Model Of Impaired Glucose Tolerance Research Articles

Integrated gut microbiome and UHPLC-MS metabolomics to reveal the prevention mechanism of pidanjiangtang granules on IGT Rats

IntroductionPidanjiangtang (PDJT) is a traditional Chinese medicine formula empirically used to treat impaired glucose tolerance (IGT) based on the "Pidan" theory from the classic ancient book Nei Jing. However, the mechanism of PDJT intervention for IGT remains to be studied. ObjectiveThis study aims to explore the mechanism of PDJT granules intervention in IGT by integrating gut microbiome and UHPLC-MS untargeted metabolomics. Materials and methodsThe IGT model was established in 6-week-old male Sprague-Dawley (SD) rats by feeding them a high-fat diet and using an STZ injection. The low, medium, and high doses of PDJT were used for six weeks. metformin (Glucophage) was used as the positive control drug. The efficacy of PDJT was evaluated using fasting blood glucose (FBG), blood glucose maximum (BGmax), blood lipid, and inflammatory factor levels. Finally, 16S rDNA gut microbiome sequencing with metabolomics analysis was used to explore the pharmacological mechanism of PDJT intervention in IGT. ResultsPDJT could reverse the phenotype of IGT rats, reduce blood glucose levels, improve lipid metabolism disorder, and reduce inflammatory response. Gut microbiome analysis found that PDJT can improve gut microbiota composition and abundance of three phyla (Firmicutes, Bacteroidota, Desulfobacterota) and four genera (unclassified_f__Lachnospiraceae, Ruminococcus, Allobaculum, Desulfovibrio), which play an important role in the process of PDJT intervention on glucose metabolism and lipid metabolism in IGT rats. UHPLC-MS untargeted metabolomics showed that PDJT could regulate the levels of 258 metabolites in lipid metabolism pathways, inflammatory response pathways, fat and protein digestion, and absorption. The combined analysis of the two omics showed that improving the body's metabolism by gut microbes may be the possible mechanism of PDJT in treating IGT. Thus, this study provides a new method to integrate gut microbiome and UHPLC-MS untargeted metabolomics to evaluate the pharmacodynamics and mechanism of PDJT intervention in IGT, providing valuable ideas and insights for future research on the treatment of IGT with traditional Chinese medicine.

4D-DIA-based proteomics analysis reveals the protective effects of Pidanjiangtang granules in IGT rat model

Ethnopharmacological relevanceThe Pidanjiangtang (PDJT) formula was founded on the "Pidan" theory from the "Nei Jing." PDJT is considered to eliminate the accumulation of pathological products, remove heat sources, and prevent damage to organs such as the liver and islets. It is widely used in clinical practice to treat impaired glucose tolerance (IGT). However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. ObjectiveThis study aimed to determine the therapeutic effect of PDJT on IGT rats and explore the mechanism of PDJT intervention on IGT by four-dimensional independent data acquisition (4D-DIA) proteomics analysis. Materials and methodsThe IGT model was established by a high-fat diet combined with Streptozotocin (STZ) injection. The IGT rats were treated with low, medium, and high doses of PDJT orally for 42 days and compared with the Metformin positive control group. The therapeutic effects of PDJT on IGT rats were evaluated using the oral glucose tolerance test (OGTT), serum lipoprotein detection, insulin detection, liver histopathology, and hepatic steatosis assessment. 4D-DIA proteomics analysis was used to explore the differential proteins (DEPs) and potential pathways of PDJT. Finally, Western blotting and ELISA techniques were used to verify DEPs and major targets. ResultsPDJT can enhance glucose metabolism, restore islet β cell function, regulate lipoprotein metabolism, reduce hepatic steatosis, and consequently slow down the progression of IGT. In the proteomic analysis, a total of 355 DEPs were identified, and critical proteins were validated. The results indicated that the JAK2/STAT1 signaling pathway plays a pivotal role in the effects of PDJT. IκB-ζ may be a potential target for PDJT in regulating the inflammatory response of IGT. ConclusionPDJT is an effective formula for improving IGT, with its potential mechanism linked to the JAK2/STAT1/IκB-ζ signaling pathway. This study offers a novel approach to investigating the mechanisms of TCM formula through proteomics and offers new insight into exploring TCM treatment for IGT.

