Central visfatin potentiates glucose-stimulated insulin secretion and β-cell mass without increasing serum visfatin levels in diabetic rats

IntroductionOur previous study revealed that plasma visfatin levels were lower in pregnant women with gestational diabetes (GDM) than non-GDM independent of prepreganacy BMI. We examined whether central visfatin modulates energy and glucose homeostasis via altering insulin resistance, insulin secretion or islet morphometry in diabetic rats.MethodsPartial pancreatectomized, type 2 diabetic, rats were interacerbroventricularly infused with visfatin (100 ng/rat/day, Px-VIS), visfatin + visfatin antagonist, CHS-828 (100 μg/rat/day, Px-VIS-ANT), or saline (control, Px-Saline) via osmotic pump, respectively, for 4 weeks.ResultsCentral visfatin improved insulin signaling (pAkt → pFOXO-1) but not pSTAT3 in the hypothalamus. Central visfatin did not alter serum visfatin levels in diabetic rats whereas the levels were higher in non-diabetic rats than diabetic rats. Body weight at the 2nd week was lowered in the Px-VIS group due to decreased food intake in the first two weeks compared to the Px-Saline group and energy expenditure was not significantly different among the treatment groups of diabetic rats. Visfatin antagonist treatment nullified the central visfatin effect. Px-VIS increased whole body glucose disposal rates in euglycemic hyperinsulinemic clamp compared to Px-Saline and lowered hepatic glucose output, whereas Px-VIS-ANT blocked the visfatin effect on insulin resistance (P < 0.05). In hyperglycemic clamp study, the area under the curve of insulin in first and second phase were significantly higher in the Px-VIS group than the Px-Saline group without modifying insulin sensitivity at the hyperglycemic state, whereas the increase in serum insulin levels was blocked in the Px-VIS-ANT group. Central visfatin also increased β-cell mass by increasing β-cell proliferation.ConclusionsCentral visfatin improved glucose homeostasis by increasing insulin secretion and insulin sensitivity at euglycemia through the hypothalamus in diabetic rats. Therefore, visfatin is a positive modulator of glucose homeostasis by delivering the hypothalamic signals into the peripheries.     

Zinc and N-acetylcysteine modify mercury distribution and promote increase in hepatic metallothionein levels

This study investigated the ability of zinc (Zn) and N-acetylcysteine (NAC) in preventing the biochemical alterations caused by mercury (Hg) and the retention of this metal in different organs. Adult female rats received ZnCl₂ (27 mg/kg) and/or NAC (5 mg/kg) or saline (0.9%) subcutaneously and after 24 h they received HgCl₂ (5 mg/kg) or saline (0.9%). Twenty-four hours after, they were sacrificed and analyses were performed. Hg inhibited hepatic, renal, and blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, decreased renal total thiol levels, as well as increased serum creatinine and urea levels and aspartate aminotransferase activity. HgCl₂-exposed groups presented an important retention of Hg in all the tissues analyzed. All pre-treatments demonstrated tendency in preventing hepatic δ-ALA-D inhibition, whereas only ZnCl₂ showed this effect on blood enzyme. Moreover, the combination of these compounds completely prevented liver and blood Hg retention. The exposure to Zn and Hg increased hepatic metallothionein levels. These results show that Zn and NAC presented promising effects against the toxicity caused by HgCl₂.     

Increased whole blood manganese concentrations observed in children with iron deficiency anaemia

A prospective observational study was carried out at Alder Hey Children's Hospital, Liverpool, England, UK on children aged 1–6 years attending the pathology department for routine blood tests (n = 225). Whole blood manganese concentrations were measured plus the following markers of iron status; haemoglobin, MCV, MCH, RBC count, ferritin, transferrin saturation and soluble transferrin receptors. Multiple regression analysis was performed, with blood manganese as the dependent variable and factors of iron status, age and gender as independent variables. A strong relationship between blood manganese and iron deficiency was demonstrated (adjusted R² = 34.3%, p < 0.001) and the primary contributing factors to this relationship were haematological indices and soluble transferrin receptors. Subjects were categorised according to iron status using serum ferritin, transferrin saturation and haemoglobin indices. Children with iron deficiency anaemia had higher median blood manganese concentrations (16.4 μg/L, range 11.7–42.4, n = 20) than children with iron sufficiency (11 μg/L, range 5.9–20.9, n = 59, p < 0.001). This suggests that children with iron deficiency anaemia may be at risk from manganese toxicity (whole blood manganese >20 μg/L), and that this may lead to neurological problems. Treatment of iron deficiency in children is important both to improve iron status and to reduce the risk of manganese toxicity.     

