Insulin Secretion In Diabetic Rats Research Articles

A review on the phytochemistry and biological activities of Curculigo latifolia Dryand ex. W.Aiton

Curculigo latifolia Dryand. ex W. T. Aiton, from the genus Curculigo, is a medicinal plant traditionally used to treat numerous illnesses such as fever, stomach aches, jaundice, wounds, and inflammation. C. latifolia is a perennial herb that is widely found in tropical and subtropical regions, such as Southeast Asia, Southern China, Bangladesh, Australia, and the Andaman Islands. This review collates the reported studies on the different aspects of C. latifolia from its plant description, nutritional value, phytochemistry, chemical composition, and pharmacological properties. This review aims to identify gaps in the literature and provide useful references for future work on this plant. Previous studies have shown that C. latifolia contains high mineral contents of calcium, iron, and magnesium, which are essential components of human health. Moreover, the plant is rich in phytochemicals, which play a prominent role in various pharmacological activities. The most common compounds identified included curculigoside, crassifoside I, nyasicoside, and curculigine. C. latifolia demonstrated high antioxidant activity through its ability to scavenge superoxide anions, 1,1–diphenyl–2–picrylhydrazyl (DPPH) and 2,2’-azino–bis(3–ethylbenzthiazoline–6–sulfonic acid) (ABTS) radicals, reducing ferric ions to ferrous complexes, iron chelation, and β –carotene bleaching. It was also shown that the roots, stems, and leaves of C. latifolia were effective in exerting antimicrobial activity against several microbial strains, including Bacillus cereus, Bacillus subtillis, Enterobacter aerogenes, Erwinia sp., Klebsiella sp., Pseudomonas sp., Candida albicans, Salmonella choleraesuis and Staphylococcus aureus. Moreover, the root, fruit, leaf, petiole, and rhizome extracts were found to improve glucose uptake and insulin secretion in diabetic rats, suggesting their antidiabetic potential. C. latifolia presents a wide range of medicinal properties that could make it a promising functional food or source of food supplements to prevent nutrition–related or chronic diseases.

Regulation of carbohydrate metabolism and insulin secretion in diabetic rats following treatment with Hypericum perforatum L. hairy root aqueous methanol extract

Hairy root (HR) cultures of Hypericum perforatum L. have shown promise in controlling hyperglycemia, regulating blood lipid and enzyme profiles, and improving metabolic function in vivo. These benefits are mainly attributed to the phenolic acids, flavonoids, and xanthones present in HR extracts. However, the specific mechanism underlying these effects remains unclear. This study was performed to elucidate the biochemical and molecular mechanisms driving HR the antihyperglycemic and antidiabetic effects of HR extracts. HR extract (200 mg/kg body weight) was administered daily for 14 days to healthy rats and rats with streptozotocin-induced diabetes, with glibenclamide serving as a positive control. The phenolic composition of the HR extracts was confirmed through high-performance liquid chromatography/diode array detection/electrospray ionization mass spectrometry (HPLC/DAD/ESI-MSn ) analysis. The results showed that HR extract treatment increased the plasma insulin level and pancreatic poly (adenosine diphosphate-ribose) polymerase (PARP) activity in diabetic rats, thus normalizing blood glucose levels. Additionally, it reduced the activity of gluconeogenic enzymes, increased the activity of glycolytic enzymes, and normalized the glycogen content in the liver. HR extract-treated rats also exhibited increased hepatic adenosine monophosphate-activated protein kinase (AMPK) mRNA expression and a decreased protein kinase Cε (PKCε) concentration. In conclusion, HR extract demonstrated insulinotropic effects and effectively regulated hepatic carbohydrate metabolism in diabetic rats by modulating AMPK expression and the PKCε concentration. These findings suggest the potential use of HR extract as an herbal medicine for diabetes treatment and a source of antidiabetic drug development.