Vitamin D protects against high glucose-induced pancreatic β-cell dysfunction via AMPK-NLRP3 inflammasome pathway

Vitamin D deficiency is considered a pandemic and has been postulated to increase the risk of type 2 diabetes mellitus (T2DM). Activation of nod-like receptor protein 3 (NLRP3) signaling induced by hyperglycemia stress has been recognized as a key priming stage for pancreatic β-cell inflammation in T2DM pathogenesis. AMP-activated protein kinase (AMPK) activation attenuates NLRP3 inflammasome upregulation in diabetes. This study investigated whether vitamin D3 could protect cells against high glucose-induced inflammation by modulating this critical step. A human cross-sectional study of 78 healthy, glucose-tolerant volunteers and 399 patients with type 2 diabetes was undertaken. The relationship between serum 25(OH)D3 levels and β-cell function was assessed using Pearson correlation analysis and multiple linear regression, and a high-glucose diet-induced rat model of impaired glucose tolerance was used to evaluate the effects of cholecalciferol. Intraperitoneal glucose tolerance tests and an ELISA were performed to detect the function of pancreatic islets. Glucose-stimulated insulin secretion, pyroptosis, reactive oxygen species (ROS) production, and NLRP3 pathway were evaluated together to determine the role of vitamin D in high glucose-induced pancreatic β-cell dysfunction in INS-1E cells. The clinical results showed a positive association between serum 25(OH)D3 levels and β-cell function in male patients with type 2 diabetes. In vivo, cholecalciferol significantly reduced blood glucose levels and improved insulin secretion in response to glucose loading in the high glucose diet-induced rat model. In vitro studies have demonstrated that 1,25(OH)2D3 promotes insulin release in both islets and INS-1E cells. Mechanistically, our results demonstrated that vitamin D3 can activate AMPK, inhibiting the mTOR pathway, thus inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in β-cell dysfunction. This study showed that vitamin D protects against high-glucose-induced β-cell dysfunction by enhancing the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.

Screening study of the antihyperglycemic action of new solid quercetin dispersions

The aim – to screen new solid dispersions of quercetin for the presence of antihyperglycemic action and to identify the most active substances that are promising for the creation of antidiabetic drugs.
 Materials and methods. The object of the study was 4 new solid dispersions of quercetin, developed at the National University of Pharmacy. Solid dispersions of quercetin were prepared by the liquid-phase method; hydroxypropyl methylcellulose (HPMC) or polyvinylpyrrolidone (PVP) in ratios of 1:1 and 1:2 were used as a carrier. The antihyperglycemic effect of the studied substances at a dose of 50 mg / kg was assessed in rats by the ability to lower blood glucose levels after carbohydrate loading in a model of impaired glucose tolerance induced by dexamethasone and in experimental type 2 diabetes mellitus induced by dexamethasone.
 Results. It was found that with impaired glucose tolerance, a solid dispersion of quercetin with HPMC (1:1) showed a pronounced antihyperglycemic effect – the glucose level 30 minutes after glucose load significantly decreased by 28 % and did not differ from the action of metformin, which was confirmed by the value of the area under glycemic crooked. When solid dispersions with PVP (1:1 and 1:2) were used, the antihyperglycemic effect was less pronounced. In a model of type 2 diabetes mellitus, a significant antihyperglycemic effect was found only in a solid dispersion of quercetin with HPMC (1:1) at the metformin level, which indicates an increase in the solubility and absorption of quercetin.
 Conclusions. A pronounced antihyperglycemic effect at the metformin level was found in a solid dispersion of quercetin with HPMC in a 1:1 ratio with impaired glucose tolerance and type 2 diabetes mellitus. It has been proven that a solid dispersion of quercetin with HPMC is a promising substance for creating a monocomponent drug or for inclusion in a new antidiabetic combined drug

Identifying potential therapeutic targets of Tang-Yi-Ping for the treatment of impaired glucose tolerance: a tandem mass tag-labeled quantitative proteomic analysis.

