[Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet ß cells].

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet ß cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet ß cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Investigation on the mechanism of acupuncture in treatment of diabetes mellitus type 2 based on the network of islet macrophages-pancreatic adipose cells-islet β cells / 中国针灸

To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.

Abrus precatorius Leaf Extract Reverses Alloxan/Nicotinamide-Induced Diabetes Mellitus in Rats through Hormonal (Insulin, GLP-1, and Glucagon) and Enzymatic (α-Amylase/α-Glucosidase) Modulation.

BACKGROUND: Abrus precatorius is used in folk medicine across Afro-Asian regions of the world. Earlier, glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) was confirmed experimentally in STZ/nicotinamide-induced diabetic rats; however, the underlying mechanism of antidiabetic effect and pancreato-protection remained unknown. OBJECTIVE: This study elucidated antidiabetic mechanisms and pancreato-protective effects of APLE in diabetic rats. MATERIALS AND METHODS: APLE was prepared by ethanol/Soxhlet extraction method. Total phenols and flavonoids were quantified calorimetrically after initial phytochemical screening. Diabetes mellitus (DM) was established in adult Sprague-Dawley rats (weighing 120-180 g) of both sexes by daily sequential injection of nicotinamide (48 mg/kg; ip) and Alloxan (120 mg/kg; ip) over a period of 7 days. Except control rats which had fasting blood glucose (FBG) of 4.60 mmol/L, rats having stable FBG (16-21 mmol/L) 7 days post-nicotinamide/Alloxan injection were considered diabetic and were randomly reassigned to one of the following groups (model, APLE (100, 200, and 400 mg/kg, respectively; po) and metformin (300 mg/kg; po)) and treated daily for 18 days. Bodyweight and FBG were measured every 72 hours for 18 days. On day 18, rats were sacrificed under deep anesthesia; organs (kidney, liver, pancreas, and spleen) were isolated and weighed. Blood was collected for estimation of serum insulin, glucagon, and GLP-1 using a rat-specific ELISA kit. The pancreas was processed, sectioned, and H&E-stained for histological examination. Effect of APLE on enzymatic activity of alpha (α)-amylase and α-glucosidase was assessed. Antioxidant and free radical scavenging properties of APLE were assessed using standard methods. RESULTS: APLE dose-dependently decreased the initial FBG by 68.67%, 31.07%, and 4.39% compared to model (4.34%) and metformin (43.63%). APLE (100 mg/kg) treatment restored weight loss relative to model. APLE increased serum insulin and GLP-1 but decreased serum glucagon relative to model. APLE increased both the number and median crosssectional area (×106 µm2) of pancreatic islets compared to that of model. APLE produced concentration-dependent inhibition of α-amylase and α-glucosidase relative to acarbose. APLE concentration dependently scavenged DPPH and nitric oxide (NO) radicals and demonstrated increased ferric reducing antioxidant capacity (FRAC) relative to standards. CONCLUSION: Antidiabetic effect of APLE is mediated through modulation of insulin and GLP-1 inversely with glucagon, noncompetitive inhibition of α-amylase and α-glucosidase, free radical scavenging, and recovery of damaged/necro-apoptosized pancreatic ß-cells.

Beneficial Effect of Thymelaea hirsuta on Pancreatic Islet Degeneration, Renal Fibrosis, and Liver Damages as Demonstrated in Streptozotocin-Induced Diabetic Rat.

OBJECTIVE: In Morocco, Thymelaea hirsuta (T. hirsuta) (Thymelaeacea) is a medicinal plant widely used to treat and prevent diabetes. The present study aimed to evaluate the medium-term antidiabetic effect of aqueous extract (AqTh) and ethyl acetate fraction (EaTh) of Th and to investigate their putative protective effect on pancreatic islet degeneration, diabetic nephropathy, and liver damages in streptozotocin (STZ)-diabetic rats. METHODS: Experimental diabetes in rats was induced by a single intraperitoneal injection of 50 mg/kg of STZ. During the treatment period (4 weeks), 200 mg/kg AqTh and 50 mg/kg EaTh were orally administrated daily to STZ-diabetic rats. A group of parameters including fasting blood glucose, biochemical parameters, and intestinal α-glucosidase inhibition were studied. Furthermore, histological study of the pancreas, kidney, liver, and aorta was also realized. RESULTS: At the end of the treatment, both AqTh and EaTh had normalized fasting blood glucose to 1.08 and 1.25 g/l, respectively. AqTh has also reduced urinary creatinine and HbAc1. The EaTh showed inhibitory activity against intestinal α-glucosidase, whereas AqTh did not have this inhibitory effect. Furthermore, pancreas hematoxylin and eosin staining showed that AqTh or EaTh prevents pancreatic islet cell degeneration. As the same kidney, Masson's trichrome staining has shown a significant prevention of renal fibrosis in AqTh- or EaTh-treated diabetic rats. On the other hand, liver hematoxylin and eosin staining showed that AqTh and EaTh prevent liver damage. CONCLUSION: We conclude that medium-term administration of AqTh and EaTh exerts significant antihyperglycemic effect in STZ-diabetic rats possibly through intestinal α-glucosidase inhibition and protection against pancreatic islet cell damage. Moreover, AqTh and EaTh treatment prevent nephropathy and liver complications in STZ-diabetic rats.

