Skip to main content
NCBI home page
Journal of Diabetes and Metabolic Disorders logoLink to Journal of Diabetes and Metabolic Disorders
. 2020 Aug 26;19(2):1173–1184. doi: 10.1007/s40200-020-00618-w

Effect of Curculigo pilosa supplemented diet on blood sugar, lipid metabolism, hepatic oxidative stress and carbohydrate metabolism enzymes in streptozotocin-induced diabetic rats

Kayode Olayele Karigidi 1,2,✉, Emmanuel Sina Akintimehin 1, Damilola Alex Omoboyowa 3, Foluso Olutope Adetuyi 1, Charles Ojo Olaiya 2
PMCID: PMC7843773  PMID: 33520833

Abstract

Background

Diabetes mellitus (DM) has continued to raise concern globally and Curculigo pilosa (CP) is used for its treatment and management in folkloric medicine. In this study, the in vitro antioxidant abilities of CP and the effects of CP-supplemented diets on blood sugar, lipid metabolism, oxidative stress and key carbohydrate metabolizing enzymes in streptozotocin (STZ)-induced diabetic rats were investigated.

Methods

Polyphenol contents (total phenolic and total flavonoid) and antioxidant ability of different extracts of CP were determined in vitro. Diabetes mellitus were stimulated in healthy rats by single intraperitoneal administration of 50 mg/kg streptozotocin and it was confirmed by elevated blood glucose level after 3 days. Thirty six rats were distributed into six groups of six rats each and diabetic rats were fed with 5 and 10% CP-supplemented diet for 21 days. Thereafter, the effects of the dietary regimen were evaluated on blood glucose, body weight, hepatic carbohydrate metabolizing enzymes, lipid profile, oxidative stress markers, serum markers of hepatic and renal damages and histopathology studies.

Results

Different extracts of CP contained polyphenol contents and exhibited antioxidant properties in different models used. Diabetic rats showed elevated level of blood glucose and body weight loss. Treatment of diabetic rats with CP-supplemented diet significantly (p < 0.05) lowered the blood glucose and improved body weight loss. Also, the treatment with the CP-supplemented diet significantly (p < 0.05) enhanced the activities of hepatic glycolytic (hexokinase and glucose-6-dehydrogenase) and lowered the gluconeogenic (fructose 1, 6 biphosphatase and glucose-6-phosphatase) enzymes in diabetic rats. The lipid profile, oxidative stress markers and serum markers of hepatic and renal damages were significantly (p < 0.05) restored to near normalcy in the diabetic rats. Histopathological slides also showed improvements in pancreas and hepatic tissues of diabetic rats treated with CP-supplemented diet.

Conclusion

Data obtained in this study suggested that CP-supplemented diet could be used as dietary regimen in the management of DM.

Keywords: Diabetes, Enzymes, Metabolism, Oxidative stress, Streptozotocin, Supplemented diet

Introduction

Diabetes mellitus (DM) is a disease of numerous etiologies, characterized by hyperglycemia due to defects in insulin secretion and insulin resistance [1]. It has become a global health issue with an incidence of about 500 million cases and it is one of the important causes of lower limb amputation, vision loss in working age adult and higher prevalence of end-stage renal and cardiovascular diseases [2]. In addition, DM has also been reported to cause a number of liver abnormalities, such as abnormal elevated hepatic enzymes, cirrhosis, abnormal glycogen deposition and acute liver disease [3–5]. The hyperglycemia in diabetic patients usually leads to aberration in lipid metabolism and excessive generation of free radicals which have been linked with nearly all complications of DM [6]. Due to multiple etiologies of DM, it is very difficult to treat or manage. Present orthodox drugs against DM exert their effects using various mechanisms: Enhancing the responsiveness of targeted tissues to insulin (thiazolidinediones), stimulating the beta cells to generate more insulin (meglitinides and sulfonylureas), delaying the absorption of glucose from the gastrointestinal tract (α-amylase and α-glucosidase inhibitors) and reducing the generation of glucose in the hepatic tissue (biguanides) [7]. Despite all these, many diabetic patients still rely on traditional medicine to obtain preventive or medical care for DM [8]. This is due to inadequate resources, toxicity and scarcity of the orthodox medicines. Medicinal plants are important sources of novel, safe and effective medicines for treatment of diabetes due to their marginal side effects, availability, effectiveness and relatively low cost [9].

Curculigo pilosa (CP) is a member of hypoxidaceae and popularly called African crocus. It is used locally for the production of infant food and sorghum beer [10]. Folklorically, it is well used for the treatment of infertility, hernia, diabetes and genital infections [11]. CP rhizome is rich in dietary fibre and essential minerals [10]. Previous studies have shown the presence of phytochemicals such as phenol, coumarin, steroid, terpenoid, tannins and phlobatannins [12, 13] Apart from this, it has high phenolics and exhibited enormous radical-scavenging activities [14]. Also, the antibacterial and anticandidal activities of its essential oil have been reported [12]. Previously, it has been reported that corn steep liquor extract of CP and its n-butanol fraction possess antidiabetic activities in STZ-induced diabetic rats and were able to inhibit α-glucosidase and α-amylase enzymes invitro [6, 15]. Recently, the interest of researchers in production of pro-health or pharmafood has been on the rise especially against chronic diseases. Due to folkloric uses and recent scientific validation of corn steep liquor extract of CP in diabetic rats, CP is an important candidate for consideration in production of pro-health or pharmafood against diabetes. Therefore, the study is designed to investigate the effect of CP-supplemented diet on blood sugar, lipid profile, oxidative stress and key carbohydrate metabolizing enzymes in STZ-induced diabetic rats.

Materials and methods

Sample collection

The CP rhizomes used in the study were bought in Okitipupa market, Okitipupa, Nigeria. The identification and authentication were conducted in the Department of Botany, University of Ibadan. The (UIH-22759) voucher number was deposited at their herbarium. The CP was washed, sliced, air-dried and ground into powdery form in the laboratory.

Preparation of extracts for invitro antioxidant assays

Twenty grams (20 g) of powdered CP was soaked in 200 ml acetone, methanol: acetone (1:1) and aqueous: ethanol (1:1) for 72 h and shaken intermittently. The slurry formed was filtered and the filtrate was dried under pressure with rotary evaporator. The concentrated samples were stored in the refrigerator until use for in vitro antioxidant assays.