BackgroundThis study uses the tandem mass tag (TMT)-labeled quantitative proteomic analysis to identify potential therapeutic protein targets of a Chinese prescription called Tang-Yi-Ping (TYP) for the treatment of impaired glucose tolerance (IGT) in rats.MethodsA total of 31 specific-pathogen free (SPF) male Wistar rats were used in our study. Ten were randomly selected as a control group, while 21 received a high-sugar and high-fat diet combined with an intraperitoneal injection of streptozotocin to establish IGT subjects. After eliminating 2 rats without successful modeling, 19 were randomly divided into a TYP group (n=9) and IGT model group (n=10). The TYP group was given a TYP decoction of 6.36 mg/kg−1/d−1. After 8 weeks of intervention, blood glucose-related indicators were measured, and cell morphology was observed by hematoxylin and eosin (HE) staining. TMT-labeled proteomic analysis was applied to detect the differentially expressed proteins (DEPs) in the pancreases of the three groups. The intersection of the DEPs in both the TYP group and IGT model group underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to identify the related biological functions and signal transduction pathways. Finally, western blot (WB) was used to verify the TMT proteomics results.ResultsTYP can effectively reduce blood glucose and improve islet morphology in IGT rats. We identified a total of 16 potential therapeutic protein targets of TYP, 4 of which were upregulated, while 12 were downregulated, including Rbp4, Fam3b, Flot2, etc. [fold change (FC) >1.1, P<0.05]. The significant signal transduction pathways included arginine and proline metabolism, glyceride metabolism, glycerophospholipid metabolism, mTOR, Wnt, and insulin signaling pathways.ConclusionsFor anti-IGT therapy, we found TYP regulates 16 protein targets, multiple biological functions, and multiple signal transduction pathways. This study thus makes a significant contribution to identifying new potential therapeutic targets for treating IGT.

Effect of transcutaneous auricular vagus nerve stimulation on hyperglycemia and insulin receptors expression in impaired glucose tolerance rats

To explore the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on blood glucose regulation and the expression of insulin receptors (INR) of hypothalamus, liver and skeletal muscle tissues in impaired glucose tolerance (IGT) rats, so as to reveal its mechanisms underlying improvement of IGT. Thirty-six male Wistar rats were randomly divided into control, model, transcutaneous auricular none-vagus nerve stimulation (tnVNS), and taVNS groups (n=9 in each group). The IGT model was established by feeding the rats with high-fat and high-sugar diet for 5 weeks, and subsequent intraperitoneal injection of a dose of streptozotocin (20 mg/kg). Transcutaneous electrostimulation (2 mA, 2 Hz/15 Hz) was applied to auricular concha (taVNS) or auricular margin (tnVNS), respectively. The treatment was conducted for 30 min once daily for 4 weeks. The body weight, fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG) were recorded every week. The contents of plasma insulin (INS), glucagon (GC), glycosylated hemoglobin (GHbA1c) were detected by using enzyme linked immunosorbent assay (ELISA). The expression levels of INR in hypothalamus, liver and skeletal muscle tissues were detected by Western blot. After modeling, the rats' body weight, the contents of FPG, 2 h PG, GC and GHbA1c were significantly up-regulated (P<0.001, P<0.05, P<0.01), and the content of INS and expression of INR in hypothalamus, liver and skeletal muscle tissues were significantly down-regulated in the model group compared with the control group (P<0.001, P<0.01, P<0.05). Following the treatment, the increased FPG, 2 h PG, GC, and the decreased INS and INR expression of hypothalamus, liver and skeletal muscle tissues were apparently reversed in the taVNS group relevant to the model group (P<0.001, P<0.01, P<0.05). Compared with the tnVNS group, the FPG and 2 h PG contents were considerable decreased, and the content of INS and INR expression of hypothalamus and liver were obviously increased in the taVNS group (P<0.001, P<0.05, P<0.01). taVNS can improve the blood glucose and insulin sensitivity in IGT rats, which may contribute to its effectiveness in up-regulating the expression of INR in hypothalamus, liver and skeletal muscle tissues.