Morus alba leaves ethanol extract protects pancreatic islet cells against dysfunction and death by inducing autophagy in type 2 diabetes.

BACKGROUND: Protection of pancreatic islet cells against dysfunction or death by regulating autophagy is considered to be an effective method for treatment of type 2 diabetes mellitus (T2DM). Morus alba leaves (mulberry leaves), a popular herbal medicine, have been used for prevention of T2DM since ancient times. PURPOSE: This study aimed to clarify whether Morus alba leaves ethanol extract (MLE) could protect islet cells in vivo and in vitro by regulating autophagy in T2DM, and explore the possible mechanism of action. METHODS: The main chemical constituents in MLE were analyzed by HPLC. The T2DM rat model was induced via high-fat diet combined with peritoneal injection of low-dose streptozotocin, and MLE was administered by oral gavage. Fasting blood glucose (FBG) and plasma insulin were measured, and homeostatic model assessment of ß cell function (HOMA-ß) and insulin resistance (HOMA-IR) were determined. The histomorphology of pancreas islets was evaluated by haematoxylin and eosin staining. In palmitic acid (PA)-stressed INS-1 rat insulinoma cells, cell viability was assayed by an MTT method. Expression of the autophagy-related proteins LC3 I/II, p62, p-AMPK and p-mTOR in islet tissues and INS-1 cells was evaluated by western blotting or immunohistochemistry analysis. RESULTS: The four main chemical constituents in MLE were identified as chlorogenic acid, rutin, isoquercitrin and quercitrin. MLE ameliorated hyperglycemia, insulin resistance and dyslipidemia of T2DM rats with prominent therapeutic effect. Further study indicated that MLE observably improved islet function, alleviated islet injury of T2DM rats, and inhibited PA-induced INS-1 cell death. On the other hand, MLE significantly induced autophagy in islet cells both in vivo and in vitro, and autophagy inhibitors abolished its therapeutic effect on T2DM rats and protective effect on islet cells. Apart from this, MLE markedly activated the AMPK/mTOR pathway in INS-1 cells, and the AMPK inhibitor prevented the autophagy induction ability of MLE. CONCLUSION: Together, MLE could protect islet cells against dysfunction and death by inducing AMPK/mTOR-mediated autophagy in T2DM, and these findings provide a new perspective for understanding the treatment mechanism of Morus alba leaves against T2DM.

Pharmacological, Phytochemical and histopathological basis of Conyza bonariensis in the potential management of diabetes mellitus.

To evaluate the anti-diabetic potential of aqueous methanolic extract of Conyza bonariensis amongst the Wistar rats. Phytochemical and High Performance Liquid Chromatography (HPLC) analyses of phenols and flavonoids were examined. The plant extract (250 and 500mg/kg/day) was explored for its anti-hyperglycemic effect for 14 days in normoglycemic and alloxan-induced diabetic rats using the oral glucose tolerance test (OGTT). HPLC analyses demonstrated the composition of the plant extract as gallic acid, cinnamic acid, quercetin, p-coumaric acid and syringic acid. The blood glucose concentrations in experimental diabetic as well as non-diabetic rats significantly decreased with doses 250 and 500 mg/kg in OGTT. Moreover, the significant drop in fasting glucose level was observed following 14 days of therapy. It also ameliorated the serum cholesterol, total protein, low and high density lipoproteins, glycosylated hemoglobin A1C and serum amylase with respect to untreated rats suffering from diabetes. There appeared to be no significant alteration with regard to body weight amongst the treated rats. The plant extract revamped the pancreatic islets of Langerhans and abridged alloxan-induced degenerative changes in the liver. It can be concluded that Conyza bonariensis extract has a pronounced hypoglycemic effect on diabetes due to the presence of phytochemicals.

