Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat

2011 ◽  
Vol 301 (3) ◽  
pp. E527-E538 ◽  
Author(s):  
Yi Lin ◽  
Jie Wei ◽  
Yuanyuan Li ◽  
Jun Chen ◽  
Zhao Zhou ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Endocrine Pancreas ◽  
Serum Insulin ◽  
Β Cell ◽  
Developmental Exposure ◽  
Ethylhexyl Phthalate ◽  
Dehp Exposure

—Di(2-ethylhexyl) phthalate (DEHP), a typical endocrine-disrupting chemical (EDC), is widely used as plasticizer. DEHP exposure in humans is virtually ubiquitous, and those undergoing certain medical procedures can be especially high. In this study, we investigated whether developmental DEHP exposure disrupted glucose homeostasis in the rat and whether this was associated with the early impairment in endocrine pancreas. Pregnant Wistar rats were administered DEHP (1.25 and 6.25 mg·kg−1·day−1) or corn oil throughout gestation and lactation by oral gavage. Body weight, glucose and insulin tolerance, and β-cell morphometry and function were examined in offspring during the growth. In this study, developmental DEHP exposure led to abnormal β-cell ultrastructure, reduced β-cell mass, and pancreatic insulin content as well as alterations in the expression of genes involved in pancreas development and β-cell function in offspring at weaning. At adulthood, female DEHP-exposed offspring exhibited elevated blood glucose, reduced serum insulin, impaired glucose tolerance, and insulin secretion. Male DEHP-exposed offspring had increased serum insulin, although there were no significant differences in blood glucose at fasting and during glucose tolerance test. In addition, both male and female DEHP-exposed offspring had significantly lower birth weight and maintained relatively lower body weight up to 27 wk of age. These results suggest that developmental exposure to DEHP gives rise to β-cell dysfunction and the whole body glucometabolic abnormalities in the rat. DEHP exposure in critical periods of development can be a potential risk factor, at least in part, for developing diabetes.

scholarly journals Blackthorn Flower Extract Impact on Glycaemic Homeostasis in Normoglycemic and Alloxan-Induced Hyperglycaemic C57BL/6 Mice

2021 ◽  
Vol 59 (3) ◽  
Author(s):  
Irena Crnić ◽  
Tajana Frančić ◽  
Petar Dragičević ◽  
Vedran Balta ◽  
Verica Dragović-Uzelac ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Serum Insulin ◽  
Sugar Content ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Mice Model ◽  
Flower Extract ◽  
Prunus Spinosa

Research background. The use of plants and their extracts in treatments of chronic diseases is widely known in traditional medicine. The aim of this study is to determine the effects of 10-day consumption of Prunus spinosa L. flower extract on blood glucose, glycaemic load, serum α-amlyase and serum insulin, in normoglycaemic and hypergycaemic (alloxan) mice model. Experimental approach. Normoglycemic and hyperglycemic (alloxan treated, 150 mg/kg body mass) C57BL/6 mice were treated daily, during 10 days, with Prunus spinosa L. flower extract by gavage. The sugar content within extract was determined by HPLC analysis. In mice, blood and serum blood glucose level and OGTT-test were determined by blood glucometer. Serum insulin was determined by ELISA assay and α-amlyase by colourimetric assay. Results and conclusions. The Prunus spinosa L. flower extract increased glucose in normoglycaemic mice by 30 % after 1st and 5th day and by 17 % after 10th day of consumption in normoglycaemic mice. It is a consequence of released sugars because sugar analysis revealed 59.8 mg/L monosaccharides, mainly fructose (55.7 mg/L) and glucose (24.3 mg/L) within the extract. On the opposite, the extract consumption, reduced serum blood glucose in alloxan-induced hyperglycaemic mice by 29 % after 10 days of treatment. Oral glucose tolerance test also confirmed that that in the hyperglycaemic group treated with Prunus spinosa L. flower extract glucose homeostasis was improved and showed decrease in blood glucose, since the blood glucose over the period of 120 min, glucose homeostasis is faster achieved after treatment with shows that in Prunus spinosa L. flower extract. Serum insulin increased by 49 % and serum alpha amylase by 46 % after 10 days of treatment with Prunus spinosa L. flower extract in hyperglycaemic group. Thus, it can be concluded that Prunus spinosa L. flower extract improved glucose tolerance, enhanced insulin secretion and lowered serum α-amylase activity. Novelty and scientific contribution. The results examined for the first time the potential of Prunus spinosa L. flower extract in hyperglycaemia management.