High iron level in early pregnancy increased glucose intolerance

High iron stores in pregnancy are essential in preventing negative outcomes for both infants and mothers; however the risk of gestational diabetes mellitus (GDM) might also be increased. We intend to study the relationship between increased iron stores in early pregnancy and the risk of glucose intolerance and GDM. This prospective, observational, single-hospital study involved 104 non-anemic pregnant women, divided into 4 groups based on the quartile values for ferritin at the first trimester of pregnancy. All participants were screened for GDM with 75-g oral glucose tolerance test (OGTT) at 24–28 weeks’ gestation. We observed that ferritin levels at early pregnancy were significantly correlated to glucose level after OGTT at 1-h and 2-h (rho = 0.21, p < 0.05; rho = 0.43, p < 0.001 respectively). Furthermore, in the higher quartile for ferritin (>38.8 μg/L) glycemia at 2-h OGTT was significantly higher than in the others quartiles (p = 0.002). In multivariate regression analysis, serum ferritin was a significant determinant of glycemia at 2-h OGTT. Although we did not find a significant association in the incidence of GDM in women with higher serum ferritin levels, probably in reason to the limit power of our study, our data demonstrated that the role of iron excess is tightly involved in the pathogenesis of glucose intolerance. We report for the first time that high ferritin values in early pregnancy are predictors of impaired glucose tolerance in non-anemic women. Individual iron supplementation should be evaluated in order to minimize glucose impairment risk in women with high risk of diabetes.     

Effects of Canarium odontophyllum leaves on plasma glucose and T lymphocyte population in streptozotocin-induced diabetic rats

Type 1 diabetes mellitus is a chronic disease characterized by lack of insulin production. Immune mechanisms are implicated in the pathogenesis of Type 1 diabetes. Canarium odontophyllum (CO) fruits and leaves have been shown to possess high antioxidant activity. This study was conducted to evaluate the effects of CO leaves aqueous extract on the blood glucose and T lymphocyte population in the spleen of streptozotocin (STZ)-induced diabetic rats. Nineteen male Sprague–Dawley rats were randomly divided into three groups: normal, diabetic control and CO treated diabetic groups. Diabetes was induced by a single intraperitoneal injection of 65 mg STZ/kg body weight. The extract of CO leaves was administered orally by force feeding daily at the dose of 300 mg/kg for 28 days. The rats were sacrificed at the end of the study and the spleen was harvested for flow cytometry analysis. The results showed a significant decrease in body weight of diabetic and CO treated diabetic groups compared with the normal group (p < 0.05). The fasting blood glucose level of CO treated diabetic group was significantly lower than the diabetic group (p < 0.05). Diabetic and CO treated diabetic groups showed a significant increase in the percentage of spleen CD3⁺ CD4⁺ T lymphocytes (p < 0.05) when compared with the normal group. However, there was no significant difference in the percentage of spleen CD3⁺ CD8⁺ T lymphocytes among all experimental groups. The finding suggested that an aqueous extract of CO leaves has the ability to reduce blood glucose levels in diabetic rats.     