Anemarrhena asphodeloides modulates gut microbiota and restores pancreatic function in diabetic rats.

Anemarrhena asphodeloides is an herb widely used to treat symptoms associated with diabetes in traditional Chinese medicine. However, its key components and metabolites have low bioavailability and poor host absorption. To clarify the anti-diabetic mechanism of A. asphodeloides extract (AAE), we examined the anti-diabetic effects of AAE in rats with diabetes induced by a high-fat diet and streptozotocin. Faeces levels of the main components and metabolites of AAE were significantly higher than levels in plasma, which indicated that gut microbiota might play important roles in its anti-diabetic effect. Microbiological studies showed that unabsorbed components increased the diversity of the gut microbiota, enriched potentially beneficial bacteria, and suppressed potentially harmful bacteria. In vitro studies showed that AAE promoted the proliferation of Blautia coccoides, a bacterium with positive implication for diabetes, in a dose-dependent manner. AAE also promoted pancreatic cell regeneration and restored the function of pancreatic islet cells via peroxiredoxin 4 overexpression. Overall, these results suggest that AAE alleviates diabetes via modulating gut microbiota and protein expression.

Dietary zinc restriction promotes degeneration of the endocrine pancreas in mice.

Zinc is a key component of several proteins, interacting with the pancreatic hormones insulin and amylin. The role of zinc in insulin oligomerization and crystallinity is well established, although the effects of dietary zinc restriction on both energetic metabolism and ß-pancreatic hormonemia and morphology remain unexplored. Here we report the effects of dietary zinc restriction on the endocrine pancreas and metabolic phenotype of mice. Nontransgenic male Swiss mice were fed a low-zinc or control diet for 4 weeks after weanling. Growth, glycemia, insulinemia and amylinemia were lower and pancreatic islets were smaller in the intervention group despite the preserved insulin crystallinity in secretory granules. We found strong immunostaining for insulin, amylin and oligomers in apoptotic pancreatic islet. High production of ß-pancreatic hormones in zinc-restricted animals counteracted the reduced islet size caused by apoptosis. These data suggest that zinc deficiency is sufficient to promote islet ß-cell hormonal disruption and degeneration.

Protective efficacy of Tinospora sinensis against streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora sinensis Lour. (Merr.) belongs to the family Menispermaceae and its stem extract have been used traditionally in broad aspects of therapeutic remedies including debility, dyspepsia, fever, jaundice, ulcer, bronchitis, urinary disease, skin disease, liver disease and diabetes. AIM OF THE STUDY: The aim of the study was to evaluate the protective effects of methanol extract of stem of Tinospora sinensis (METS) on streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles. MATERIALS AND METHODS: A high-performance liquid chromatography technique (HPLC) was used to identify and quantify the major phytochemicals present in the METS. Diabetic rats were administered with METS at a dose of (100, 200 and 400 mg/kg respectively orally) and standard drug Metformin (300 mg/kg) was given orally to group serving positive control. Effect of the METS on glucose homeostasis, oxidative stress, antioxidant status, histopathology of pancreas and also on intracellular reactive oxygen species (ROS), mitochondrial membrane potential, apoptosis, cell cycle of pancreatic islet cells were studied in diabetic rats. RESULTS: The major phytochemicals identified and quantified by HPLC in the extract were berberine, caffeic acid, myricetin and ferulic acid. This result showed that methanol extract exhibited good antioxidant effect. The methanol extract of the plant prevented the diabetogenic effect of STZ and significantly lowered the fasting blood glucose level, glycated haemoglobin and increased insulin and C-peptide level in treated rats. METS reduced apoptosis of STZ treated islet cells by significantly decreasing pro-inflammatory cytokines (TNFα, IL6), intracellular ROS generation, lipid peroxidation, nitric oxide (NO) production and increasing mitochondrial membrane potential and sub-G0 peak area, enzymatic and nonenzymatic antioxidants. CONCLUSION: The results revealed that the methanol extract of the stem of the plant possesses protective effects against diabetes and associated complications.

Nigella sativa stimulates insulin secretion from isolated rat islets and inhibits the digestion and absorption of (CH2O)n in the gut.