scholarly journals Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

2020 ◽  
Author(s):  
S. Neda Mousavy Gharavy ◽  
Bryn Owen ◽  
Steven J. Millership ◽  
Pauline Chabosseau ◽  
Grazia Pizza ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Cell Function ◽  
Sexually Dimorphic ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

AbstractVariants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. Here, we show that systemic inactivation of C2cd4b in mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. Female C2cd4b mice display unchanged body weight but abnormal glucose tolerance and defective in vivo, but not in vitro, insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, male C2cd4b null mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic β cell function at larval stages in C2cd4ab null zebrafish. These studies suggest that C2cd4b may act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in man.

Duodenal-jejunal bypass protects GK rats from β-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1

2011 ◽  
Vol 300 (5) ◽  
pp. E923-E932 ◽  
Author(s):  
Madeleine Speck ◽  
Young Min Cho ◽  
Ali Asadi ◽  
Francesco Rubino ◽  
Timothy J. Kieffer
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Wistar Rats ◽  
Enteroendocrine Cells ◽  
Cell Populations ◽  
Cell Area ◽  
Β Cell ◽  
Enteroendocrine Cell ◽  
Gk Rats ◽  
Jejunal Bypass

Dramatic improvement of type 2 diabetes is commonly observed after bariatric surgery. However, the mechanisms behind the alterations in glucose homeostasis are still elusive. We examined the effect of duodenal-jejunal bypass (DJB), which maintains the gastric volume intact while bypassing the entire duodenum and the proximal jejunum, on glycemic control, β-cell mass, islet morphology, and changes in enteroendocrine cell populations in nonobese diabetic Goto-Kakizaki (GK) rats and nondiabetic control Wistar rats. We performed DJB or sham surgery in GK and Wistar rats. Blood glucose levels and glucose tolerance were monitored, and the plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. β-Cell area, islet fibrosis, intestinal morphology, and the density of enteroendocrine cells expressing GLP-1 and/or GIP were quantified. Improved postprandial glycemia was observed from 3 mo after DJB in diabetic GK rats, persisting until 12 mo after surgery. Compared with the sham-GK rats, the DJB-GK rats had an increased β-cell area and a decreased islet fibrosis, increased insulin secretion with increased GLP-1 secretion in response to a mixed meal, and an increased population of cells coexpressing GIP and GLP-1 in the jejunum anastomosed to the stomach. In contrast, DJB impaired glucose tolerance in nondiabetic Wistar rats. In conclusion, although DJB worsens glucose homeostasis in normal nondiabetic Wistar rats, it can prevent long-term aggravation of glucose homeostasis in diabetic GK rats in association with changes in intestinal enteroendocrine cell populations, increased GLP-1 production, and reduced β-cell deterioration.

scholarly journals Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

2008 ◽  
Vol 114 (9) ◽  
pp. 591-601 ◽  
Author(s):  
Xiao C. Li ◽  
Tang-dong Liao ◽  
Jia L. Zhuo
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Serum Insulin ◽  
Fasting Blood Glucose ◽  
Weight Ratio ◽  
Glomerular Injury ◽  
Glucagon Receptor