A review on the phytochemistry and biological activities of Curculigo latifolia Dryand ex. W.Aiton

Curculigo latifolia Dryand. ex W. T. Aiton, from the genus Curculigo, is a medicinal plant traditionally used to treat numerous illnesses such as fever, stomach aches, jaundice, wounds, and inflammation. C. latifolia is a perennial herb that is widely found in tropical and subtropical regions, such as Southeast Asia, Southern China, Bangladesh, Australia, and the Andaman Islands. This review collates the reported studies on the different aspects of C. latifolia from its plant description, nutritional value, phytochemistry, chemical composition, and pharmacological properties. This review aims to identify gaps in the literature and provide useful references for future work on this plant. Previous studies have shown that C. latifolia contains high mineral contents of calcium, iron, and magnesium, which are essential components of human health. Moreover, the plant is rich in phytochemicals, which play a prominent role in various pharmacological activities. The most common compounds identified included curculigoside, crassifoside I, nyasicoside, and curculigine. C. latifolia demonstrated high antioxidant activity through its ability to scavenge superoxide anions, 1,1–diphenyl–2–picrylhydrazyl (DPPH) and 2,2’-azino–bis(3–ethylbenzthiazoline–6–sulfonic acid) (ABTS) radicals, reducing ferric ions to ferrous complexes, iron chelation, and B-carotene bleaching. It was also shown that the roots, stems, and leaves of C. latifolia were effective in exerting antimicrobial activity against several microbial strains, including Bacillus cereus, Bacillus subtillis, Enterobacter aerogenes, Erwinia sp., Klebsiella sp., Pseudomonas sp., Candida albicans, Salmonella choleraesuis and Staphylococcus aureus. Moreover, the root, fruit, leaf, petiole, and rhizome extracts were found to improve glucose uptake and insulin secretion in diabetic rats, suggesting their antidiabetic potential. C. latifolia presents a wide range of medicinal properties that could make it a promising functional food or source of food supplements to prevent nutrition–related or chronic diseases.

Semi-modified okara whey diet increased insulin secretion in diabetic rats fed a basal or high fat diet.

Lifestyle and diet preferences are primarily responsible for developing type 2 diabetes. In this study, okara was manufactured into okara whey crackers (OWC) to investigate its dietary role in controlling diabetes in streptozotocin-diabetic rats with and without a high-fat diet. Forty-eight rats were divided into eight groups. G1-G4 were nondiabetic and fed a basal diet, a basal diet with 30% crackers, high fat diet, and a high-fat diet with 30% crackers, respectively. G5-G8 were diabetic groups that received similar diets as previous groups. Blood glucose, liver function, lipid pattern, pancreas and liver histopathology, and insulin immunohistochemistry were performed. OWC improved measured parameters and histopathology of the liver and pancreas in diabetic rats. The area % of positive insulin cells was increased in G6 (5.20%) and G8 rats (2.83%) fed OWC compared to diabetic rats (1.17%). In conclusion, the use of 30% OWC in a semi-modified diet has controlled the hyperglycemia and hyperlipidemia associated with diabetes.

Orally deliverable nanoformulation of liraglutide against type 2 diabetic rat model

The present study was designed to evaluate the hypoglycemic effect of nanoparticle based drug delivery system of liraglutide loaded in Poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) upon oral delivery in experimentally induced type 2 diabetes mellitus in Wistar rats. NPs were synthesized using double emulsion solvent evaporation method. Physiochemical characterization of NPs revealed small particle size of 159.25 ± 24.46 nm with 75 ± 7.8% liraglutide encapsulation efficiency and 7 ± 1% as liraglutide loading efficiency. The NPs were also studied for in vitro release study and stability studies in various gastrointestinal fluid pH conditions which demonstrated the stability of NPs under these conditions. In-vivo model in wistar rats induced by high fat diet (HFD) along with Streptozotocin (STZ) were treated with liraglutide NPs for 8 weeks at two doses (75 and 150 μg/kg, orally). The rats were monitored for various biochemical and physiological parameters at regular intervals i.e. baseline before initiation of the experiment, at the 1st, 5th, and 9th week of STZ administration. Further in vivo study showed alleviation of HFD-STZ induced diabetes mellitus as evident from the reduction in biochemical parameters like blood glucose (both fasting and post prandial blood glucose), HbA1c, fructosamine levels, serum triglycerides, serum total cholesterol. Physiological parameters such as body weight and food intake were also in support of the data. Moreover, liraglutide NPs demonstrated hypoglycemic activity by significantly increasing the insulin secretion in diabetic rats. To the best of our knowledge, we for the first time proposing the orally deliverable NPs of liraglutide that ameliorates HFD-STZ induced diabetes mellitus effectively as compared to conventional liraglutide.