Palmatine ameliorates high fat diet induced impaired glucose tolerance

BackgroundThe impaired glucose tolerance (IGT) is a representative prediabetes characterized by defective glucose homeostasis, and palmatine (PAL) is a natural isoquinoline alkaloid with multiple pharmacological effects. Our study aims to investigate the therapeutic effect of PAL on the impaired glucose tolerance.MethodsMale Sprague–Dawley rats were used to establish an IGT model with high fat diet (HFD). Oral glucose tolerance test (OGTT) and further biochemical analysis were conducted to determine the effect of PAL on glucose intolerance in vivo. Molecular details were clarified in a cellular model of IGT induced by Palmitate (PA) on INS-1 cells.ResultsOur study demonstrated a relief of IGT with improved insulin resistance in HFD induced rats after PAL treatment. Besides, promoted pancreas islets function was validated with significantly increased β cell mass after the treatment of PAL. We further found out that PAL could alleviate the β cell apoptosis that accounts for β cell mass loss in IGT model. Moreover, MAPK signaling was investigated in vivo and vitro with the discovery that PAL regulated the MAPK signaling by restricting the ERK and JNK cascades. The insulin secretion assay indicated that PAL significantly promoted the defective insulin secretion in PA-induced INS-1 cells via JNK rather than ERK signaling. Furthermore, PAL treatment was determined to significantly suppress β cell apoptosis in PA-induced cells. We thus thought that PAL promoted the PA-induced impaired insulin release by inhibiting the β cell apoptosis and JNK signaling in vitro.ConclusionIn summary, PAL ameliorates HFD-induced IGT with novel mechanisms.

Bifidobacterium from breastfed infant faeces prevent high-fat-diet-induced glucose tolerance impairment, mediated by the modulation of glucose intake and the incretin hormone secretion axis.

Probiotics are defined as microorganisms that can exert health benefits for the host. Among the recognized probiotics, Bifidobacterium are the most frequently used probiotics in humans. The aim of this study was to evaluate the antidiabetic activity of Bifidobacterium strains isolated from breastfed infant faeces, both in vitro, using the Caco-2 monolayer transwell model, and in vivo, using a mice model of impaired glucose tolerance induced by a high-fat diet (HFD). The cell-free supernatant of Bifidobacterium lactis A12 showed better inhibitory activity of α-glucosidase and inhibited the glucose absorption and transport than B. lactis BB12, which is a typical probiotic with antidiabetic capabilities. B. lactis A12 improved the impaired glucose intolerance, restored islet function and morphology with insulin resistance induced by the HFD in C57BL/6J mice. Furthermore, in small intestine tissues, the cell-free supernatant of B. lactis A12 decreased the messenger RNA expressions of sucrase-isomaltase, live B. lactis A12 cells decreased glucose transporters 2. B. lactis A12 significantly stimulated the glucagon like peptide-1 (GLP-1) secretion and upregulated proglucagon messenger RNA levels. B. lactis A12 protect against the deleterious effects of HFD-induced diabetes by inhibiting the utilization, absorption, and transport of glucose by intestinal epithelial cells and promoting the expression and secretion of GLP-1. © 2020 Society of Chemical Industry.

Are Diabetes Risk Scores the Best Way to Identify Those Who Will Benefit Most from Lifestyle Prevention?