Short repeats in the heme oxygenase 1 gene promoter is associated with increased levels of inflammation,ferritin and higher risk of type-2 diabetes mellitus

ObjectiveWe evaluated the relationship between the HO1 genotype, ferritin levels and the risk of type-2 diabetes and inflammation.Research methodsEight hundred thirty-five individuals were evaluated and classified according to their nutritional status and the presence of type-2 diabetes: 153 overweight (OW); 62 obese (OB); 55 type-2 diabetes mellitus (DM); 202 OWDM; 239 OBDM and 124 controls (C). We studied biochemical (glycemia, insulin, lipid profile, liver enzyme, creatinine, hsCRP), hematological (hemoglobin, free erythrocyte protoporphyrin, transferrin receptor and serum Fe and ferritin) and oxidative stress (SOD, GHS and TBARS) parameters. We determined heme oxygenase activity and the (GT)_n polymorphism in its gene promoter.ResultsIndividuals with diabetes, independent of nutritional status, showed high levels of ferritin and HO activity compared to control subjects. Allelic frequency was not different between the groups (Chi², NS) however, genotypes were different (Chi², P < 0.001). The SS (short-short) genotype was higher in all DM individuals compared to controls and MM was higher in controls. SM (short-medium) genotype was an independent risk factor for DM in logistic regression analysis. We observed high risk for type-2 diabetes mellitus in the presence of SM genotype and high levels of ferritin (OR adjusted: 2.7; 1.9–3.6; p < 0.001; compared to control group). It was also significantly related to inflammation.ConclusionThe SM genotype in HO1 gene promoter and ferritin levels were associated with higher risk for type-2 diabetes and for having a higher marker of inflammation, which is the main risk factor for the development of chronic diseases.     

Efficacy of natural diosgenin on cardiovascular risk,insulin secretion,and beta cells in streptozotocin (STZ)-induced diabetic rats

Costus igneus, has been prescribed for the treatment of diabetic mellitus in India for several years. The aim of this study is to investigate the effects of plant derived diosgenin on cardiovascular risk, insulin secretion, and pancreatic composition through electron microscopical studies of normal and diabetic rats. Diosgenin at a dose of 5 or 10 mg/kg per body weight (bw) was orally administered as a single dose per day to diabetic induced rats for a period of 30 days. The effect of diosgenin on blood glucose, HbA1c, PT, APTT, Oxy-LDL, serum lipid profile, electron microscopical studies of pancreas, antioxidant enzymes (in liver, kidney, pancreas) and hepatoprotective enzymes in plasma and liver were measured in normal and diabetic rats. The results showed that fasting blood glucose, PT, APTT, Oxy-LDL, TC, TG, LDL, ALT, AST, ALP, glucose-6-phosphatase, fructose-1,6-bisphosphatase and LPO levels were significantly (p < 0.05) increased, whereas HDL, SOD, CAT, GSH and the glycolytic enzyme glucokinase levels were significantly (p < 0.05) decreased in the diabetes induced rats and these levels were significantly (p < 0.05) reversed back to normal in diabetes induced rats after 30 days of treatment with diosgenin. Electron microscopical studies of the pancreas revealed that the number of beta cells and insulin granules were increased in streptozotocin (STZ) induced diabetic rats after 30 days of treatment with diosgenin. In conclusion, the data obtained from the present study strongly indicate that diosgenin has potential effects on cardiovascular risk, insulin secretion and beta cell regeneration in STZ induced diabetic rats, these results could be useful for new drug development to fight diabetes and its related cardiovascular diseases.     

Chronic insulin infusion induces reversible glucose intolerance in lean rats yet ameliorates glucose intolerance in obese rats