Invitro antioxidant assays

The total phenolic (TPC) of extracts was evaluated according to the Folin-Ciocalteu phenol reagent method of [16], the total flavonoid (TFC) of the samples was approached according to the method of [17], the reducing potential (RP) of extracts was evaluated using the method of [18] and the total antioxidant capacity (TAC) of samples was approached by the method of [19]. The 1, 1 diphenyl-2-picrylhydrazyl (DPPH) scavenging activity and ferric reducing antioxidant potential (FRAP) of the samples were evaluated according to the methods of [20, 21] respectively. The nitric oxide (NO) inhibition assay of the extracts was approached by the method of [22] and the 2, 2-azobis-3-ethylbenzothiazoline-6-sulfonate (ABTS) scavenging activity of the samples was determined using the method of [23].

Feed formulation

The feed formulation was done according to the method of [24]

Normal diet 5% CP- supplemented diet 10% CP- supplemented diet
Skimmed milk (g) 40 38.47 36.92
Fat (g) 10 9.84 9.68
Premix (g) 4 4 4
Corn starch (g) 46 43.69 39.40
CP (g) – 5 10
Total (g) 100 100 100
Open in a new tab

Experimental animals

Forty healthy male Wistar albino rats of eight weeks weighing (80–100) g were purchased from the animal holding facility, Physiology Department, University of Ibadan. The rats were subjected to 2 week-acclimatization before the induction of DM. The rats were given standard pellet diet and water ad libitum. The experimental procedures were conducted according to the guidelines of National Institute of Health (NIH) for care and use of laboratory animals (NIH Publication No. 80–23) revised in 2011 [25].

Induction of DM

Diabetes mellitus was stimulated in overnight fasted rats by single intraperitoneal dose (50 mg/kg body weight) of STZ dissolved in freshly prepared cold (0.1 M, pH 4.5) citrate buffer [26]. Three days after administration of STZ, blood samples were gotten from the tail vein of overnight fasted rats and used for blood sugar determination. Rats with fasting blood glucose ≥230 mg/dL were chosen and used in this study.

Experimental design

After the stimulation of DM, the rats were distributed into six groups of at least 6 rats each. The first group were the control group fed with normal diet (CB); the second group were undiabetic rats fed with 5% CP-supplemented diet (CF); the third group were undiabetic rats fed with 10% CP-supplemented diet (CT); the fourth group were diabetic rats fed with normal diet (DB); the fifth group were diabetic rats fed with 5% CP-supplemented diet (DF); the sixth group were diabetic rats fed with 10% CP-supplemented diet (DT) for three weeks. Body weight level and blood glucose measurements were conducted on the first and last days of the dietary treatment. After 21 days of dietary treatment, the blood was collected by ocular puncture from overnight fasted rats into plain sample bottles and centrifuged to obtain serum used for the biochemical assays. Thereafter, the overnight fasted rats were euthanized under sodium pentobarbitone.

Biochemical assays

Albumin was determined according to the method of [27], creatinine was determined using the method of [28], urea was evaluated using the method of [29], triglycerides was assayed using the method of [30], cholesterol and high density cholesterol were determined according to the method of [31], total bilirubin and conjugated bilirubin were determined by the method of [32], aspartate transaminase (AST) and alanine transaminase (ALT) were evaluated according to the method of [33] and alkaline phosphatase (ALP) was assayed using the method of [34]. The assays were done according to the manufacturer’s guides (Randox diagnostic kit, UK). Cardiac risk ratio (CRR) and Atherogenic index (AI) were evaluated according to the method of [35, 36] respectively.

Hepatic homogenate preparation

The Liver from the rats were homogenized with 0.1 M Tris-HCl buffer (pH 7.4) and centrifuged at 10,000×g for 10 min at 4 °C. The supernatant gotten was used for the determination of oxidative stress markers and key enzymes in carbohydrate metabolism. The protein contents of the supernatant was assayed using the method of [37].

Determination of hyperglycemia induced oxidative stress

Oxidative stress in the liver tissues was determined using lipid peroxidation (LPO) and nitric oxide (NO) assays. The LPO was evaluated according to the method of [38] while the NO was assayed according to the method of [39].

Determination of key enzymes of carbohydrate metabolism

Hexokinase (HK) activity was determined using the method of [40], Glucose-6-phosphate dehydrogenase (G6PDH) activity was evaluated according to the method of [41], Glucose-6-phosphatase (G6Pase) activity was approached using the method of [42] and Fructose-1, 6-bisphosphatase (F1, 6BPase) activity was determined using the method of [43].

Histopathology

Hepatic and pancreatic tissues were fixed for 24 h in 10% formaldehyde, thereafter was processed and histology was done by the method [44].

Statistical analysis

Results are presented as the mean ± SD. Analysis of variance (P < 0.05) was used to establish the significance of differences between the means (SPSS version 20). Graph pad prism (version 5) was used to draw the charts.

Results

Bioactive components and antioxidant activities

The antioxidant activities of various extracts of Curculigo pilosa are presented in Table 1. Acetone extract exhibited the highest bioactive components and scavenging activities among the extracts examined. The acetone extract had significantly (p < 0.05) higher contents of TPC (91.82 ± 0.61 mg GAE/g) and TFC (66.97 ± 8.97 mg QUE/g). The same trend was also exhibited in antioxidant assays; total antioxidant (43.58 ± 1.91 mg AAE/g), ferric reducing antioxidant potential (74.57 ± 2.00 mg Fe2+E/g), reducing potential (53.48 ± 4.51 mg AAE/g), 2, 2-azobis-3-ethylbenzothiazoline-6-sulfonate (1.74 ± 0.01 mg TEAC/g). Also, acetone extract of Curculigo pilosa exhibited highest DPPH and NO scavenging activities as shown by its lower IC50 value of 0.10 ± 0.02 mg/ml and 0.13 ± 0.03 mg/ml respectively.

Table 1.