Rationale: Lifestyle intervention programs are effective for preventing diabetes among those with impaired glucose tolerance (IGT), with little evidence of benefit in other high-risk states. The selection of those who are eligible for lifestyle intervention is often made via diabetes prediction tools which identity those at high risk of diabetes. Unless such scores preferentially identify IGT, this will lead to poor performance of diabetes prevention programs. We developed an IGT-specific risk model and a diabetes-specific risk model, and compare their abilities to identify those with IGT. Methods: Data from population-based surveys conducted in Mauritius in 1987, 1992 and 1998 were used to develop prediction models for IGT and DM. A cross-sectional sample in 1987 was used to develop the IGT model. A cohort sample from 1987 to 1992 was used to develop the DM model. Logistic regression was used to develop the scores. The performances were investigated by calculating area under the receiver operator curve (aROC). The Youden index was used to find a cutpoint in probability. Both scores were tested on independent samples. Results: The aROC for IGT and DM models were 0.68 and 0.69 respectively. The sensitivity of the IGT model (derived on 1987 data) in identifying IGT individuals on independent samples from 1992 was 66%. Among those above the Youden index cutpoint, 23%, 9% and 68% had IGT, IFG and NGT, respectively. In the DM model, sensitivity for IGT was 60%. Among those above the cutpoint 24%, 8% and 67% had IGT, IFG and NGT, respectively. Increasing the cutpoints to levels at which 40% of those above the cutpoint had IGT resulted in sensitivities for IGT of 15% and 5% in the IGT and DM models, respectively. Conclusion: Our results show that risk scores perform poorly in identifying people with IGT, and that without screening identified populations with an oral glucose tolerance test, a high proportion of people entering DM prevention programs will not have IGT-the only state shown to respond to lifestyle. Disclosure C.I. Sari: None. D.J. Magliano: None. P.Z. Zimmet: None. J. Tuomilehto: None. K. Sudhirsen: None. S. Söderberg: Other Relationship; Self; GlaxoSmithKline plc.. Speaker's Bureau; Self; Actelion Pharmaceuticals US, Inc.. Other Relationship; Self; Swedish Heart-Lung Foundation. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp. J.E. Shaw: Advisory Panel; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp.. Speaker's Bureau; Self; Mylan. Advisory Panel; Self; Novo Nordisk Inc..

Zuo Gui Wan Alters Expression of Energy Metabolism Genes and Prevents Cell Death in High-Glucose Loaded Mouse Embryos.

Background Zuo Gui Wan (ZGW) is a classic formula in traditional chinese medicine (TCM). Previous studies have shown that it is beneficial for impaired glucose tolerance (IGT) of adults and the offspring as well. This study aimed to understand the molecular mechanisms of the efficacy of ZGW on IGT. Methods We used high-glucose loaded 2-cell stage mouse embryos as a model and took advantage of single-cell RNA sequencing technology to analyze the transcriptome of the model with or without ZGW. Differential gene expression analysis was performed with DESeq2. Results High glucose can downregulate genes in the ribosome pathway, while ZGW can reverse this inhibition and as a result prevent embryo cell death caused by high glucose. Furthermore, high glucose can affect sugar metabolism and influence mitochondrial function, but ZGW can promote sugar metabolism via the tricarboxylic acid cycle mainly through upregulating the genes in the respiratory chain and oxidative phosphorylation. Conclusions ZGW had a protective effect on embryonic cell death caused by glucose loading. The reversion of inhibition of ribosome pathway and regulation of mitochondrial energy metabolism are main effects of ZGW on high-glucose loaded embryos. This research not only revealed the global gene regulation changes of high glucose affecting 2-cell stage embryos but also provided insight into the potential molecular mechanisms of ZGW on the IGT model.

Bone mineral density (BMD), vitamin D levels, body mass index (BMI) and exocrine pancreatic function in patients with Chronic Pancreatitis (CP)

Vitamin D deficiency is considered a pandemic and has been postulated to increase the risk of type 2 diabetes mellitus (T2DM). Activation of nod-like receptor protein 3 (NLRP3) signaling induced by hyperglycemia stress has been recognized as a key priming stage for pancreatic β-cell inflammation in T2DM pathogenesis. AMP-activated protein kinase (AMPK) activation attenuates NLRP3 inflammasome upregulation in diabetes. This study investigated whether vitamin D3 could protect cells against high glucose-induced inflammation by modulating this critical step. A human cross-sectional study of 78 healthy, glucose-tolerant volunteers and 399 patients with type 2 diabetes was undertaken. The relationship between serum 25(OH)D3 levels and β-cell function was assessed using Pearson correlation analysis and multiple linear regression, and a high-glucose diet-induced rat model of impaired glucose tolerance was used to evaluate the effects of cholecalciferol. Intraperitoneal glucose tolerance tests and an ELISA were performed to detect the function of pancreatic islets. Glucose-stimulated insulin secretion, pyroptosis, reactive oxygen species (ROS) production, and NLRP3 pathway were evaluated together to determine the role of vitamin D in high glucose-induced pancreatic β-cell dysfunction in INS-1E cells. The clinical results showed a positive association between serum 25(OH)D3 levels and β-cell function in male patients with type 2 diabetes. In vivo, cholecalciferol significantly reduced blood glucose levels and improved insulin secretion in response to glucose loading in the high glucose diet-induced rat model. In vitro studies have demonstrated that 1,25(OH)2D3 promotes insulin release in both islets and INS-1E cells. Mechanistically, our results demonstrated that vitamin D3 can activate AMPK, inhibiting the mTOR pathway, thus inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in β-cell dysfunction. This study showed that vitamin D protects against high-glucose-induced β-cell dysfunction by enhancing the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.