BackgroundAlthough insulin resistance (IR) is a key factor in the pathogenesis of type 2 diabetes (T2D), the precise role of insulin in the development of IR remains unclear. Therefore, we investigated whether chronic basal insulin infusion is causative in the development of glucose intolerance.MethodsNormoglycemic lean rats surgically instrumented with i.v. catheters were infused with insulin (3 mU/kg/min) or physiological saline for 6 weeks. At infusion-end, plasma insulin levels along with glucose tolerance were assessed.ResultsSix weeks of insulin infusion induced glucose intolerance and impaired insulin response in healthy rats. Interestingly, the effects of chronic insulin infusion were completely normalized following 24 h withdrawal of exogenous insulin and plasma insulin response to glucose challenge was enhanced, suggesting improved insulin secretory capacity. As a result of this finding, we assessed whether the effects of insulin therapy followed by a washout could ameliorate established glucose intolerance in obese rats. Obese rats were similarly instrumented and infused with insulin or physiological saline for 7 days followed by 24 h washout. Seven day-insulin therapy in obese rats significantly improved glucose tolerance, which was attributed to improved insulin secretory capacity and improved insulin signaling in liver and skeletal muscle.ConclusionModerate infusion of insulin alone is sufficient to cause glucose intolerance and impair endogenous insulin secretory capacity, whereas short-term, intensive insulin therapy followed by insulin removal effectively improves glucose tolerance, insulin response and peripheral insulin sensitivity in obese rats.General significanceNew insight into the link between insulin and glucose intolerance may optimize T2D management.     

The roles of aerobic exercise training and suppression IL-6 gene expression by RNA interference in the development of insulin resistance

ObjectiveTo demonstrate the hypothesis that aerobic exercise training inhibits the development of insulin resistance through IL-6 and probe into the possible molecular mechanism about it.MethodsRats were raised with high-fat diets for 8 weeks to develop insulin resistance, and glucose infusion rates (GIRs) were determined by hyperinsulinemic–euglycemic clamping to confirm the development of insulin resistance. Aerobic exercise training (the speed and duration time in the first week were respectively 16 m/min and 50 min, and speed increased 1 m/min and duration time increased 5 min every week following it) and/or IL-6shRNA plasmid injection (rats received IL-6shRNA injection via the tail vein every two weeks) were adopted during the development of insulin resistance. The serum IL-6, leptin, adiponectin, fasting blood glucose, fasting serum insulin, GIR, IL-6 gene expression levels, p-p38 in various tissues and p-STAT3/t-STAT3 ratio in the liver were measured.ResultsRats fed with high-fat diets for 8 weeks were developed insulin resistance and the IL-6mRNA levels of IL-6shRNA injection groups in various tissues were significantly lower than those of control group (P < 0.05), respectively. The development of insulin resistance in exercise rats significantly decreased, however, compared with that, the GIR of exercise rats injected by IL-6shRNA was lower (P < 0.05). The IL-6mRNA levels were highest in the fat tissue and lowest in the skeletal muscles in all the rats. The serum adiponectin levels decreased (P < 0.05) following the development of insulin resistance, and it increased (P < 0.05) when the rats were intervened by aerobic exercise training for 8 weeks at the same time. However, there were not significant differences when serum leptin concentrations were compared (P > 0.05). The p-p38 significantly increased in the rats fed with high-fat diets, however, p-p38 of the exercise high-fat diets rats in the liver and fat tissues significantly decreased than that (P < 0.05). The changes of p-p38 in exercise rats injected by IL-6shRNA were irregular. The activation of STAT3 in the liver significantly increased (P < 0.05) following the development of insulin resistance, and it decreased (P < 0.05) when the rats were intervened by aerobic exercise training for 8 weeks at the same time, and the gene silencing of IL-6 did not have effects on the activation of STAT3 in the liver (P > 0.05).ConclusionsIn conclusion, aerobic exercise training prevented the development of insulin resistance through IL-6 to a certain degree. The gene expression and secretion of IL-6 could inhibit the development of insulin resistance. The mechanism of the effects were possibly related with elevating the levels of serum adiponectin, and/or inhibiting the activation of STAT3 in the liver and p38MAPK in the skeletal muscles, liver and fat tissues.     