Assessing of Antidiabetic and Ameliorative Effect of<i> </i>Lupin Seed Aqueous Extract on Hyperglycemia, Hyperlipidemia and Effect on pdx1, Nkx6.1, Insulin-1, GLUT-2 and Glucokinase Genes Expression in Streptozotocin-induced Diabetic Rats

Diabetes mellitus (DM) belong to the major health problems causing mortality and morbidity in the world. Our study aimed to investigate effects of Lupinus Albus (LA) seed extract on streptozotocin (STZ)-induced diabetic rats. Thirty mature Sprague Dawley male rats were used in this study. Three experimental groups were used as follows: GI- Control rats (Normal), GII- Diabetic rats and GIII- Diabetic rats treated with LA aqueous extract (7mg/100g B.wt) by oral gavage. Insulin, Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c) and serum lipid profile assays of all rats were carried out. Gene expressions of Pancreatic and duodenal homeobox 1 (Pdx-1), homeobox protein (Nkx6.1), insulin-1, liver glucose transporter-2 (GLUT-2) and glucokinase were performed by real-time PCR. Results obtained for diabetic rats orally gavage with LA extract revealed an improvement in insulin with reduction in FBG, HbA1c% and significant improvement in serum lipid profile. Additionally, LA aqueous extract induced a mild increase in expression of biomarkers genes for pancreatic βeta cells (β-cells) function, insulin secretion, liver GLUT-2 and glucokinase when compared to STZ-diabetic rats. This research highlights LA seed extract as a nutraceutical for improving insulin secretion in diabetic rats.

Probiotic Lactobacillus gasseri SBT2055 improves insulin secretion in a diabetic rat model

The probiotic Lactobacillus gasseri SBT2055 (LG2055) has a protective effect against metabolic syndrome in rats and humans. Metabolic syndrome increases the risk of type 2 diabetes mellitus. In this study, Goto-Kakizaki rats were used as a diabetic model and fed diets containing LG2055-fermented or nonfermented skim milk for 4 wk. Indices of diabetes such as blood glucose levels, serum glucagon levels, plasma levels of insulin, C-peptide, and glucagon-like peptide-1, tissue glycogen contents, and pancreatic mRNA levels were measured. The plasma C-peptide levels and pancreatic mRNA levels of insulin genes (Ins1 and Ins2) and Pdx1 (a transcriptional factor of insulin genes) were increased in LG2055 diet-fed rats. The increase in insulin secretion corresponded to an improvement in serum and pancreatic inflammatory status, associated with decreases in serum levels of serum amyloid P and pancreatic levels of granulocyte colony-stimulating factor. Insulin resistance in Goto-Kakizaki rats was ameliorated by increased glycogen storage in the liver and quadriceps femoris muscles and decreased serum free fatty acid levels. This improvement may be related to the increased cecal production of short-chain fatty acids. In conclusion, dietary LG2055 improved insulin secretion in diabetic rats by improving the inflammatory status in the pancreas and serum.

Identification and preparation of a glycol-protein fraction AN from tea extracts and its in vivo and in vitro anti-hyperglycosemia activity

The present study compared active ingredients of tea from different sources to select tea type and the fraction of tea extracts for the highest anti-hyperglycemic activity, and to verify anti-hyperglycemic activity of the selected tea extract. Tea extracts were separated and enriched by molecular weight using ultra-filtration technology. The extracts were first screened by α-glucosidase inhibition assay, followed by using a rat inverted intestine sac system to measure the effect on glucose transport. Both alloxan-induced diabetic rat model and high-fat diet combined with streptozotocin-induced rat diabetes mellitus model were used to study the effects of active components on blood glucose, body weight, insulin resistance. The experimental results showed that the different kinds of tea extracts had different inhibitory effects on α-glucosidase, and the inhibitory effect of tea extract E on α-glucosidase was stronger. The effects of different components of tea extract E also varied greatly, of which Fraction AN protein had stronger inhibitory effect on α-glucosidase than other fragments, and Fraction AN protein had a strong inhibitory effect on glucose transport, reduced blood sugar and normalized insulin secretion in diabetic rats. The results suggest that a glycol-protein fraction(AN) from the extracts might be responsible for the anti-hyperglycemic activity of tea polysaccharides. The AN glycol-protein fraction has strong inhibitory effects on both α-glucosidase activity and glucose transport by the small intestine. It also reduced blood glucose level and normalized insulin secretion in diabetic rats, and has a protective effect on diabetic rats.

