Molecular mechanisms interlinking biological clock and diabetes mellitus: Effective tools for better management.

BACKGROUND AND AIM: Advances in circadian biology have delineated the link between perturbed biological clock and metabolic diseases. Circadian disturbances are associated with the onset, progression and severity of diabetes mellitus. METHODS: We conducted a literature survey using the key terms - circadian, diabetes, circadian and diabetes, clock genes and diabetes, chronotherapy and peripheral clocks in science direct, PubMed, Google, and Embase till August 23, 2021. RESULTS: Misalignment between peripheral clocks located in pancreas, intestine, liver, adipose tissue and skeletal muscle and with the central oscillator alters the secretion of insulin, incretins, adipokines and soluble factors resulting in the derangement of metabolism leading to chronic hyperglycemia. CONCLUSION: Management of circadian health restores glucose homeostasis confirming that chronotherapy will help in the management of diabetes mellitus. Further, administration of circadian clock modifiers has proved potential therapeutic agents to treat diabetes mellitus. The aim of the review is to highlight the molecular mechanisms linking biological clock and diabetes mellitus and how they are useful for effective management of the disease.

ß-Caryophyllene promotes oxidative stress and apoptosis in KB cells through activation of mitochondrial-mediated pathway - An in-vitro and in-silico study.

Beta-caryophyllene (BCP), are natural bicyclic sesquiterpenes which are present in numerous plants worldwide. BCP has antioxidant, antimicrobial, and antifungal properties. Here, we studied its anticancer, anti-inflammatory, and cytotoxic effects. Cells treated with BCP, in a dose-dependent manner, exhibited morphological changes, showed lower cell growth, underwent apoptosis and lost the ability to metastasis through the suppression of NF-Ò¡ B via PI3K/AKT signalling pathway. These results elucidate that the inhibition of NF-Ò¡ B and PI3K/AKT is one of the most important mechanism by which BCP suppresses cancer cell proliferation and enhances apoptosis.

Modulatory effect of isopulegol on hepatic key enzymes of glucose metabolism in high-fat diet/streptozotocin-induced diabetic rats.

To investigate the antidiabetic effect of isopulegol in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic rats. Animals were made diabetic by feeding HFD for 4 weeks followed by single intraperitoneal injection of STZ (35 mg/kg b.w.; 0.1 M citrate buffer; pH 4.0). Plasma insulin, haemoglobin and glycogen content were decreased while increased glucose and glycated haemoglobin were observed in diabetic rats. An increase in glucose-6-phosphatase, fructose-1,6-bisphosphatase, phosphoenol pyruvate carboxykinase with a decrease in hexokinase, glucose-6-phosphate dehydrogenase and glycogen synthase activities was observed in diabetic rats. The expression of cyclic response element binding protein (CREB) was increased in the hepatic tissue of diabetic rats. Isopulegol dose dependently (50, 100 and 200 mg/kg b.w.) improved insulin secretion, glucose tolerance and decreased glucose levels in diabetic-treated rats. At the effective dose of 100 mg/kg b.w., isopulegol restored the activities of metabolic enzymes and down-regulated CREB expression. Thus, isopulegol restored glucose homeostasis through its insulinotrophic property.

Isopulegol Mitigates Hyperglycemia Mediated Oxidative and Endoplasmic Reticulum Stress in HFD/STZ Induced Diabetic Rats.

BACKGROUND: Oxidative and endoplasmic reticulum stresses contribute to the pathogenesis of ß-cell dysfunction in diabetes mellitus. This study investigates the effect of isopulegol on the above stresses in HFD/STZ induced diabetic rats. METHODS: Animals in group I and II were placed in normal pellet diet and group II was treated with isopulegol at 200 mg/kg b.w. Animals in groups III-V were placed in HFD for 4 weeks and made diabetic with single intraperitoneal injection of STZ (35 mg/kg b.w) in 0.1 M citrate buffer (pH 4.5). Group III served as diabetic control while animals in group IV and V were treated with isopulegol (100 mg/kg b.w) and metformin (25 mg/kg b.w) respectively for 28 d. RESULTS: The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione sulphur transferase (GST), glutathione reductase (GR) and the levels of vitamin-E, vitamin-C, reduced glutathione (GSH) were significantly (p <0.05) decreased in plasma and tissues of diabetic rats. Thiobarbituric acid reactive acid substances (TBARS) and lipid hydroperoxides (LHP), indices of lipid peroxidation were also significantly (p <0.05) increased in diabetic rats. In pancreatic tissue ER stress markers PERK, elf2α, ATF4 and in hepatic tissue oxidative stress marker UCP-2 expression was significantly (p <1.0) increased in diabetic rats. Administration of isopulegol significantly improved antioxidant status and decreased oxidative and ER stress markers in diabetic treated rats. Histopathological studies on liver and kidney supported the above findings. The results are comparable with the standard drug metformin. CONCLUSIONS: Isopulegol a naturally occurring monoterpene alcohol attenuated oxidative and ER stress in HFD/STZ induced diabetic rats.