Antioxidant potential of various extracts of Curculigo pilosa

50% Ethanol Acetone Meth: Acetone
TPC (mg GAE/g) 42.83 ± 1.92c 91.82 ± 0.61a 83.14 ± 3.01b
TFC (mg QUE/g) 16.85 ± 0.89b 66.97 ± 8.97a 64.90 ± 7.40a
TAC (mg AAE/g) 38.05 ± 0.29b 43.58 ± 1.91a 42.70 ± 0.72a
FRAP (mg Fe2+E/g) 46.61 ± 1.61b 74.57 ± 2.00a 49.65 ± 2.14b
ABTS (mg TEAC/g) 1.72 ± 0.01a 1.74 ± 0.01a 1.72 ± 0.01a
RP (mg AAE/g) 36.78 ± 1.69b 53.48 ± 4.51a 58.36 ± 7.04a
DPPH (IC50 mg/ml) 0.20 ± 0.04b 0.10 ± 0.02a 0.12 ± 0.02a
NO (IC50 mg/ml) 0.19 ± 0.02b 0.13 ± 0.03a 0.15 ± 0.03a
Open in a new tab

Values were represented as Mean ± SD. Values with different letter across the same row are significantly (P < 0.05) different. TPC = total phenolic; TAC = Total antioxidant capacity; TFC = Total flavonoid; FRAP = Ferric reducing antioxidant power; RP = Reducing potential; ABTS = 2, 2-azobis-3-ethylbenzothiazoline-6-sulfonate; DPPH = Diphenyl-2-picrylhydrazyl scavenging activity; NO = Nitric oxide scavenging activity

Blood glucose level and body weight

The effects of CP-supplemented diet on blood glucose (mg/dl) and body weight (g) are presented in Fig. 1. The concentration of blood sugar in diabetic rats was significantly (p < 0.05) increased upon administration of streptozotocin (50 mg/kg) when compared with undiabetic rats. However, after a dietary regimen for 21 days on CP-supplemented diet, there was a significant (p < 0.05) decrease in the elevated blood glucose concentration of diabetic rats. Although, the decrease was dose dependent, there was no difference significantly (p < 0.05) in the blood glucose concentration of diabetic rats given the different dietary regimen. Also, positive response was recorded in the body weight of diabetic rats fed with CP-supplemented diet relative to the diabetic control. The response was not significant (p < 0.05) in diabetic rats given 5% CP-supplemented diet but was significant in diabetic rats given 10% CP-supplemented diet.

Fig. 1.

Fig. 1

Open in a new tab

Effect of Curculigo pilosa supplemented diet on blood glucose and weight of diabetic rats. (a) when control group was compared p < 0.05 with diabetic groups, (b) when untreated diabetic group was compared p < 0.05 with treated diabetic group and # when control group was compared p < 0.05with undiabetic groups fed with supplemented diet

Biochemical assays

The effects of the CP-supplemented diet on serum liver function tests (AST, ALT, ALP, TB, CB and GGT), kidney function tests (albumin, creatinine and urea) and lipid profiles (Triglycerides, cholesterol, HDL-cholesterol, cardiac risk ratio and atherogenic index) are shown in Figs. 2, 3 and 4 respectively. These kidney function biomarkers (creatinine and urea) were significantly (p < 0.05) elevated in diabetic rats but the increment were decreased upon treatment with supplemented diet. The response to the treatment was dose dependent in the diabetic rats given different dietary regimen. Also, Albumin concentration was significantly (p < 0.05) decreased in diabetic rats but upon treatment with dietary regimen, the albumin level was increased towards normalcy in the treated diabetic rats. On liver function tests, ALP, AST, ALT and GGT activities were significantly (p < 0.05) elevated in the rats administered with STZ relative to the undiabetic rats. However, supplemented diet was able to reduce the activities significantly (p < 0.05) in comparison with the control rats. The decreases in activities of these enzymes were dose dependent in diabetic rats treated with different dietary regimen. Bilirubins (total and conjugated) concentration were significantly (p < 0.05) decreased in the rats administered with STZ in comparison to the control rats that were not administered. The reductions in these bilirubins were slightly elevated upon dietary intervention for 21 days towards normalcy. There was no significant difference in bilirubin contents of diabetic rats fed with 5% and 10% supplemented diet.

Fig. 2.

Fig. 2

Open in a new tab

Effect of Curculigo pilosa supplemented diet on kidney damage biomarker of diabetic rats. (a) when control group was compared p < 0.05 with diabetic groups, (b) when untreated diabetic group was compared p < 0.05 with treated diabetic group and # when control group was compared p < 0.05with undiabetic groups fed with supplemented diet

Fig. 3.

Fig. 3

Open in a new tab

Effect of Curculigo pilosa supplemented diet on liver damage biomarker of diabetic rats. (a) when control group was compared p < 0.05 with diabetic groups, (b) when untreated diabetic group was compared p < 0.05 with treated diabetic group and # when control group was compared p < 0.05with undiabetic groups fed with supplemented diet

Fig. 4.

Fig. 4

Open in a new tab

Effect of Curculigo pilosa supplemented diet on lipid profile of diabetic rats. (a) when control group was compared p < 0.05 with diabetic groups, (b) when untreated diabetic group was compared p < 0.05 with treated diabetic group and # when control group was compared p < 0.05 with undiabetic groups fed with supplemented diet

The lipid profile parameters (cholesterol, triglycerides and HDL-cholesterol) were significantly (p < 0.05) altered in the rats administered STZ in comparison with the control rats. Triglycerides and cholesterol were elevated while HDL-cholesterol was decreased in rats treated with STZ. However, the alterations were significantly (p < 0.05) regulated toward normalcy upon treatment with the CP-supplemented diet. The regulations were dose dependent on the dietary regimens. The calculated cardiac risk and atherogenic index ratio were significantly (p < 0.05) increased in diabetic rats but treatment with different dietary regimens was able to reduce the increment significantly (p < 0.05) in the treated diabetic rats. The decreases in calculated cardiac risk ratio and atherogenic index in diabetic rats fed with the supplemented diet were dose dependent on CP inclusion in the diet.

Oxidative stress and key enzymes of carbohydrate metabolism

The effects of the supplemented diet on oxidative stress (LPO and NO) and key carbohydrate metabolizing enzymes (HK, G6PDH, G6pase and F1, 6 Bpase) are presented in Figs. 5 and 6 respectively. The LPO and NO were significantly (p < 0.05) elevated in the rats treated with STZ when compared with the control rats. However, the increases in oxidative stress markers were reduced significantly (p < 0.05) upon treatment with the CP-supplemented diets; the reductions were dose dependent in the NO assay. The Induction of DM led to significant (p < 0.05) aberrations in activities of the carbohydrate metabolizing enzymes. Hexokinase and G6PDH activities were significantly reduced in diabetic rats relative to the control rats. However, treatment with CP-supplemented diets were able to significantly (p < 0.05) up-regulate the activities of these enzymes in the treated diabetic rats. The G6pase and F1, 6 Bpase activities were significantly (p < 0.05) increased in rats administered STZ relative to the control rats. Treatment with the supplemented diet was able to reduce the elevated activities of these enzymes in the treated diabetic rats. The regulations were dose dependent.

Fig. 5.