Diabetes-associated microbiota in fa/fa rats is modified by Roux-en-Y gastric bypass

Roux-en-Y gastric bypass (RYGB) and duodenal jejunal bypass (DJB), two different forms of bariatric surgery, are associated with improved glucose tolerance, but it is not clear whether the gut microbiota contributes to this effect. Here we used fa/fa rats as a model of impaired glucose tolerance to investigate whether (i) the microbiota varies between fa/fa and nondiabetic fa/+ rats; (ii) the microbiota of fa/fa rats is affected by RYGB and/or DJB; and (iii) surgically induced microbiota alterations contribute to glucose metabolism. We observed a profound expansion of Firmicutes (specifically, Lactobacillus animalis and Lactobacillus reuteri) in the small intestine of diabetic fa/fa compared with nondiabetic fa/+ rats. RYGB-, but not DJB-, treated fa/fa rats exhibited greater microbiota diversity in the ileum and lower L. animalis and L. reuteri abundance compared with sham-operated fa/fa rats in all intestinal segments, and their microbiota composition resembled that of unoperated fa/+ rats. To investigate the functional role of RYGB-associated microbiota alterations, we transferred microbiota from sham- and RYGB-treated fa/fa rats to germ-free mice. The metabolic phenotype of RYGB-treated rats was not transferred by the transplant of ileal microbiota. In contrast, postprandial peak glucose levels were lower in mice that received cecal microbiota from RYGB- versus sham-operated rats. Thus, diabetes-associated microbiota alterations in fa/fa rats can be modified by RYGB, and modifications in the cecal microbiota may partially contribute to improved glucose tolerance after RYGB.

A novel animal model of impaired glucose tolerance induced by the interaction of vitamin E deficiency and (60)Co radiation.

Impaired glucose tolerance (IGT), known as the prediabetes stage, is usually induced by habits of life or environmental factors. Established IGT animal models are mostly conducted with chemical compounds such as streptozocin or genetic modification. However, the occasion of exposure to these factors in daily life is seldom. The objective of this study was to establish a new animal model of IGT induced by VE deficiency in diet and exposure to radiation. SD rats were treated individually or in combination of these two factors. In the combination group, the calculated insulin sensitivity index decreased; then HOMA-β value increased. Oxidative damage and IGT were observed. Insulin secretion level in perfusate from pancreas response to glucose was characterized by a rapid but reduced first phase and an obviously defective second phase upon pancreas perfusion. Histopathological images demonstrated the pathological changes. Western blotting analysis showed that the insulin signaling pathway was downregulated. The interaction of VE deficiency in diet and exposure to radiation could break the equilibrium of oxidation and antioxidation and result in IGT. More importantly, a new IGT model was successfully established which may be conducive to further research into development of drugs against human IGT.

Targeting development of incretin-producing cells increases insulin secretion.

Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control.