Nigella sativa seeds are traditionally reputed as possessing anti-diabetic properties. As a result, we aim to explore the mechanism of its anti-hyperglycemic activity. The present study uses various experimental designs including gastrointestinal (GI) motility, intestinal disaccharidase activity and inhibition of carbohydrate digestion and absorption in the gut. The animals used as type 2 diabetic models were induced with streptozotocin to make them as such. Oral glucose tolerance test was performed to confirm that the animals were indeed diabetic. The extract reduced postprandial glucose, suggesting it interfered with glucose absorption in the gut. It also improved glucose (2.5g/kg, b/w) tolerance in rats. Furthermore, treatment with N. sativa produced a significant improvement in GI motility, while reduced disaccharidase enzyme activity in fasted rats. The extract produced a similar effect within an acute oral sucrose (2.5g/kg, b/w) load assay. Following sucrose administration, a substantial amount of unabsorbed sucrose was found in six different parts of the GI tract. This indicates that N. sativa has the potentiality to liberate GI content and reduce or delay glucose absorption. A potential hypoglycemic activity of the extract found in insulin release assay, where the extract significantly improved insulin secretion from isolated rat islets. These concluded present findings give rise to the implication that N. sativa seeds are generating postprandial anti-hyperglycemic activity within type 2 diabetic animal models via reducing or delaying carbohydrate digestion and absorption in the gut as well as improving insulin secretion in response to the plasma glucose.

MODERN ASPECTS OF SUGAR-REDUCING EFFECT OF THICK BEAN EXTRACT BASED ON A TYPE II DIABETES MODEL ON THE BACKGROUND OF OBESITY.

There have been presented the results of the histomorphological research of the effect of the beans' thick extract (BTE) on the state of the pancreas on the model of diabetes mellitus type 2 on the background of obesity in the rats in our research. The simulation of type 2 diabetes on the background of obesity in the animals has led to the development of signs of insulin's inhibition of insulin producing apparatus - some different expressions of dystrophy and degeneration of the ß-cells. The consequence of the hyperfunction has been exhaustion and even death of ß-cells, the development of the diabetic condition. The redistribution of pancreatic islet ß-content of cells has contributed to the increase of the small islands and had a compensatory nature. The treatment of the animals by the BTE has fully prevented an excessive negative impact on revenues of carbohydrates insulin producing apparatus, because it improves the morphological status of ß-cells, reduces the part of small pancreatic islets, almost restores medium and large islets to the level of the «Intact control¼ group. The comparison drug - metformin - has a positive effect on the morphological status of the pancreatic ß-cells, but this effect is obviously not enough for improving or restoring the normal % of distribution of islets.

Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines.

BACKGROUND: Type 1 diabetes is an autoimmune disease directed to the pancreatic islets where inflammation leads to the death of insulin-producing ß cells and insulin deficiency. Type 2 diabetes, which is closely related to overweight, is characterized by insulin resistance. In both cases, proinflammatory cytokines play an important role by causing insulitis and insulin resistance. The gum resin of Boswellia species and its pharmacologically active compounds, including 11-keto-ß-boswellic acids have been shown to suppress the expression of proinflammatory cytokines in various immune-competent cells. PURPOSE: To review the present evidence of the therapeutic effects of boswellic extracts (BE) and/or 11-keto-ß-boswellic acids in the prevention/treatment of diabetes mellitus and to provide comprehensive insights into the underlying molecular mechanisms. METHODS: This review considers all available informations from preclinical and clinical studies concerning BEs, 11-keto-ß-boswellic acids, proinflammatory cytokines and diabetes mellitus collected via electronic search (PubMed) and related publications of the author. RESULTS: Type 1 diabetes: Studies in mice with autoimmune diabetes revealed that in the model of multiple injections of low doses of streptozotocin (MLD-STZ), an extract of the gum resin of Boswellia serrata and 11-keto-ß-boswellic acid (KBA) suppressed the increase in proinflammatory cytokines in the blood, infiltration of lymphocytes into pancreatic islets and increase in blood glucose. In a second model, i.e. the nonobese diabetic (NOD) mouse, KBA prevented the infiltration of lymphocytes into pancreatic islets. Regarding the clinical effects, a case report provided evidence that BE suppressed the blood levels of tyrosine phosphatase antibody (IA2-A), a marker for insulitis, in a patient with late-onset autoimmune diabetes of the adult (LADA). Type 2 diabetes: In a preclinical study in rats where obesity was alimentary induced, the administration of BE significantly reduced food intake, overweight, proinflammatory cytokines such as interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) and ameliorated the parameters of glucose and lipid metabolism. Similar results were obtained in a second animal study, where type 2 diabetes was induced by a combination of a high-fat/high-fructose diet and a single dose of streptozotocin. Two clinical trials with patients with type 2 diabetes receiving the resin of Boswellia serrata demonstrated improvement in the blood glucose, HbA1c and lipid parameters. CONCLUSION: Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required.