Fig. 5

Open in a new tab

Effect of Curculigo pilosa supplemented diet on lipid peroxidation and nitric oxide generation of diabetic rats. (a) when control group was compared with diabetic groups p < 0.05, (b) when untreated diabetic group was compared with treated diabetic group p < 0.05 and # when control group was compared with undiabetic groups fed with supplemented diet p < 0.05

Fig. 6.

Fig. 6

Open in a new tab

Effect of Curculigo pilosa supplemented diet on key carbohydrate metabolism enzymes of diabetic rats. (a) when control group was compared p < 0.05 with diabetic groups, (b) when untreated diabetic group was compared p < 0.05 with treated diabetic group and # when control group was compared p < 0.05with undiabetic groups fed with supplemented diet

Histopathology studies

The effects of supplemented diet on liver and pancreas tissues are presented in Figs. 7 and 8. The liver and pancreas of control rats fed normal diet appeared structurally normal but diabetic rats showed poor morphology which was moderately averted by the dietary regimen. Also undiabetic rats fed with the dietary regimen showed moderately poor morphology. The treatment-related observations seen in the hepatic tissues of diabetic rats include perivascular and periportal infiltration of inflammatory cells, severe portal triditis, sinusoids infiltration, necrotic hepatocytes and darly stained nuclei. The treatment-related observations in pancreas tissues were haemorrhage, architectural deformation by fat lobules, diffused islets of Langerhans, poor architecture, degenerated acinar cells and thickened interlobular connective tissues.

Fig. 7.

Fig. 7

Open in a new tab

Photomicrograph(×400) of a liver section stained by H&E showing. CB: Central venules have no congestion, the morphology of the hepatocytes appear normal. CF: Central venules have no congestion, the morphology of the hepatocytes appears abnormal and the sinusoids are mildly filled by lysed red cells CT: Moderate perivascular and periportal infiltration of inflammatory cells, the morphology of several hepatocytes appear normal, the sinusoids not infiltrated and appear normal. DB: Severe perivascular and periportal infiltration of inflammatory cells, there is severe portal triditis, the sinusoids appear mildly infiltrated DF: The morphology of most of the hepatocytes appear normal, very few necrotic hepatocytes seen, the sinusoids appear shows focal area of mild infiltrates DT: Liver parenchyma with focal area of inflammatory cells infiltration, the morphology of some of the hepatocytes show darly stained nuclei, the sinusoids appear normal and not infiltrated

Fig. 8.

Fig. 8

Open in a new tab

Photomicrograph (×400) of a pancreas section stained by H&E showing. CB: Normal architecture, the pancreas shows normal acinar cells containing abundant granular eosinophilic cytoplasm, normal interlobular connective tissues and septa are seen. There are normal islets of langerhans. CF: Lymphoid follicle, the pancreas shows normal acinar cells slender arrow, containing abundant granular eosinophilic cytoplasm, the interlobular connective tissues is thickened and mildly congested. There are normal islets of langerhans CT: Normal architecture, the pancreas shows haemorrhage, interlobular connective tissues show increased connective tissues and septa are seen. There are normal islets of langerhans. DB: Poor architecture, the pancreas shows architectural deformation by fat lobules, there are normal and diffused islets of Langerhans. DF: Moderately poor architecture, the pancreas shows lymphoid follicle, normal acinar cells are seen, normal interlobular connective tissues and septa are seen. There are normal islets of langerhans. DT: Moderately poor architecture, the pancreas shows some degenerated acinar cells, mildly thickened interlobular connective tissues with mild congestion noted. There is degenerated islets of langerhans seen

Discussion

Many studies have shown positive correlation between food rich in phytochemicals and low incidence of a chronic disease such as diabetes mellitus [45–48]. Dietary control remains one of the most desirable avenues for the prevention and management of this disease [49]. Due to the complicity of free radicals in the pathogenesis of this disease, antioxidant-rich botanicals might be required in the management of DM [50, 51]. In this study, the modulatory effect of CP-supplemented diet on blood sugar, lipid profile, oxidative stress and key carbohydrate metabolizing enzymes in STZ-induced diabetic rats was examined. Phytochemical and antioxidant analyses of different extracts of CP showed the enormous polyphenol contents and scavenging abilities of CP, which positions it as a good ingredient for supplementation in the management of DM.

Administration of STZ (50 mg/kg) in the rats usually damage pancreas leading to hyperglycemia and disturbances in protein, carbohydrate and fat metabolism which are hallmarks of DM [52]. In this study, the excessive increases in the level of blood sugar and weight loss exhibited by diabetic rats were significantly reduced after 21 days-dietary regimen of CP-supplemented diet. The reduction of blood glucose and weight gain in diabetic rats might be due to the ability of the dietary regimen to restore the damaged β-cells and overcoming insulin resistance with concomitant control of glucose homeostasis which resulted into weight gain [6].

Similar to other studies, the induced hyperglycemia resulted into a concomitant rise in cholesterol, triglycerides and decreases in HDL concentration [53]. This might be due to the action of lipase which is activated during insulin deficiency leading to uninhibited release of fatty acids from fat depot in diabetes [54]. In the present study, the abnormalities in lipid profile were restored to near normalcy upon dietary treatment with CP-supplemented diet. This mitigation also showed that the supplemented diet might prevent diabetes-related cardiovascular diseases as low HDL-cholesterol and elevated levels of cholesterol and triglyceride in serum have been implicated as powerful indicators of cardiovascular diseases [55].

One of the key features of experimental diabetes is alterations in kidney function biomarkers; albumin, creatinine and urea [6]. These biomarkers have been used consistently to evaluate diabetic kidney damage in animal models [56]. In this study, there was decrease in serum albumin but increase in serum creatinine and urea. However, upon our dietary intervention for 21 days, the values were returned to near normalcy. Albumin, a serum binding protein with antioxidant and anti inflammatory properties [57, 58] is not usually present in urine. Though, we did not evaluate the urinary albumin level in this study but the decrease might be due to inadequate reabsorption from urine by kidney which is an indicative of kidney damage. Also, it might have been used up to mop enhanced free radicals in diabetic rats. Urea and creatinine are byproducts of body metabolism, which are removed from the body via the kidney. Their increased serum concentration in diabetic rats might be due to the inability of an impaired kidney to remove them from the blood [56]. However, reverting back to near normalcy by our supplemented diet demonstrated the renoprotective ability of our diet.