Anti-diabetic effect of a novel N-Trisaccharide isolated from Cucumis prophetarum on streptozotocin–nicotinamide induced type 2 diabetic rats

Ethnopharmacological relevanceCucumis prophetarum (L.) is used in traditional Indian medicine for the treatment of inflammation related problems.Aim of the studyThe present investigation was designed to study the effect of N-Trisaccharide (a new compound isolated from the fruit of C. prophetarum (L.)) on hyperglycemia in streptozotocin (STZ)–nicotinamide (NA) induced type 2 diabetic rats.Materials and methodsDifferent doses of N-Trisaccharide (25 and 50 mg/kg b.w.) were administered once daily for 28 days to STZ–NA induced diabetic rats. Plasma insulin and glycogen levels were measured. The activities of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase were measured. Further, histological studies on pancreas were also carried out.ResultsThe active compound at doses of 25 and 50 mg/kg b.w. given orally for 14 days showed 47.7% and 69.3% antihyperglycemic activity, respectively. Treatment at the same doses for 28 days provided complete protection against STZ–NA challenge (65 and 230 mg/kg b.w., respectively), intraperitoneally. N-Trisaccharide significantly (p ≤ 0.05) increased the plasma insulin and liver glycogen levels in diabetic rats. The altered enzyme activities of carbohydrate metabolism in the liver and kidney of the diabetic rats were significantly (p ≤ 0.05) improved. Additionally, N-Trisaccharide increased glycogen synthase and decreased glycogen phosphorylase activity in diabetic rats. Histological studies confirmed an increase in insulin level is due to stimulation of injured pancreatic β-cells.ConclusionThe results of the study suggested that N-Trisaccharide possesses propitious effect on STZ–NA induced type 2 diabetes, indicating its usefulness in diabetes management.     

Ameliorative effect of 20-OH ecdysone on streptozotocin induced oxidative stress and β-cell damage in experimental hyperglycemic rats

The present study was to evaluate the effects of 20-OH ecdysone on hyperglycemia mediated oxidative stress in streptozotocin induced diabetic rats. Diabetes was induced in experimental rats by single intraperitoneal injection of STZ (45 mg/kg b.w.) dissolved in 0.1 mol/L citrate buffer (pH 4.5). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and the levels of non-enzymic antioxidants vitamin C, vitamin E and reduced glutathione (GSH) were decreased while increases in the levels of LPO markers were observed in liver and kidney tissues of diabetic rats. Moreover, hepatic markers (aspartate aminotransferase and alanine aminotransferase) and renal markers (urea, creatinine) were significantly increased in diabetic rats as compared to control rats. Upon treatment with 20-OH ecdysone to diabetic rats showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. These results indicated that 20-OH ecdysone exerts a protective action on pancreatic beta cell function and overcomes oxidative stress through its hypoglycemic potential. The effect produced by the 20-OH ecdysone on various parameters was comparable to that of glibenclamide – an antidiabetic drug.     

Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase,phosphoenolpyruvate carboxykinase,and GLUT4 translocation in experimental diabetic rats

Diabetes mellitus is a chronic metabolic disorder affecting about 6% of population worldwide with its complications and is rapidly reaching epidemic scale. Cinnamomum zeylanicum is widely used in alternative system of medicine for treatment of diabetes. In the present study, we have performed bioassay guided fractionation of chloroform extract of C. zeylaniucm and identified cinnamaldehyde (CND) as an active principle against diabetes. In continuation to it, a detailed study was undertaken to elucidate its mode of antidiabetic action in STZ induced diabetic rats. Oral administration of CND (20 mg/kg bw) to diabetic rats for 2 months showed significant improvement (p < 0.001) in muscle and hepatic glycogen content. In vitro incubation of pancreatic islets with CND enhanced the insulin release compared to glibenclamide. The insulinotropic effect of CND was found to increase the glucose uptake through glucose transporter (GLUT4) translocation in peripheral tissues. The treatment also showed a significant improvement in altered enzyme activities of pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) and their mRNA expression levels.Furthermore, the median lethal dose (LD₅₀) of CND could not be obtained even at 20 times (0.4 g/kg bw) of its effective dose. With the high margin of safety of CND, it can be developed as a potential therapeutic candidate for the treatment of diabetes.     