Identification of morin as an agonist of imidazoline I-3 receptor for insulin secretion in diabetic rats.

Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetics. Morin has been demonstrated to increase plasma insulin. However, the mechanism(s) remains unknown. The present study is designed to investigate the effect of morin on the imidazoline receptor (I-R) that regulates insulin secretion. We used Chinese hamster ovary (CHO) cells transfected with an I-R expression construct (NISCH-CHO-K1 cells) to identify the direct effect of morin on the I-R. Moreover, the imidazoline I3 receptor (I-3R) is known to be present in pancreatic β cells and involved in insulin secretion. Therefore, we applied a specific antagonist (KU14R) to block I-3R in diabetic rats. Additionally, the effect of morin on insulin secretion was characterized in isolated pancreatic islets. Morin decreased blood glucose levels by increasing plasma insulin levels in diabetic rats. In CHO cells expressing an I-R, morin increased calcium influx in a dose-dependent manner. Additionally, KU14R dose-dependently inhibited the morin-induced effects, including hypoglycemia and the increase in insulin secretion and plasma C-peptide levels, in diabetic rats. Furthermore, morin enhanced insulin secretion from isolated pancreatic islets, and this effect was also dose-dependently inhibited by KU14R. Phospholipase C (PLC) is known to couple with the I-R, and a PLC inhibitor dose-dependently attenuated the insulin secretion induced by morin in isolated pancreatic islets. Taken together, these data suggest that morin can activate I-3R to enhance insulin secretion. Therefore, it would be useful to develop morin into a treatment for diabetic disorders.

Chronic activation of central AMPK attenuates glucose-stimulated insulin secretion and exacerbates hepatic insulin resistance in diabetic rats.

We investigated the effects of chronic AMP-activated kinase (AMPK) activation in the hypothalamus on energy and glucose metabolism in 90% pancreatectomized diabetic rats. Diabetic rats fed a high fat diet were divided into 3 groups and intracerebroventricular (ICV) administered with one of the following: 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, AMPK activator; 80 μg/day), AICAR+compound C (AMPK inhibitor; 6.2 μg/day), or an artificial cerebrospinal fluid (control) by means of osmotic pumps for 4 weeks. In the hypothalamus, central AICAR activated the phosphorylation of AMPK whereas adding compound C suppressed the activation. AICAR increased body weight and epididymal and retroperitoneal fat mass by increasing energy intake for the first 2 weeks and decreasing energy expenditure, whereas compound C reversed the AICAR effect on energy metabolism. Indirect calorimetry revealed that ICV-AICAR decreased carbohydrate oxidation, but not fat oxidation, compared to the control. During euglycemic hyperinsulinemic clamp, central AICAR increased hepatic glucose output at hyperinsulinemic states. ICV-AICAR increased expressions of hepatic genes involved in fatty acid synthesis and decreased expression of hepatic genes related to thermogenesis whereas compound C nullified the AICAR effect. Insulin secretion in the first and second phases decreased in AICAR-treated rats at hyperglycemic clamp, but compound C nullified the decrease. However, central AICAR did not alter β-cell mass via its proliferation or apoptosis. In conclusion, chronic hypothalamic AMPK activation impaired energy metabolism and glucose homeostasis by increasing food intake, increasing hepatic glucose output and decreasing insulin secretion in diabetic rats. The impairment of energy and glucose homeostasis by AMPK activation was nullified by an AMPK inhibitor.

β-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing β-cell mass in non-diabetic and diabetic rats