Hibiscus sabdariffa renews pancreatic ß-cells in experimental type 1 diabetic model rats.

This study evaluated the antidiabetic potentials of flavonoid-rich aqueous fraction of methanolic extract of Hibiscus sabdariffa calyx (HSCE) on the pancreatic ß-cells of experimental type I diabetic model rats. Type 1 diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of 80mg/kg b/w streptozotocin (STZ) dissolved in 0.1M citrate buffer (pH 6.3). The rats were divided into five groups (n=12) including normal control group, test group I, diabetic negative control, test group II, and diabetic positive control. The test groups received 1.75g/kg b/w of HSCE by gavage for 15 days. Animals were sacrificed; the splenic portion of their pancreas and serum were evaluated for histopathological and biochemical parameters respectively. The regenerative effects of the extract on STZ-diabetes ß-cells damage was evident from the results of the histopathological analysis and the biochemical parameters evaluated in the serum. Reduced levels of glutathione, catalase and superoxide dismutase in the serum of diabetic rats were significantly improved in the H. sabdariffa-treated rats (P<0.05). Histological examination of pancreatic islet sections revealed degenerative and necrotic changes (D) in the pancreatic islet of Langerhans, ß-cell degranulation, pyknotic ß-cell nuclei, decreased islet cellular density, and severe vacuolation (V) in the islet of STZ-diabetic negative control group. The morphology of the pancreas of HSCE-treated diabetic rats (test group II) revealed remarkable improvements in the islet of Langerhans. Stereological studies also revealed that HSCE-treatment remarkably improved volume of the pancreatic islets and the numerical density of ß-cell (number of ß-cells per unit area of islet) depleted by STZ diabetes. The study concluded that possible antidiabetic mechanism of Hibiscus sabdariffa in STZ diabetes is through induction of ß-cell regeneration and its strong antioxidant potential.

Astragalin augments basal calcium influx and insulin secretion in rat pancreatic islets.

Astragalin is a flavonol glycoside with several biological activities, including antidiabetic properties. The objective of this study was to investigate the effects of astragalin on glycaemia and insulin secretion, in vivo, and on calcium influx and insulin secretion in isolated rat pancreatic islets, ex vivo. Astragalin (1 and 10 mg / kg) was administered by oral gavage to fasted Wistar rats and serum glucose and plasma insulin were measured. Isolated pancreatic islets were used to measure basal insulin secretion and calcium influx. Astragalin (10 mg/ kg) decreased glycaemia and increased insulin secretion significantly at 15-180 min, respectively, in the glucose tolerance test. In isolated pancreatic cells, astragalin (100 µM) stimulated calcium influx through a mechanism involving ATP-dependent potassium channels, L-type voltage-dependent calcium channels, the sarcoendoplasmic reticulum calcium transport ATPase (SERCA), PKC and PKA. These findings highlight the dietary coadjuvant, astragalin, as a potential insulin secretagogue that may contribute to glucose homeostasis.

Antidiabetic Effects of a Short Peptide of Potato Protein Hydrolysate in STZ-Induced Diabetic Mice.

Alcalase- generated potato protein hydrolysate (APPH) is a potential bioactive peptide against diabetes mellitus (DM) and DM-associated secondary effects in animal models. The aim of the present study was to find the efficiency of a deca-peptide DIKTNKPVIF (DF) from APPH against DM. Six-week-old male ICR mice were divided into the following groups: Control, Control+DF (received 50 mg/kg DF), streptozotocin (STZ)-induced DM group, DM+Acarbose group (20 mg/kg of acarbose), DM+DF-L (25 mg/kg of DF), DM+DF-H (50 mg/kg of DF), and DM+APPH (50 mg/kg of APPH). Comparable to APPH, treatment with DF effectively regulated blood glucose level and also controlled plasma total glycerol (TG), total cholesterol (TC), insulin, and HbA1c levels in DM animals. DF treatment also showed evidence of ameliorating DM-associated damages in the pancreatic islets and in the liver, heart, and kidney tissues. Therefore, the results demonstrate that the short synthetic peptide-DF may effectively provide protection against DM-associated damages.

Synergistic Effect of Two Major Components of Malva verticillata in the Recovery of Alloxan-Damaged Pancreatic Islet Cells in Zebrafish.