There exists an association between diabetes and liver injury. It has been suggested that concentrations of liver enzymes in serum are strongly associated with insulin resistance and glycemic status [59–61]. Liver injury in diabetes might be due to excessive intracellular accumulation of glycogen due to increased synthesis sometimes leading to hepatomegaly [62] or build up of lipid, an abnormality known as non-alcoholic fatty liver disease (NAFLD) [3]. In this study, diabetic rats exhibited elevated enzymes’ activity which corroborate with the works of other researchers [63]. Dietary regimen for 21 days was able to lower the activity of these enzymes in the diabetic rats. The attenuation of hepatocellular damage by our regimen is an evidence of chemoprotective and glycemic control abilities of the CP- supplemented diet. This ability may further enhance the optimized lipid, protein and carbohydrate metabolisms in the hepatic tissue of diabetic rats [54]. Also, the levels of bilirubin are reduced by stimulation of DM in the rats. Bilirubin, an end product of heme catabolism has been shown to possess ability to scavenge free radicals and prevent inflammation [64, 65]. The reduced levels of bilirubins in diabetic rats were increased by the dietary intervention of CP. The increased level of bilirubins in treated diabetic also buttressed the high phenolics and antioxidant abilities of CP as exhibited by its extracts. The present study agrees with some studies that have shown the protective role of bilirubin in vascular diseases [66, 67]. Also, there were mild elevations in AST, ALT, ALP and GGT activities of undiabetic rats treated with CP-supplemented diet suggesting a possible hepatoxic effect of the diet.

Induction of experimental diabetes is usually accompanied by elevation of oxidative stress in diabetic rats [68]. Oxidative stress enhances pro-inflammatory cytokines production which leads to the release of insulin counter-regulatory hormones that promote ketoacidosis [69]. Two of the important markers of oxidative stress are lipid peroxidation (LPO) and nitric oxide (NO) generation. In this study, the elevated levels of LPO and NO are ameliorated by the dietary intervention after 21 days. This might be due to the decreased generation of free radicals owning to improve glucose homeostasis in treated diabetic rats and the antioxidant abilities of CP.

Liver is a primary site of glucose production and utilization in the body. An impaired insulin action results into disorderliness of carbohydrate metabolism that affects the activities of several key enzymes of gluconeogenesis and glycolysis [70]. This action also leads to aberrant glucose production and glucose utilization [71]. As stated earlier, administration of streptozotocin usually leads to disturbance in carbohydrate metabolism which is consistence with diabetes [72]. In the present study, similar trend was observed, administration of STZ led to aberration in key carbohydrate metabolizing enzymes; HK, G6Pase, F1,6Bpase and G6PDH in diabetic rats.

The HK is the first enzyme in glycolysis and it catalyzes the reaction between glucose and adenosine triphosphate (ATP) to form glucose-6-phosphate while G6PDH channels excess glucose into another pathway (Pentose phosphate pathway) for anabolism [73]. The F1,6Bpase and G6pase are two important gluconeogenic enzymes responsible for catalyzing the committed steps in gluconeogenesis and serve as key point of regulation of this pathway [74]. In diabetic state, HK and G6PDH activities were reduced resulting into decreased glucose utilization while G6pase and F1, 6Bpase activities were increased leading to enhanced glucose production. Dietary intervention of CP-supplemented diet for 21 days was able to return the activities of these enzymes to near normalcy thereby optimizing glucose homeostasis in the diabetic rats given the supplemented diets. The result of this study agrees with the work of some researchers who have shown normalization of activities of these enzymes of carbohydrate metabolism as a strategy for management of diabetes mellitus [74, 75].

Histopathological examination of liver and pancreas further confirmed the protective ability of CP-supplemented diet against hyperglycemia mediated tissues’ damage in diabetes rats. The antidiabetic activity of the CP-supplemented diet might be due to vast presence of phytochemicals in CP. For example, Karigidi and Olaiya (2019) reported the presence of stilbene, a phytochemical that has been well reported for antidiabetic activity in the corn steep liquor extract of CP [6, 76, 77].

Despite all the benefits of CP-supplemented diets in STZ- induced diabetic rats, signs of toxicity were shown in the control rats fed with CP-supplemented diets. For example, the activities of liver enzymes(ALT, AST, ALP and GGT) and kidney function markers (creatinine and urea) were elevated in the control rats fed with different supplemented diet. This suggested that CP powder could be toxic to healthy rats, which might limit its use. In future, there might be need to subject CP powder to processing techniques that can remove toxic products from this plant to make it’s powder safe in non-diabetic models and then ascertain if the aforementioned biological activities in diabetic rats are not lost.

Conclusion

This present study showed that CP-supplement diet could lower glucose level and improve body weight in streptozotocin diabetic rats. Also it could modulate the aberrant lipid metabolism, enzymes’ markers, oxidative stress and key carbohydrate metabolism enzymes in diabetic rats. However, there are signs of toxicity in control rats fed with the supplemented diets. Therefore, CP-supplemented diet should be used with caution in the management and treatment of DM.