Objectiveβ-Amyloid accumulation in the brain may impair glucose homeostasis in both the brain and peripheral tissues. The present study investigated whether β-amyloid deposition in the hippocampus impairs glucose homeostasis by altering insulin sensitivity, glucose-stimulated insulin secretion or β-cell mass. MethodsMale rats were divided into two groups: a non-diabetic sham group and a diabetic partial pancreatectomized (Px) group. Each group was then subdivided into three treatment groups that received intra-CA1 infusions of β-amyloid (25–35; AMY), β-amyloid (35–25; RAMY; non-plaque forming), or saline at a rate of 3.6nmol/day for 14days. ResultsAfter 4weeks, cognitive function measured by passive avoidance and water maze tests was impaired in non-diabetic rats that received AMY compared with rats that received saline or RAMY. Furthermore, diabetes exacerbated cognitive dysfunction in AMY-infused rats. This was associated with the hyperphosphorylation of tau as a result of attenuated insulin signaling (pAkt→pGSK) through decreased phosphorylation of cAMP responding element binding protein in the hippocampus of non-diabetic and diabetic rats. AMY exacerbated whole-body and hepatic insulin resistance in non-diabetic and diabetic rats. However, AMY potentiated glucose-stimulated insulin secretion in non-diabetic and diabetic rats, but caused decreased β-cell mass via increased β-cell apoptosis and decreased β-cell proliferation. As a result, glucose homeostasis was maintained by potentiating insulin secretion in diabetic rats, but may not be sustainable with further decreases in β-cell mass. ConclusionCognitive dysfunction attributable to β-amyloid accumulation in the hippocampus might be related to disturbed glucose homeostasis due to increased insulin resistance and decreased β-cell mass.

Central Prolactin Modulates Insulin Sensitivity and Insulin Secretion in Diabetic Rats

Background: Prolactin secretion is self-regulating as it acts upon hypothalamic dopaminergic systems which inhibit prolactin release from the anterior pitutary. Circulating prolactin improves glucose homeostasis by increasing insulin action and secretion, but central prolactin effects on glucose homeostasis have not been examined. Here, we determined that chronic central infusion of prolactin modulates insulin resistance and β-cell function and mass in 90% of pancreatectomized diabetic male rats. Methods: Diabetic rats were divided into three groups according to the dose of intracerebroventricular infusion of prolactin during 4 weeks: (1) low-dose prolactin (Low-PRL; 0.1 µg/h), (2) high-dose prolactin (High-PRL; 1 µg/h) and (3) vehicle only (cerebrospinal fluid). Nondiabetic rats were centrally infused with the vehicle. Results: Chronic intracerebroventricular infusion of Low-PRL lowered body weight and epididymal fat pads by increasing hypothalamic dopamine levels that reduced serum prolactin levels and potentiated leptin signaling. However, High-PRL slightly exacerbated energy dysregulation, decreased hypothalamic dopamine levels, and elevated serum prolactin levels. Both dosages promoted β-cell mass but in a different manner: Low-PRL decreased β-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. Conclusions: In contrast to the exacerbation of insulin resistance caused by High-PRL, Low-PRL may improve energy and glucose metabolism by increasing hypothalamic dopamine levels in diabetic rats.

Effect of Insulin on Arsenic Toxicity in Diabetic Rats—Liver Function Studies

Arsenic (iAs)-induced diabetic mellitus has been debated by several workers. However, role of insulin in iAs-induced diabetes is yet to be investigated. Present report suggests that iAs promotes insulin secretion in diabetic rats and inhibits hyperglycemia. Whereas, reverse effects were recorded after insulin treatment to diabetic and iAs-treated rats. These conditions affect accumulation of iAs in liver. It decreased in diabetic and iAs-treated rats but increased after insulin treatment. Reciprocal effects were observed on serum transaminases and total bilirubin. Nevertheless, activity of glucose-6-phosphatase in the liver was stimulated by insulin treatment to diabetic and arsenic-fed rats. These results suggest that manifestations of arsenic-induced diabetes mellitus are not modulated or reversed by insulin. Observations on liver function further suggest that iAs is less toxic in diabetic rats. This protective effect has been attributed to noninsulin-dependent carbohydrate regulatory mechanisms. Diabetes certainly alters the pharmacodynamics and pharmacokinetics of iAs in rat.

Effect of butanol fraction from Cassia tora L. seeds on glycemic control and insulin secretion in diabetic rats