729 RENAL AND METABOLIC EVALUATIONS IN RATS WITH METABOLIC SYNDROME INDUCED BY FRUCTOSE

Introduction and objectives: High fructose fed rats has previously been described as an animal model of impaired glucose tolerance. The aim of this study was to evaluate the contribution of overloading of fructose on metabolic and renal function in rats. Design and methods: Male Wistar rats (50–60 g) were divided into control group (CG, n = 6) and Fructose Group (FG, 10% fructose, drinking water, 8 weeks, n = 7). Renal Angiotensin I Converting Enzyme activity (ACE) was evaluated by fluorimetry. Angiotensins Quantification were analyzed by HPLC. The kidney was collected for histological glomerular analysis (5 μm, Picrosirius Red) to evaluate the collagen deposition at Glomerular Tuft (CGT) and Bowman[Combining Acute Accent]s Capsule (CBC). Blood was collected to biochemical assays (Labtest, BR). Results: There was no difference in Lee Index between groups, however the adiposity was increased in FG (8 ± 0,5 g/kg) when compared with CG (6 ± 1 g/kg). Basal glycemia and Triglycerides were augmented in FG when compared with CG. Renal ANG II was increased in FG (63 ± 8,4 pmol/g) when compared with CG (29 ± 2,5 pmol/g). However, there was no changes in renal ACE activity (CG: 5 ± 0,7 vs 4,6 ± 0,7 mU/mg prot). The CGT was higher (25%) in FG when compared with CG. The CBC was also increased in FG (29%) when compared with CG. Conclusions: In conclusion, our data suggest that fructose is related metabolic alterations associated with an increased renal collagen deposition. Moreover, the elevated renal AngII induced by fructose could be involved in tissue damage and contribute to decrease in renal function.

Effects of an inulin‐chromium complex on glycemic index in obesity

To determine the effects of an inulin fructan polymer‐chromium complex (FCC) derived from dahlia root juice on glycemic responses, groups of congenic lean and obese LA/Ntul/ /‐cp rats were administered an oral glucose tolerance (OGT) alone or in combination with measured amounts of the FCC. Glycemic responses and the glucose area under the curve (AUC) of obese rats were significantly impaired compared to similarly‐fed lean littermates. Oral FCC administration resulted in a significant 50% reduction toward normalization of the peak glycemic response during OGT in both lean and obese rats, a 75% reduction in the total glucose area of lean rats and a 50% reduction of the total glucose area of obese rats. The greatest segment of the reduced glucose area occurred during the post absorptive phase of the OGT response in both phenotypes. The results of this study are consistent with an acute FCC‐mediated improvement in glycemic control in a congenic obese animal model of impaired glucose tolerance, and suggest that the FCC complex may be a useful nutritional adjunct in the dietary treatment of obesity and other glucose‐intolerant states as they may occur in man and animals. Institutional Support.

Impaired glucose tolerance plus hyperlipidaemia induced by diet promotes retina microaneurysms in New Zealand rabbits

With the increasing prevalence of diabetes mellitus and metabolic syndrome worldwide, experimental models are required to better understand the pathophysiology and therapeutic approaches to preserve pancreatic beta cells, attenuate atherosclerosis and protect target organs. The aims of this study were to develop an experimental model of impaired glucose tolerance combined with hypercholesterolaemia induced by diet and assess metabolic alterations and target organ lesions. New Zealand male rabbits were fed high-fat/high-sucrose (10/40%) and cholesterol-enriched diet for 24 weeks, when they were sacrificed. Biochemistry, fundus photographs with fluorescein angiography and pathological analyses were performed. Cholesterol-fed and normal animals of same age were compared. The animals with diet-induced impaired glucose tolerance combined with hypercholesterolaemia gained weight, increased blood glucose, total cholesterol, LDL-C and triglycerides and decreased HDL-C (P < 0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) index were increased, while there was a reduction in the HOMA-β (P < 0.05 for all vs. baseline). Histomorphologic findings of this model were aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration. Early clinical features of diabetic retinopathy with hyperfluorescent dots consistent with presence of retina microaneurysms were seen since week 12, progressing up to the end of the experiment (P < 0.0005 vs. baseline and 12 weeks). Our model reproduced several metabolic characteristics of human diabetes mellitus and promoted early signs of retinopathy. This non-expensive model is suitable for studying mechanistic pathways and allowing novel strategic approaches.