Malva verticillata (Chinese mallow) has long been used in traditional medicines and herbal teas in Asia. The n-BuOH fraction (Fr) from M. verticillata promoted significant recovery of alloxan-damaged (AXD) pancreatic islets (PIs) in zebrafish (ZF). Two major components were isolated from M. verticillata through repeated-column chromatography. Based on several spectroscopic methods, including nuclear magnetic resonance (NMR), infrared spectroscopy (IR), and fast atom bombardment-mass spectrometry (FAB-MS), the chemical structures of compounds 1 and 2 were determined. In addition, the quantity of both compounds in the n-BuOH Fr was investigated through high-performance liquid chromatography (HPLC) and the quantities of compounds 1 and 2 in the n-BuOH Fr were determined to be 5.58% ± 0.16% and 2.85% ± 0.13%, respectively. The n-BuOH Fr, compounds 1 and 2, and the mixture of compounds 1 and 2 (MX, 1 and 2, the ratio of both compounds in n-BuOH Fr, 1.96:1) were evaluated for their ability to recover AXD PIs and for their KATP channel-blocking mechanism using diazoxide in ZF. The n-BuOH Fr (10 µg/mL) and compounds 1 and MX (1 µg/mL) exhibited a recovery effect on AXD PIs. The n-BuOH Fr (10 µg/mL) and MX (1 µg/mL) were also confirmed to be useful KATP channel activators. A synergistic effect of MX in the recovery of AXD PIs was first confirmed in ZF, and it was discovered that 2 acted as an insulin sensitivity activator that increased the activity of compound 1.

Primary study on the hypoglycemic mechanism of 5rolGLP-HV in STZ-induced type 2 diabetes mellitus mice.

5rolGLP-HV is a promising dual-function peptide for the treatment of diabetes and thrombosis simultaneously. For investigating the therapeutic mechanism of 5rolGLP-HV for type 2 diabetes mellitus (T2DM), STZ-induced diabetic mice were established and treated with 5rolGLP-HV. The results showed that daily water and food intake, blood glucose, serum and pancreatic insulin levels significantly decreased after 5rolGLP-HV treatment with various oral concentrations, and 16 mg/kg was the optimal dose for controlling diabetes. 5rolGLP-HV treatment decreased the MDA levels and the T-SOD activity in serum and pancreatic of diabetic mice (but not up to significant difference), and significantly increased the expression of signal pathways related genes of rolGLP-1, also the density of insulin expression and the numbers of apoptosis cells in islets of diabetic mice were significantly decreased in comparison to the negative diabetic mice. These effects above may be clarified the hypoglycemic mechanisms of 5rolGLP-HV, and 5rolGLP-HV may be as a potential drug for diabetes in future.

Grape seed extract effects on serum amylase levels and immunohistochemical alterations in Streptozotocin-induced diabetic rats.

In this study, serum amylase activity and structural changes of the pancreatic tissue in rats under the effects of grape seed extract were investigated. Thirty-two female Wistar albino rats were divided into 4 groups. First one was the control group. The second group was the streptozotocin (STZ)-induced diabetes mellitus (DM) group (45 mg/kg), while the third group was the grape seed extract (GSE) group, where the GSE was administrated intragastrically for 20 days (at 0.6 ml/rat). Lastly, the fourth group was the diabetes mellitus+GSE (DM+GSE) group. Blood samples were taken and analyzed for amylase activity. Caspase 3 expressions were inspected with immunohistochemistry. Amylase levels in the diabetic group were found to be the lowest (794.00±44.85 U/L, p<0.001), while the GSE group had the highest value (1623.63±80.04 U/L, p<0.001) Number of apoptotic cells was increased in Langerhans islets of the diabetic group. In the control and GSE groups, the apoptotic cells were found to be almost entirely absent. Increased number of apoptotic cells was found in the DM group, while decreased number of apoptotic cells was found in the DM+GSE group. Furthermore, atrophy in Langerhans islets, hyperemia in capillary veins, hydropic degeneration and necrosis in islet cells were determined in the diabetic group. Only mild hydropic degeneration in islet cells of Langerhans was observed in the DM+GSE group. Histopathologically beneficial changes in the pancreases were detected when grape seed extract was given to diabetic rats. As a conclusion, GSE was determined to have positive effects on the function and structure of the pancreas, improving enzyme activities and the structure of the Langerhans islets.

Diet-induced glucose homeostasis dysregulation is enhanced by taurine supplementation in ovariectomized mice.

Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic ß cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low.

Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models.

Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.