Ameliorating effect of berbamine on hepatic key enzymes of carbohydrate metabolism in high-fat diet and streptozotocin induced type 2 diabetic rats.

BACKGROUND: Aberrations in the activities of key enzymes of carbohydrate metabolism is well documented in diabetes mellitus. Previous studies have shown that active ingredients in the extracts of Berberis aristata exhibits diverse pharmacological activities in animal models. OBJECTIVE: The present study was undertaken to investigate whether berbamine (BBM), an alkaloid from the roots of Berberis aristata can ameliorate the altered activities of carbohydrate metabolic enzymes in high fat diet (HFD)/streptozotocin (STZ) induced diabetic rats. RESULTS: Supplementation of HFD for 4 weeks followed by intraperitonial administration of single low dose of STZ (40 mg/kg b.w.) to Sprague Dawley rats resulted in significant hyperglycemia with a decline in plasma insulin levels. The rats also exhibited decreased hemoglobin with an increase in glycated hemoglobin levels. The activities of hexokinase, glucose-6-phosphate dehydrogenase were decreased whereas increases in the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase were observed in the hepatic tissues of diabetic control rats. Glycogen content in the hepatic and skeletal muscle tissues were found to be decreased in diabetic rats. Oral administration of BBM for 56 days, dose dependently (50, 100, 200 mg/kg b.w.) improved insulin secretion in diabetic treated rats. Immunohistochemical studies on pancreas revealed a strong immunoreactivity to insulin in BBM treated rats. At the effective dose of 100 mg/kg b.w., BBM restored the altered activities of carbohydrate metabolic enzymes and also improved glycogen content in insulin dependent tissues. CONCLUSION: From the biochemical and histochemical data obtained in this study we conclude that BBM ameliorated the activities of metabolic enzymes and maintained glucose homeostasis in HFD/STZ induced diabetic rats and it can be used as a potential phytomedicine for the management of diabetes mellitus.

Geraniol, a natural monoterpene, ameliorates hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.

CONTEXT: Geraniol, an acyclic monoterpene alcohol is found in medicinal plants, is used traditionally for several medical purposes including diabetes. OBJECTIVES: The present study evaluates the antihyperglycemic potential of geraniol on key enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced in experimental rats, by a single intraperitoneal (i.p) injection of STZ [40 mg/kg body weight (b.w.)]. Different doses of geraniol (100, 200 and 400 mg/kg b.w.) and glyclazide (5 mg/kg b.w.) were administrated orally to diabetic rats for 45 days. Body weight, food intake, plasma glucose, insulin, blood haemoglobin (Hb), glycosylated haemoglobin (HbA1c), hepatic glucose metabolic enzymes and glycogen were examined. RESULTS: The LD50 value of geraniol is 3600 mg/kg b.w. at oral administration in rats. Administration of geraniol in a dose-dependent manner (100, 200, 400 mg/kg b.w.) and glyclazide (5 mg/kg b.w.) for 45 days significantly improved the levels of insulin, Hb and decreased plasma glucose, HbA1C in diabetic-treated rats. Geraniol at its effective dose (200 mg/kg b.w.) ameliorated the altered activities of carbohydrate metabolic enzymes near normal effects compared with two other doses (100 and 400 mg/kg b.w.). Geraniol treatment to diabetic rats improved hepatic glycogen content suggesting its anti-hyperglycemic potential. Geraniol supplement was found to preserve the normal histological appearance of hepatic cells and pancreatic ß-cells in diabetic rats. DISCUSSION AND CONCLUSIONS: The present findings suggest that geraniol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes even though clinical studies used to evaluate this possibility are warranted.

ß-Caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia mediated oxidative and inflammatory stress in experimental diabetic rats.