Compliance with ethical standards

Conflict of interest

The authors do not have any conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Cam ME, Hazar-Yavuz AN, Yildiza S, Ertas B, Adakul BA, Taskin T, Alan S, Kabasakal L. The methanolic extract of Thymus praecox subsp. skorpiliivar. skorpiliirestores glucose homeostasis, ameliorates insulin resistance and improvespancreatic β-cell function on streptozotocin/nicotinamide-induced type 2diabetic rats Journal Ethnopharmacol 2019;(231): 29–38. [DOI] [PubMed]
  • 2.International Diabetes Federation the IDF Diabetes Atlas, Ninth Edition; 2019.
  • 3.Levinthal GN, Tavill AS. Liver disease and diabetes mellitus. Clin Diabetes. 1999;17(2):1–20. [Google Scholar]
  • 4.Guven A, Yavuz O, Cam M, Ercan F, Bukan N, Comunoglu C, Gokce F. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats. ActaHistochem. 2006;108:85–93. doi: 10.1016/j.acthis.2006.03.005. [DOI] [PubMed] [Google Scholar]
  • 5.Mohamed J, Nafizah AHN, Zariyantey AH, Budin SB. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation Sultan QaboosUniver. Med J. 2016;16(2):132–141. doi: 10.18295/squmj.2016.16.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Karigidi KO, Olaiya CO, Antidiabetic activity of corn steep liquor extract of Curculigo pilosa and its solvent fractions in streptozotocin-induced diabetic rats, J TraditiComplemen Med 10.1016/j.jtcme.2019.06.005, 2019. [DOI] [PMC free article] [PubMed]
  • 7.Cicero LTC, Yenshou L, Arlene PB, Yi-Ching C, Shao-Chih C, Wen-Chin Y.Herbal Therapies for Type 2 Diabetes Mellitus: Chemistry, Biology, and Potential Application of Selected Plants and Compounds Evidence-Based ComplemenAltern Med Volume 2013 |Article ID 378657 | 33 pages | 10.1155 /2013/378657. [DOI] [PMC free article] [PubMed]
  • 8.Kasole R, Martin HD, Kimiywe J. Traditional Medicine and Its Role in the Management of Diabetes Mellitus: (Patients’ and Herbalists’ Perspectives Evidence-Based ComplemenAltern Med Volume 2019, Article ID 2835691, 12 pages. 10.1155/2019/2835691. [DOI] [PMC free article] [PubMed]
  • 9.Nasri H, Shirzad H, Baradaran A, Rafieian-kopaei M. Antioxidant plants and diabetes mellitus. J Res Med Sci Off J Isfahan Univ Med Sci. 2015;20:491–502. doi: 10.4103/1735-1995.163977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Sofidiya MO, Oduwole B, Bamgbade E, Odukoya O, Adenekan S. Nutritional composition and antioxidant activities of Curculigo pilosa (Hypoxidaceae) rhizome African. J Biotechnol. 2011;10(75):17275–17281. [Google Scholar]
  • 11.Nie Y, Dong X, He Y, Yuan T, Han T, Rahman K, Qin L, Zhang Q. Medicinal plants of genus Curculigo: traditional uses and a phytochemical and ethnopharmacological review. J Ethnopharmacol. 2013;147:547–563. doi: 10.1016/j.jep.2013.03.066. [DOI] [PubMed] [Google Scholar]
  • 12.Gbadamosi IT, Egunyomi A. Phytochemical screening and invitro anticandidal activity of extracts and essential oil of Curculigo pilosa (Schum and Thonn) Engl. Hypoxidaceae Afr J Biotechnol. 2010;9(8):1236–1240. [Google Scholar]
  • 13.Olaiya CO, Karigidi KO. Hypoglycemic effects of corn steep liquor extracts in Streptozotocin-induced diabetic rats. Int J Biochem Res Rev. 2016;13(2):1–8. [Google Scholar]
  • 14.Adefegha SA, Oyeleye SI, Oboh G. African crocus (Curculigo pilosa) and wonderful kola (Buchholziacoriacea) seeds modulate critical enzymes relevant to erectile dysfunction and oxidative stress. J Complement Integrat Med 2018; DOI: 10.1515/jcim-2016-0159, 15. [DOI] [PubMed]
  • 15.Karigidi KO, Olaiya CO. In vitro Antidiabetic, antioxidant and anti-lipid peroxidative activities of corn steep liquor extracts of Curculigopilosa and its solvent fractions, J herbs. Spic Med Plants. 2019;25(4):377–388. [Google Scholar]
  • 16.Kim DO, Jeong SW, Lee CY. Antioxidant capacity of phenolic phytochemicals from various cultivars of plums. Food Chem. 2003;81:321–326. [Google Scholar]
  • 17.Park Y-S, Jung S-T, Kang S-G, Heo BK, Arancibia-Avila P, Toledo F, Gorinstein S. Antioxidants and proteins in ethylene-treated kiwifruits. Food Chem. 2008;107:640–648. [Google Scholar]
  • 18.Oyaizu M. Studies on products of browning reactions: Antioxidative activities of products of browning reaction prepared from glucosamine. Jpn J Nutr. 1986;44:307–315. [Google Scholar]
  • 19.Prieto P, Pineda M, Aguilar M. Spectrophotometric quantitation of antioxidant capacity through the formation of a phosphomolybdenum complex: specific application to the determination of vitamin E. Anal Biochem. 1999;26(9):337–341. doi: 10.1006/abio.1999.4019. [DOI] [PubMed] [Google Scholar]
  • 20.Gyamfi M, Yonamine M, Aniya Y. Free radical scavenging action of medicinal herbs from Ghana: Thonningia sanguine on experimentally induced liver injuries. Gen Pharmacol. 1999;32(6):661–667. doi: 10.1016/s0306-3623(98)00238-9. [DOI] [PubMed] [Google Scholar]
  • 21.Benzie IFF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem. 1996;239(1):70–76. doi: 10.1006/abio.1996.0292. [DOI] [PubMed] [Google Scholar]
  • 22.Mondal S, Chakraborty G, Gupta M, Muzumdar U. In vitro antioxidant activity of Diospyros malabarica kostel bark. Ind J Experimen Biol. 2006;44:39–44. [PubMed] [Google Scholar]
  • 23.Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorisation assay. Free Radic Biol Med. 1999;26(9–10):1231–1237. doi: 10.1016/s0891-5849(98)00315-3. [DOI] [PubMed] [Google Scholar]
  • 24.Oyetayo FL, Akomolafe SF, Odeniyi IA. Effects of dietary supplementation of Chrysophyllum albidum fruit pulp powder on some biochemical parameters in a type 2 diabetes rat model. Vegetos. 2019;32:190–199. doi: 10.1007/s42535-019-00022-7. [DOI] [Google Scholar]
  • 25.National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals . Guide for the Care and Use of Laboratory Animals. 8. Washington DC: National Academies Press (US); 2011. [PubMed] [Google Scholar]
