered main causes of degenerative alterations in liver and kidney [23]. CE normalized the histology of liver and kidney @ 0.20 g/kg b. wt. but @ 0.10 g/kg b. wt. this effect was non-significant (P > 0.05). The restoration of histology of liver and kidney may be credited to presence of 2-hydroxycinnamaldehyde identified in C. cassia bark exhibited an inhibitory effect on the production of nitric oxide by inhibiting the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), indicating that this substance can potentially be used as an anti-inflammatory agent [12, 13].
Alloxan® targets the pancreatic beta cells to develop diabetes [24]. In this trial, diabetes induction in rats led to elevate blood glucose level as observed by Misra and Aiman [25]. CE @ 0.10 and 0.20 g/kg b.wt. significantly (P < .0.05) reduced in raised blood glucose level at fourth week of trial and in subsequent weeks no more significant (P < .0.05) reduction by CE @ 0.10 g/ kg b. wt till the end of study. This anti-diabetic effect of CE may be due to the presence of Methyl-hydoxychalone polymer (MHCP) in cinnamon which successfully mimics the effect of insulin. MHCP triggers insulin synthesis via the activation of glycogen synthase and inhibition of glycogen synthase kinase-3β activity [12, 26].
Reduction in body weight in DM may be due to the increased muscle hypotrophy and reduced tissue proteins [27]. The effect of CE on body weight gain @ 0.10 g/kg b.wt. was non-significant but @ 0.20 g/kg b. wt. was highly significant (P < 0.01) throughout the experiment. These results may be attributed to presence of cinnamic acid and flavonoids which act on increased insulin signaling pathway, stimulation of insulin secretion, delay of carbohydrate digestion and glucose absorption, improvement of pancreatic β-cell functionality, enhanced glucose uptake, inhibition of hepatic gluconeogenesis and inhibition of protein glycation and insulin fibrillation [28].
Conclusions
Anti-diabetic activity of cinnamon extract was found significant in Alloxan® induced hyperglycemic rats in dose-dependent manners. The outcomes of this experiment showed that the cinnamon extract has ability to restore hematologic disturbances and histologic damages in uterus, liver and kidney related to diabetes in females. Hence, CE can be recommended for the management of glucose homeostasis to avoid diabetes-associated disturbances in females.
Authors contribution
AS Qureshi, M Usman and N Ehsan conceived the idea and finalized manuscript: AS Qureshi and M Usman supervised the lab work. J Ghaffor, A Sarfraz and Z Umar conducted lab work, applied statistics and prepared rough draft.
Compliance with ethical standards
Conflict of interest
Authors have no conflict of interest to declare.
Ethical approval
All procedures performed in this study involving rats were in accordance with the research ethical standards of the University of Agriculture, Faisalabad, Pakistan.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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