Oxidative and inflammatory stress has been implicated in the onset and progression of diabetes mellitus and its complications. The present study was designed to evaluate the effect of ß-Caryophyllene (BCP) on hyperglycemia mediated oxidative and inflammatory stress in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in experimental rats by a single intraperitoneal injection of STZ (40 mg/kg b.w.) dissolved in 0.1 M citrate buffer (pH 4.5). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes and the levels of non-enzymic antioxidants were decreased while increases in the levels of lipidperoxidative markers, protein carbonyls and conjugated dienes were observed in pancreatic tissues of diabetic rats. An elevation of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were observed in plasma and pancreatic tissues of diabetic rats. Intragastric administration of BCP (200 mg/kg b.w) for 45 days significantly decreased glucose and increased insulin levels in diabetic rats. BCP administration significantly restored antioxidant status and decreased proinflammatory cytokines in diabetic rats. These findings were supported by histological and immunohistochemical studies. Thus, we conclude that oral administration of BCP effectively rescued ß-cells by mitigating hyperglycemia through enhancing insulin release and also averted oxidative/inflammatory stress in pancreatic tissue of diabetic rats. The efficacy of BCP was compared with glibenclamide, a standard antidiabetic drug.

ß-Caryophyllene, a natural sesquiterpene, modulates carbohydrate metabolism in streptozotocin-induced diabetic rats.

The study was designed to evaluate the antihyperglycemic effects of ß-caryophyllene (BCP), a natural sesquiterpene from spices on streptozotocin (STZ) induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w.) in adult male Wistar rats. Diabetic rats exhibited an increase in glucose and HbA1c with a significant fall in insulin and hemoglobin levels. Aberrations in carbohydrate metabolic enzymes were noticed in liver, kidney and skeletal muscle of diabetic rats. A fall in liver and skeletal muscle glycogen with alterations in glycogen synthase and phosphorylase activities was also observed. Oral administration of BCP in dose dependent manner and glibenclamide (600 µg/kg b.w.), a standard oral hypoglycemic drug to diabetic rats for 45 days significantly decreased glucose with increased plasma insulin levels and ameliorated the altered activities of carbohydrate metabolic enzymes to near normal. The insulinotropic effect of BCP was supported by immunohistochemical studies. BCP at a dose of 200mg/kg b.w. exerted significant antidiabetic effects than other two doses (100 and 400mg/kg b.w.). We conclude that administration of BCP has beneficial effects in glucose homeostasis in diabetic rats.

Thymoquinone ameliorates chemical induced oxidative stress and ß-cell damage in experimental hyperglycemic rats.

The present study was aimed to investigate the effect of thymoquinone (TQ) on pancreatic insulin levels, tissue antioxidant and lipid peroxidation (LPO) status in streptozotocin (STZ) nicotinamide (NA) induced diabetic rats. Diabetes was induced in experimental rats by a single intraperitoneal (i.p) injection of STZ (45 mg/kg b.w) dissolved in 0.1 mol/L citrate buffer (pH 4.5), 15 min after the i.p administration of NA (110 mg/kg b.w). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the levels of low-molecular weight antioxidants Vitamin C, Vitamin E and reduced glutathione (GSH) were decreased while increases in the levels of lipid peroxidation markers were observed in liver and kidney tissues of diabetic control rats as compared to control rats. In addition, diabetic rats showed an obvious decrease in pancreatic insulin levels. Administration of TQ (80 mg/kg b.w) to diabetic rats for 45 days significantly reversed the damage associated with diabetes. Biochemical findings were supported by histological studies. These results indicated that TQ exerts a protective action on pancreatic beta cell function and overcomes oxidative stress through its antioxidant properties.

Beneficial effects of thymoquinone on hepatic key enzymes in streptozotocin-nicotinamide induced diabetic rats.

AIMS: The present study was designed to evaluate the antihyperglycemic potential of thymoquinone (TQ), major constituent of Nigella sativa seeds on the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ)-nicotinamide (NA)-induced diabetic rats. MAIN METHODS: Diabetes was induced in experimental rats weighing 180-220g, by a single intraperitoneal (i.p) injection of STZ (45mg/kg b.w), 15min after the i.p administration of NA (110mg/kg b.w). Diabetic rats were administered TQ intragastrically at 20, 40, 80mg/kg b.w for 45days. The levels of plasma glucose, insulin, glycated hemoglobin (HbA(1C)) and hemoglobin (Hb) were measured. The activities of hexokinase, glucose 6-phosphate dehydrogenase, glucose 6-phosphatase and fructose 1,6-bisphosphatase were assayed in liver homogenates. KEY FINDINGS: Oral administration of TQ for 45days, dose dependently improved the glycemic status in STZ-NA induced diabetic rats. The levels of insulin, Hb increased with significant decrease in glucose and HbA(1C) levels. The altered activities of carbohydrate metabolic enzymes were restored to near normal. No significant changes were noticed in normal rats treated with TQ. SIGNIFICANCE: These results show that TQ at 80mg/kg b.w is associated with beneficial changes in hepatic enzyme activities and thereby exerts potential antihyperglycemic effects.