  • 26.Adedara IA, Awogbindin IO, Anamelechi JP, Farombi EO. Garcinia kola seed ameliorates renal, hepatic, and testicular oxidative damage in streptozotocin-induced diabetic rats.Pharmaceutl biol. 2014:1–10 DOI: 10.3109/13880209.2014.937504 [DOI] [PubMed]
  • 27.Doumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with BCG. ClinChimActa. 1971;31:87–96. doi: 10.1016/0009-8981(71)90365-2. [DOI] [PubMed] [Google Scholar]
  • 28.Bartels H, Bohmer M. In vitro determination of Creatinine and urea. Clin Chem. 1972;2:37–193. doi: 10.1016/0009-8981(72)90432-9. [DOI] [PubMed] [Google Scholar]
  • 29.Weatherburn MW. Colorimetric methods for serum urea determination. Anal Chem. 1967;39:971–974. [Google Scholar]
  • 30.Allain GC, Poon LS, Chan CS, Richmond W. Quantitative determination of cholesterol using enzymatic colorimetric method. Clin Chem. 1974;20:470–475. [PubMed] [Google Scholar]
  • 31.Jendrassik L, Grof P. In vitro determination of total and direct bilirubin. Biochemica. 1938;297:81. [Google Scholar]
  • 32.Jacobs NJ, Van Denmark PJ. Determination of triglycerides. Arch BiochemBiophys. 1960;88:250–255. [Google Scholar]
  • 33.Reitman S, Frankel S. A colorimetric method for the determination of serum glutamicoxaloacetic and glutamicpyruvictransaminases. Am J Clin Pathol. 1957;28:56–63. doi: 10.1093/ajcp/28.1.56. [DOI] [PubMed] [Google Scholar]
  • 34.Rec GSCC (DGKC) Colorimetric method for serum alkaline phosphatase determination. J Clin Chem ClinBiochem. 1972;10:182. [Google Scholar]
  • 35.Ikewuchi CJ, Ikewuchi CC. Alteration of plasma lipid profiles and atherogenic indices by Stachytarphetajamaicensis L (Vahl) Boikemistri. 2009;21:71–77. [Google Scholar]
  • 36.Takasaki Y. Serum lipid levels and factors affecting atherogenic index in Japanese children. J PhysiolAnthropol Appl Hum Sci. 2005;24:511–515. doi: 10.2114/jpa.24.511. [DOI] [PubMed] [Google Scholar]
  • 37.Gornall AG, Bardawill CJ, David MM. Determination of serum proteins by means of the biuret reaction. J Biol Chem. 1949;177(2):751–766. [PubMed] [Google Scholar]
  • 38.Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351–358. doi: 10.1016/0003-2697(79)90738-3. [DOI] [PubMed] [Google Scholar]
  • 39.Green LC, Wagner DA, Glogowski J, Skiper PL, Wishnock JS, Tannenbaum SR. Analysis of nitrate, nitrite and [15 N] nitrate in biological fluids. Anal Biochem. 1982;126:131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  • 40.Brandstrup N, Kirk JE, Bruni C. The hexokinase and phosphogluco isomerase activities of aortic and pulmonary artery tissue in individuals of various ages. J Gerontol. 1957;12:166–171. doi: 10.1093/geronj/12.2.166. [DOI] [PubMed] [Google Scholar]
  • 41.Ellis HA, Kirkman HN. A colorimetric method for assay of erythrocytic glucose 6-phosphate dehydrogenase. Proc Soc Exp Biol Med. 1961;106:607–609. doi: 10.3181/00379727-106-26418. [DOI] [PubMed] [Google Scholar]
  • 42.Koide H, Oda T. Pathological occurrence of glucose 6-phosphatase in serum in liver diseases. ClinChimActa. 1959;4:554–561. doi: 10.1016/0009-8981(59)90165-2. [DOI] [PubMed] [Google Scholar]
  • 43.Gancedo JM, Gancedo C. Fructose-1,6-diphosphatase, phosphofructokinase and glucose-6-phosphate dehydrogenase from fermenting and non fermenting yeasts. Arch Microbiol. 1971;76:132–138. doi: 10.1007/BF00411787. [DOI] [PubMed] [Google Scholar]
  • 44.Avwioro OG. Histochemistry and tissue pathology, principle and techniques. Nigeria: Claverianum press; 2010. [Google Scholar]
  • 45.Abshirini M, Mahaki B, Bagheri F, Siassi F, Koohdani F, Sotoudeh G. Higher intake of phytochemical-rich foods is inversely related to prediabetes: a case-control study. Int J Prev Med. 2018;9:64. doi: 10.4103/ijpvm.IJPVM_145_18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Wang PY, Fang JC, Gao ZH, Zhang C, Xie SY. Higher intake of fruits, vegetables or their fiber reduces the risk of type 2 diabetes: a meta-analysis. J Diabetes Investig. 2016;7:56–69. doi: 10.1111/jdi.12376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Zhang Y-J, Gan R-Y, Li S, Zhou Y, Li A-N. Dong-Ping Xu and Hua-Bin Li Antioxidant Phytochemicals for the Prevention and Treatment of Chronic Diseases Molecules. 2015;20:21138–21156. doi: 10.3390/molecules201219753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Lui RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. The American J ClinNutrit. 2003;78(3):517S–520S. doi: 10.1093/ajcn/78.3.517S. [DOI] [PubMed] [Google Scholar]
  • 49.Kwon YI, Apostolidis E, Kim YC, Shetty K. Health benefits of traditional corn, beans and pumpkin: in vitro studies for hyperglycemia and hypertension management. J Med Food. 2007;10:266–275. doi: 10.1089/jmf.2006.234. [DOI] [PubMed] [Google Scholar]
  • 50.Karigidi KO, Olaiya CO.Curculigo pilosa mitigates against oxidative stress and structural derangements in pancreas and kidney of streptozotocin-induced diabetic rats Journal of Complementary and Integrative Medicine 2020; 20190217 10.1515/jcim-2019-0217. [DOI] [PubMed]
  • 51.Choudhury H, Pandey M, Hua CK, Mun CS, Jing JK. Kong L et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review J TraditComplem Med. 2018;8:361–376. doi: 10.1016/j.jtcme.2017.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Wahba NS, Shaban SF, Asmaa A, Kattaia A, Kandeel SA. Efficacy of zinc oxide nanoparticles in attenuating pancreatic damage in a rat model of streptozotocin-induced diabetes. UltrastructPathol, 2016. 2016;40(6):358–373. doi: 10.1080/01913123.2016.1246499. [DOI] [PubMed] [Google Scholar]
  • 53.Erejuwa OO, Nwobodo NN, Akpan JL, Okorie UA, Ezeonu CT, Ezeokpo BC, Nwadike K, Erhiano E, Abdul Wahab M, Sulaiman S. Nigerian honey ameliorates hyperglycemia and dyslipidemia in Alloxan-induced diabetic rats. Nutrients. 2016;8:95. doi: 10.3390/nu8030095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Subbiah R, Kasiappan R, Karuran S, Sorimuthu S. Beneficial effects of aloe vera leaf gel extract on lipid profile status in rats with streptozotocin diabetes. Clin and Exp Pharmacol Physiol. 2006;33:232–237. doi: 10.1111/j.1440-1681.2006.04351.x. [DOI] [PubMed] [Google Scholar]