Diet-induced impaired glucose tolerance and gestational diabetes in the dog

Glucose metabolism was compared in dogs consuming a chow/meat diet throughout pregnancy (P group, n = 6) and dogs switched to a high-fat/high-fructose (HFF) diet during the 4th-5th gestational week (gestation ≃9 wk; P-HFF group; n = 6). An oral glucose tolerance test (OGTT; 0.9 g/kg) was administered in the 6th-7th gestational week, and a hyperinsulinemic [0-120 min: 1.8 pmol·kg(-1)·min(-1) (low insulin); 120-240 min: 9 pmol·kg(-1)·min(-1) (high insulin)] euglycemic clamp was performed the following week. Nonpregnant (NP) female dogs underwent OGTTs but not clamp studies. All P-HFF dogs exhibited impaired glucose tolerance (IGT) or gestational diabetes (GDM), but only one P dog had IGT. Insulin concentrations in P and P-HFF dogs were significantly lower than in NP dogs 30 and 60 min after the OGTT. Therefore, mean islet size and area were evaluated in P and NP dogs. These values did not differ between groups, and proliferating endocrine cells were rare in pregnancy. During exposure to high insulin, glucose infusion rate and hindlimb glucose uptake were ∼30% greater (P < 0.05) and net hepatic glucose output was more suppressed (-5.5 ± 6.1 vs. 7.8 ± 2.8 mg·100 g liver(-1)·min(-1), P < 0.05) in P than in P-HFF dogs. In conclusion, in the 2nd trimester the canine pancreas does not exhibit islet hypertrophy, hyperplasia, or neogenesis. Combined with the lack of pancreatic adaptation, a HFF diet during late pregnancy produces a canine model of IGT and GDM without hyperinsulinemia but exhibiting liver and muscle insulin resistance.

Involvement of low adiponectin levels in impaired glucose tolerance

To investigate the association between serum adiponectin levels and 2-hour post–75-g oral glucose load glycemia, we conducted 75-g oral glucose tolerance tests in 50 subjects who had been diagnosed as having impaired glucose tolerance (IGT) within the prior 3 years. When adjusted for age, body mass index, and sex, serum adiponectin levels in the IGT and diabetes mellitus groups were significantly lower than those in the normal glucose tolerance and impaired fasting glucose groups ( P < .0001). To determine which variables had significant impacts on 2-hour post–oral glucose glycemia, we performed multiple regression analyses. In stepwise analysis, serum adiponectin levels showed the highest F value (F = 6.43), suggesting the adiponectin level to be an independent predictor of 2-hour post–oral glucose glycemia. Thus, our clinical data suggest the involvement of low adiponectin levels in IGT and diabetes mellitus. To further assess this possibility, we prepared mice fed a high-fat diet for 2 months as an IGT model. Afterward, we compared the 2-hour postglucose glycemia in the IGT mice overexpressing recombinant adiponectin with that in control IGT mice. Mice overexpressing adiponectin showed significantly blunted 2-hour postglucose glycemia (5.66 ± 0.39 mmol/L) as compared with control mice (8.52 ± 0.67 mmol/L), whereas fasting glycemia was not significantly altered by adiponectin overexpression. Taken together, our results reveal the plasma glucose level in response to a glucose load to be negatively associated with serum adiponectin levels, suggesting low adiponectin levels to be one of the predictors of abnormal glucose homeostasis in IGT.

The cannabinoid receptor‐1 antagonist rimonabant inhibits platelet activation and reduces pro‐inflammatory chemokines and leukocytes in Zucker rats

We investigated the effect of rimonabant on inflammation and enhanced platelet reactivity in type 2 diabetic Zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome. Rimonabant (10 mg kg(-1) by gavage) was fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels were determined by ELISA. Leukocyte populations were quantitatively assessed using a veterinary differential blood cell counter. Platelet activation was assessed by flow-cytometry, platelet aggregation, and adhesion of isolated platelets to immobilized fibrinogen. RANTES and MCP-1 serum levels were increased in obese vs lean Zucker rats and significantly reduced by long-term treatment with rimonabant, which slowed weight gain in rats with the metabolic syndrome. Neutrophils and monocytes were significantly increased in young and old obese vs lean Zucker rats and lowered by rimonabant. Platelet-bound fibrinogen was significantly enhanced in obese vs lean Zucker rats of both age, and was reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which were both attenuated by rimonabant therapy. We demonstrate positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower RANTES and MCP-1 levels by rimonabant in Zucker rats. This may potentially contribute to a reduction of cardiovascular risk.