Insulin mimetic impact of Catechin isolated from Cassia fistula on the glucose oxidation and molecular mechanisms of glucose uptake on Streptozotocin-induced diabetic Wistar rats

Diabetes mellitus is the most common and serious metabolic disorder among people all over the world. Many plants have successfully been used to overcome this problem. Cassia fistula, an ethnomedicnal plant, is widely used in Indian medicine to treat diabetes. Methanol extract of stem of plant, reduced the blood glucose levels in Streptozotocin-induced diabetic rats. Bioassay guided fractionation was followed to isolate Catechin from methanol extract. Catechin was administered to Streptozotocin (60 mg/kg b.w.)-induced diabetic male Wistar rats at different doses (5, 10, 20 mg/kg b.w.) for 6 weeks to assess its effect on fasting plasma glucose. The plasma glucose was significantly (p<0.05) reduced when compared to the control. Oral administration of Catechin (20 mg/kg b.w.) markedly increased tissue glycogen, and ¹⁴C-glucose oxidation without any change in plasma insulin and C-peptide. Catechin restored the altered Glucokinase, glucose-6 Phosphatase, Glycogen Synthase and Glycogen Phosphorylase levels to near normal. GLUT4 mRNA and protein expression were enhanced after Catechin treatment. The results of this experimental study indicated that Catechin possesses hypo-glycemic, Glucose oxidizing and insulin mimetic activities and hence it could be used as a drug for treating diabetes.     

Oral Angiotensin-(1–7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet

Obesity is characterized by a pro-inflammatory state commonly associated with type 2 diabetes and fat-liver disease. In the last few years, different studies pointed out the role of Angiotensin (Ang)-(1–7) in the metabolic regulation. The aim of the present study was to evaluate the effect of oral-administration of Ang-(1–7) in metabolism and inflammatory state of high-fat feed rats. Twenty-four male Sprague Dawley rats were randomized into three groups: High Fat Diet (HFD); Standard Diet (ST); High Fat Diet + Angiotensin-(1–7) [HFD + Ang-(1–7)]. Glycemic profile was evaluated by glucose tolerance and insulin sensitivity tests, plasmatic glucose and insulin. Cholesterol, HDL and triglycerides analyses presented lipidic profile. RT-PCR evaluated mRNA expression to ACE, ACE2, resistin, TLR4, IL-6, TNF-α and NF-κB genes. The main results showed that oral Ang-(1–7) decreased body weight and abdominal fat-mass. In addition, HFD + Ang-(1–7) treated rats presented enhanced glucose tolerance, insulin-sensitivity and decreased plasma-insulin levels, as well as a significant decrease in circulating lipid levels. These alterations were accompanied by a marked decreased expression of resistin, TLR4, ACE and increased ACE2 expression in liver. Furthermore, Ang-(1–7) decreases phosphorylation of MAPK and increases NF-κB expression. These alterations diminished expression of interleukin-6 and TNF-α, ameliorate inflammatory state in liver. In summary, the present study showed that oral-treatment with Ang-(1–7) in high-fat feed rats improved metabolism down-regulating resistin/TLR4/NF-κB-pathway.     

Increased secretion of insulin and proliferation of islet β-cells in rats with mesenteric lymph duct ligation

Background &; aimsIt has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet β-cells in rats.MethodsMale Sprague–Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of β-cells was assessed immunohistochemically using antibodies against insulin and Ki-67.ResultsDuring the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p < 0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p < 0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p < 0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p < 0.05) and 120 min (2.5-fold; p < 0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2 min (more than 1.4-fold; p < 0.05). Immunohistochemistry showed that the ratios of β-cell area/acinar cell area and β-cell area/islet area, and also β-cell proliferation, were significantly higher in the ligation group than in the sham group (p < 0.05, p < 0.01 and p < 0.01, respectively). The insulin content per unit wet weight of pancreas was also significantly increased in the ligation group (p < 0.05).ConclusionsIn rats with ligation of the mesenteric lymph duct, insulin secretion during the OGTT or IVGTT was higher, and the insulin content and β-cell proliferation in the pancreas were also increased. Our data show that mesenteric lymph duct flow has a role in glucose metabolism.     