  • 55.Nesto RW. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome, am J Cardiovasc. Drugs. 2005;5:379–387. doi: 10.2165/00129784-200505060-00005. [DOI] [PubMed] [Google Scholar]
  • 56.Li W, Wang G, Lu X, Jiang Y, Xu L, Zhao X. Lycopene ameliorates renal function in rats with streptozotocin-induced diabetes. Int J Clin Exp Pathol. 2014;7(8):5008–5015. [PMC free article] [PubMed] [Google Scholar]
  • 57.Halliwell B. Albumin: an important extracellular antioxidant? Biochem Pharmacol. 1988;37:569–571. doi: 10.1016/0006-2952(88)90126-8. [DOI] [PubMed] [Google Scholar]
  • 58.Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res. 2002;55:820–829. doi: 10.1016/s0008-6363(02)00492-3. [DOI] [PubMed] [Google Scholar]
  • 59.Zhang Y, Lu X, Hong J, Chao M, Gu W, Wang W, Ning G. Positive correlations of liver enzymes with metabolic syndrome including insulin resistance in newly diagnosed type 2 diabetes mellitus. Endocr. 2010;38:181–187. doi: 10.1007/s12020-010-9369-6. [DOI] [PubMed] [Google Scholar]
  • 60.Succurro E, Arturi F, Grembiale A, Iorio F, Fiorentino TV, Andreozzi F, Sciacqua A, Hribal ML, Perticone F, Sesti G. One-hour post-load plasma glucose levels are associated with elevated liver enzymes. Nutr Metab Cardiovasc Dis. 2011;21:713–718. doi: 10.1016/j.numecd.2011.02.002. [DOI] [PubMed] [Google Scholar]
  • 61.Han N, Kyaw-Soe HH, Htet A. Determinants of Abnormal Liver Function Tests in Diabetes Patients in Myanmar. Internat J. Diab Res. 2012;1(3):36–41. [Google Scholar]
  • 62.Chatila R, West AB. Hepatomegaly and abnormal liver tests due to glycogenesis in adults with diabetes. Med. 1996;75(6):327–333. doi: 10.1097/00005792-199611000-00003. [DOI] [PubMed] [Google Scholar]
  • 63.Soliman AM. Potential impact of Paracentrotuslividus extract on diabetic rat models induced by high fat diet/streptozotocin. The J Bas Appl Zool. 2016;77:8–20. [Google Scholar]
  • 64.Chan KH, O'Connell RL, Sullivan DR, et al. Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate intervention and event lowering in diabetes (FIELD) study. Diabetologia. 2013;56(4):724–736. doi: 10.1007/s00125-012-2818-4. [DOI] [PubMed] [Google Scholar]
  • 65.Breimer LH, Mikhailidis DP. Is bilirubin a marker of vascular disease and/or cancer and is it a potential therapeutic target? CurrPharm Des. 2011;17:3644–3655. doi: 10.2174/138161211798220927. [DOI] [PubMed] [Google Scholar]
  • 66.Kimm H, Yun JE, Jo J, Jee SH. Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke; J cerebcirculat. 2009;40:3422–3427. doi: 10.1161/STROKEAHA.109.560649. [DOI] [PubMed] [Google Scholar]
  • 67.Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. Jama. 2007;298:1398–1400. doi: 10.1001/jama.298.12.1398-b. [DOI] [PubMed] [Google Scholar]
  • 68.Xie Z, Zeng X, Li X, Wu B, Shen G, Wu Q, Wu C. Curcumin attenuates oxidative stress in liver in type 1 diabetic rats. Open Life Sci. 2017;12:452–459. [Google Scholar]
  • 69.Murunga AN, Miruka DO, Driver C, Nkomo FS, Cobongela SZZ, Owira PMO. Grapefruit derived flavonoid Naringin improves ketoacidosis and lipid peroxidation in type 1 diabetes rat model. PLoS ONE. 2016;11(4):e0153241. doi: 10.1371/journal.pone.0153241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Irudayaraj SS, Christudas S, Antony S, Duraipandiyan V, Abdullah AN, Ignacimuthu S. Protective effects of Ficuscarica leaves on glucose and lipids levels, carbohydrate metabolism enzymes and β-cells in type 2 diabetic rats. Pharma Biol. 2017;55(1):1074–1081. doi: 10.1080/13880209.2017.1279671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Hikino H, Kobayashi M, Suzuki Y, Konno C. Mechanisms of hypoglycemic activity of aconitan a, a glycan from Aconitum carmichaeli roots. J Ethnopharmacol. 1989;25:295–304. doi: 10.1016/0378-8741(89)90035-4. [DOI] [PubMed] [Google Scholar]
  • 72.Sundaram R, Naresh R, Ranadevan R, Shanthi P, Sachdanandam P. Effect of iridoidglucoside on streptozotocin induced diabetic rats and its role in regulating carbohydrate metabolic enzymes. Eur J Pharmacol. 2012;674:460–467. doi: 10.1016/j.ejphar.2011.10.039. [DOI] [PubMed] [Google Scholar]
  • 73.Sankaranarayanan C, Ramajayam N, Pachaiappan P. Ameliorating effect of berbamine on hepatic key enzymes of carbohydrate metabolism in high-fat diet and streptozotocin induced type 2 diabetic rats. Biomed Pharmacother. 2018;103:539–545. doi: 10.1016/j.biopha.2018.04.066. [DOI] [PubMed] [Google Scholar]
  • 74.Saravanan G, Ponmurugan P, Deepa MA, Senthilkumar B. Modulatory effects of Diosgenin on attenuating the key enzymes activities of carbohydrate metabolism and glycogen content in Streptozotocin-induced diabetic rats. Can J Diabet. 2014;38:409–414. doi: 10.1016/j.jcjd.2014.02.004. [DOI] [PubMed] [Google Scholar]
  • 75.Basha RH, Sankaranarayanan C. β-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats. ActaHistochemica. 2014;116:1469–1479. doi: 10.1016/j.acthis.2014.10.001. [DOI] [PubMed] [Google Scholar]
  • 76.Kosuru R, Singh S. Pterostilbene ameliorates insulin sensitivity, glycemic control and oxidative stress in fructose-fed diabetic rats. Life Sci. 2017;182:112–121. doi: 10.1016/j.lfs.2017.06.015. [DOI] [PubMed] [Google Scholar]
  • 77.Gang L, Guangxiang L, Yanfeng H, Fangfang T, Zhenhua W, Yourui S, Chengjun M, Honglun W Polyphenol Stilbenes from Fenugreek (Trigonella foenum graecum L.) Seeds Improve Insulin Sensitivity and MitochondrialFunction in 3T3-L1. Adipocytes. Oxid Med CellulLongev. 2018; 10.1155/2018 /7634362. [DOI] [PMC free article] [PubMed]

Articles from Journal of Diabetes and Metabolic Disorders are provided here courtesy of Springer

RESOURCES