Cassia tora L. seeds have previously been reported to reduce blood glucose level in human and animals with diabetes. In the present study, the effects of Cassia tora L. seed butanol fraction (CATO) were studied on postprandial glucose control and insulin secretion from the pancreas of the normal and diabetic rats. Diabetes was induced by an i.p. injection of Streptozotocin (55 mg/kg BW) into the male Sprague-Dawley rats. The postprandial glucose control was monitored during a 240 min-period using a maltose loading test. In normal rats, rats fed CATO (20 mg/100 g BW/d) showed lower postprandial glucose levels in all the levels from 30 min up to 180 min than those in the control rats without CATO (p<0.05). In diabetic rats, those levels in the CATO group seemed to be lower during the 30~180 min, but only glucose level at 30 min showed significant difference compared to that in the control group. Moreover, CATO delayed the peak time of the glucose rise in both normal and diabetic rats in the glucose curves. On the other hand, when CATO was administered orally to the diabetic rats for 5 days, 12 hr fasting serum glucose level was decreased in the diabetic rats (p<0.05). Degree of a decrease in 12 hr fasting serum insulin levels was significantly less in the diabetic CATO rats as compared to diabetic control rats. On the last day of feeding, β cells of the pancreas were stimulated by 200 mg/dL glucose through a 40 min-pancreas perfusion. Amounts of the insulin secreted from the pancreas during the first phase (11~20 min) and the second phase (21~40 min) in the CATO fed diabetic rats were significantly greater than those in the diabetic control group (p<0.05). These findings indicated that constituents of Cassia tora L. seeds have beneficial effect on postprandial blood glucose control which may be partially mediated by stimulated insulin secretion from the pancreas of the diabetic rats.

Cinnamon Administration Enhances Glucose‐Induced Insulin Secretion in Diabetic Rats.

The objective of these studies was to measure the effect of orally administered cinnamon on glucose tolerance and insulin secretion in vivo. Young male Wistar rats were rendered diabetic by intravenous administration of streptozotocin (40 mg/Kg body weight) in order to produce animals with Type 2 diabetic characteristics. After a two week period of stabilization, oral glucose tolerance tests were performed tri-iweekly and blood samples were collected at 0, 15, 30, 60 & 90 minutes post-glucose for glucose and insulin analyses. Glucose and insulin responses in rats given ground cinnamon added to the glucose test solution were compared with responses in diabetic control rats given glucose test solution only. The observations indicated that acute cinnamon dosing causes a marked improvement of impaired glucose tolerance accompanied by significant increases in rates of insulin secretion in this diabetic animal model. Thus, in addition to its documented effects on peripheral tissue insulin sensitivity, the data shown here indicates that cinnamon dosing also has beneficial effects on functioning of the endocrine pancreas. Support was from USDA ARS & Phytomed, Inc.

Decreased [ 3H] YM-09151-2 binding to dopamine D 2 receptors in the hypothalamus, brainstem and pancreatic islets of streptozotocin-induced diabetic rats

In the present study dopamine was measured in the hypothalamus, brainstem, pancreatic islets and plasma, using HPLC. Dopamine D 2 receptor changes in the hypothalamus, brainstem and pancreatic islets were studied using [ 3H] YM-09151-2 in streptozotocin-induced diabetic and insulin-treated diabetic rats. There was a significant decrease in dopamine content in the hypothalamus ( P < 0.001), brainstem ( P < 0.001), pancreatic islets ( P < 0.001) and plasma ( P < 0.001) in diabetic rats when compared to control. Scatchard analysis of [ 3H] YM-09151-2 in the hypothalamus of diabetic rats showed a significant decrease in B max ( P < 0.001) and K d, showing an increased affinity of D 2 receptors when compared to control. Insulin treatment did not completely reverse the changes that occurred during diabetes. There was a significant decrease in B max ( P < 0.01) with decreased affinity in the brainstem of diabetic rats. The islet membrane preparation of diabetic rats showed a significant decrease ( P < 0.001) in the binding of [ 3H] YM-09151-2 with decreased K d ( P < 0.001) compared to control. The increase in affinity of D 2 receptors in hypothalamus and pancreatic islets and the decreased affinity in brainstem were confirmed by competition analysis. Thus our results suggest that the decreased dopamine D 2 receptor function in the hypothalamus, brainstem and pancreas affects insulin secretion in diabetic rats, which has immense clinical relevance to the management of diabetes.