Hypoglycemic effect of aspalathin,a rooibos tea component from Aspalathus linearis,in type 2 diabetic model db/db mice

Effects of aspalathin, a green rooibos tea component, on glucose metabolism were studied in vitro and in vivo. We first examined the effect of aspalathin on glucose uptake by cultured L6 myotubes and on insulin secretion from cultured RIN-5F pancreatic β-cells in vitro, and then investigated the effect of dietary aspalathin on fasting blood glucose level and conducted an intraperitoneal glucose tolerance test (IPGTT) using type 2 diabetes model mice in vivo. Aspalathin dose-dependently and significantly increased glucose uptake by L6 myotubes at concentrations 1–100 μM. It also significantly increased insulin secretion from cultured RIN-5F cells at 100 μM. Dietary aspalathin (0.1–0.2%) suppressed the increase in fasting blood glucose levels of db/db mice for 5 weeks. In IPGTT, aspalathin improved impaired glucose tolerance at 30, 60, 90, and 120 min in db/db mice. These results suggest that aspalathin has beneficial effects on glucose homeostasis in type 2 diabetes through stimulating glucose uptake in muscle tissues and insulin secretion from pancreatic β-cells.     

The anti-diabetic effects of GLP-1-gastrin dual agonist ZP3022 in ZDF rats

Aims/hypothesisCombination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly diabetic Zucker Diabetic Fatty (ZDF) rats.MethodsZDF rats aged 11 weeks were dosed s.c., b.i.d. for 8 weeks with vehicle, ZP3022, liraglutide, exendin-4, or gastrin-17 with or without exendin-4. Glycemic control was assessed by measurements of HbA1c and blood glucose levels, as well as glucose tolerance during an oral glucose tolerance test (OGTT). Beta cell dynamics were examined by morphometric analyses of beta and alpha cell fractions.ResultsZP3022 improved glycemic control as measured by terminal HbA1c levels (6.2 ± 0.12 (high dose) vs. 7.9 ± 0.07% (vehicle), P < 0.001), as did all treatments, except gastrin-17 monotherapy. In contrast, only ZP3022, exendin-4 and combination treatment with exendin-4 and gastrin-17 significantly improved glucose tolerance and increased insulin levels during an OGTT. Moreover, only ZP3022 significantly enhanced the beta cell fraction in ZDF rats, a difference of 41%, when compared to the vehicle group (0.31 ± 0.03 vs. 0.22 ± 0.02%, respectively, P < 0.05).ConclusionThese data suggest that ZP3022 may have therapeutic potential in the prevention/delay of beta cell dysfunction in type 2 diabetes.     

Glucose acts as a regulator of serum iron by increasing serum hepcidin concentrations

Mutual clinical and molecular interactions between iron and glucose metabolism have been reported. We aimed to investigate a potential effect of glucose on iron homeostasis. We found that serum iron concentrations gradually decreased over 180 min after the administration of 75 g of glucose from 109.8±45.4 mg/L to 94.4±40.4 mg/L (P<.001; N= 40) but remained unchanged in control subjects receiving tap water (N= 21). Serum hepcidin, the key iron regulatory hormone which is mainly derived from hepatocytes but also expressed in pancreatic β-cells, increased within 120 min after glucose ingestion from 19.7±9.9 nmol/L to 31.4±21.0 nmol/L (P<.001). In cell culture, glucose induced the secretion of hepcidin and insulin into the supernatant of INS-1E cultures, but did not change the amount of hepcidin detectable in the hepatocyte cell culture HepG2. We additionally confirmed the expression of hepcidin in a human islet cell preparation. These results suggest that glucose acts as a regulator of serum iron concentrations, most likely by triggering the release of hepcidin from β-cells.     

Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression

Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n = 8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mg kg^?1 d^?1, p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n = 8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF-κB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-α, MCP-1 and ICAM-1 in kidney tissues. The α₁-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-α, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-κB mediated inflammatory genes expression.     

Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice

Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35 g/kg i.v.) and following glucose plus glucagon (10 μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20 min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC_0-20) compared to that with glucose alone (p < 0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4 ± 0.34 mL/min for glucose alone and 5.8 ± 1.5 mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.