Effect of fungal polysaccharides on the modulation of plasma proteins in streptozotocin‐induced diabetic rats

To search out novel biomarkers for monitoring diabetes prognosis, we examined the effect of hypoglycemic fungal exopolysaccharides (EPS) on the differential levels of plasma proteins in streptozotocin-induced diabetic rats. The orally administrated EPS exhibited an excellent hypoglycemic effect, lowering the average plasma glucose level, and increasing insulin secretion in diabetic rats. The 2-DE analysis of rat plasma demonstrated that about 500 visualized spots were differentially regulated, of which 20 spots were identified as principal diabetes-associated proteins. The distinct effect of diabetes induction on the pattern of rat plasma proteins includes the down-regulation of albumin, apolipoprotein E (Apo E), alpha1-inhibitor-3, fetuin beta, Gc-globulin, hemopexin, vitronectin, and transthyretin (TTR) monomer, and the up-regulation of Apo A-I, Apo A-IV, ceruloplasmin, alpha1-antitrypsin, serine protease inhibitor III, and transferrin. Those protein levels were interestingly restored to those of healthy rats by EPS treatment, although the order of magnitude of the changes differed widely. Two proteins of interest showed distinct differential expression with opposite trends: TTR tetramer was significantly down-regulated and immunoglobulin (Ig) kappa light chain was significantly up-regulated upon diabetes induction, both of which were also normalized to those of healthy groups after EPS treatment.

Effects of vanadate and insulin on the activities of selected enzymes of amino acid metabolism in alloxan diabetic rat kidney.

The effects of insulin and the insulin mimetic agent "vanadate" were studied on the activities of alanine aminotransferase, aspartate aminotransferase, glutamate dehydrogenase and arginase in the cytosolic and the mitochondrial fractions of the kidney in control and alloxan induced diabetic rats. An enhancement in the activities of these enzymes were noted in both the fractions of diabetic kidney. Vanadate treatment (0.6 mg/ml in drinking water) of alloxan induced diabetic rats restored the activities of these enzymes almost completely in the cytosolic and partially in the mitochondrial fractions. Vanadate treatment also normalized hyperglycaemia without altering the depressed levels of insulin secretion in diabetic rats. The effect of insulin treatment was found to be the same as that of vanadate in diabetic rats.

Potential anti-diabetic applications of a new molecule with affinity for β3-Adrenoceptors

β 3-adrenoceptors have been described through both molecular and pharmacological studies. In this context, it has been characterized the β 3-adrenoceptors agonist activity of a new compound (Trecadrine ®), and evaluated whether it exhibits additional activity at β 1 and β 2- adrenoceptor subtypes. In addition, it has been tested its potential anti-diabetic properties in a model of alloxan-induced diabetes in rats. Our data show that Trecadrine ® induces oesophageal muscularis mucosae relaxation, indicating a putative action on β 3-adrenoceptors. In the absence of β 3-adrenoceptors antagonists, assays with β 1 and β 2-adrenergic antagonists reveal a quite remarkable selectivity for β 3-adrenoceptors. Furthermore, it has been suggested that this molecule has hypoglycaemic and lipomobilizing effects, although hypoglycaemia was not related to an increase in insulin secretion in diabetic rats. It is concluded that Trecadrine ® mainly acts through β 3-adrenoceptors, and it may constitute a potential drug in the treatment of diabetes.

Beta-cell hypersensitivity for glucose precedes loss of glucose-induced insulin secretion in 90% pancreatectomized rats.

Glucose-induced insulin secretion is impaired in the presence of chronic hyperglycaemia. Insulin secretion was studied in a diabetic rat model prior to the beta cells becoming non-responsive to glucose in order to map out the sequence of changes that accompany chronic hyperglycaemia. In vitro pancreas perfusions were carried out 1 and 2 weeks after a 90% pancreatectomy; controls underwent a sham pancreatectomy. One week post 90% pancreatectomy: (i) non-fasting plasma glucose values were 2-3 mmol/l above normal, (ii) the in vitro insulin response to 16.7 mmol/l glucose was 20 +/- 4% of shams, a response that was appropriate for the surgical reduction in beta-cell mass, (iii) the beta-cell sensitivity for glucose was increased as reflected by left-shifted dose-response curves for glucose-induced insulin secretion (half maximal insulin output 5.7 mmol/l glucose vs 16.5 mmol/l glucose in shams) and glucose potentiation of arginine-induced insulin secretion (half maximal insulin output 3.5 mmol/l glucose vs 14.8 mmol/l glucose in shams). This heightened beta-cell sensitivity for glucose was not a result of the hyperglycaemia, because similarly reduced half-maximal insulin responses were found after a 60% pancreatectomy, a surgical procedure in which plasma glucose values remained normal. In summary, a rise in beta-cell sensitivity for glucose precedes the loss of glucose-induced insulin secretion in diabetic rats.