Clinical studies have shown that patients with early Type 2 diabetes often have elevated serum glucagon rather than insulin deficiency. Imbalance of insulin and glucagon in favouring the latter may contribute to impaired glucose tolerance, persistent hyperglycaemia, microalbuminuria and glomerular injury. In the present study, we tested the hypothesis that long-term glucagon infusion induces early metabolic and renal phenotypes of Type 2 diabetes in mice by activating glucagon receptors. Five groups of adult male C57BL/6J mice were treated with vehicle, glucagon alone (1 μg/h via an osmotic minipump, intraperitoneally), glucagon plus the glucagon receptor antagonist [Des-His1-Glu9]glucagon (5 μg/h via an osmotic minipump), [Des-His1-Glu9]glucagon alone or a high glucose load alone (2% glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129% (P<0.05), raised systolic BP (blood pressure) by 21 mmHg (P<0.01), elevated fasting blood glucose by 42% (P<0.01), impaired glucose tolerance (P<0.01), increased the kidney weight/body weight ratio (P<0.05) and 24 h urinary albumin excretion by 108% (P<0.01) and induced glomerular mesangial expansion and extracellular matrix deposition. These responses were associated with marked increases in phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt signalling proteins in the liver and kidney (P<0.01). Serum insulin did not increase proportionally. Concurrent administration of [Des-His1-Glu9]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His1-Glu9]glucagon also improved glucagon-inpaired glucose tolerance, increased serum insulin by 56% (P<0.05) and attenuated glomerular injury. However, [Des-His1-Glu9]glucagon or high glucose administration alone did not elevate fasting blood glucose levels, impair glucose tolerance or induce renal injury. These results demonstrate for the first time that long-term hyperglucagonaemia in mice induces early metabolic and renal phenotypes of Type 2 diabetes by activating glucagon receptors. This supports the idea that glucagon receptor blockade may be beneficial in treating insulin resistance and Type 2 diabetic renal complications.

Abstract 404: NLR Family, Pyrin Domain-containing 3 Knockout Rescues Cardiac Dysfunction Induced by High-fat Diet Feeding

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Matthew R Peterson ◽  
Samantha Haller ◽  
Tracy Ta ◽  
Luiza Bosch ◽  
Aspen Smith ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Inflammatory Response ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Left Ventricular ◽  
Normal Diet ◽  
High Fat ◽  
Pyrin Domain

NLR family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor responsible for perpetuating an inflammatory response through production of pro-inflammatory cytokines IL-1β and IL-18. It has been implicated in the sustained inflammatory response in obesity and multiple cardiovascular disease conditions. In order to investigate NLRP3 as a potential therapeutic target in metabolic syndrome, C57BL/6 wild-type (WT) and NLRP3 knockout (NLRP3-\-) mice were fed a normal diet (ND; 12% fat chow) or a high fat diet (HFD; 45% fat chow) for 5 months. At 5 months, echocardiography and glucose tolerance tests (GTTs) were performed. Cardiac function assessed by fractional shortening (FS) was significantly impaired by HFD feeding in the WT group (0.335 HFD vs. 0.456 ND; p<0.05) but not in the NLRP3-\- (0.449 HFD vs. 0.492 ND; p>0.05). FS was higher in NLRP3-\-HFD than in WT-HFD (p<0.05). Two-dimensional analysis shows the FS difference between NLRP3-\-HFD and WT-HFD was primarily explained by the difference in left ventricular end-systolic dimension (0.2716 cm WT vs. 0.1883 cm NLRP3-\-; p<0.05). Glucose tolerance measured by area under the curve (AUC) was significantly impaired by HFD feeding for both WT (23183 ND vs. 57298 HFD; p<0.001) and NLRP3-\- (23197 ND vs. 44626 HFD; p<0.001), but significantly better in the NLRP3-\-HFD than in WT-HFD (p<0.01). HFD feeding increased fasting blood glucose (FBG) for both WT (97.7 mg . dl -1 ND vs. 164.7 mg . dl -1 HFD; p<0.01) and NLRP3-\- (80.50 mg . dl -1 ND vs. 108.8 mg . dl -1 HFD; p<0.05), but significantly less in NLRP3-\- mice (NLRP3-\- vs. WT; p<0.05). For GTTs, body weight was significantly higher in the WT than NLRP3-\- fed HFD (47.93 g vs. 36.5 g; p<0.001). Body weight explained 92% of variation in glucose tolerance (p<0.0001) and 69% of variation in fasting blood glucose (p<0.0001). WT-HFD averaged 1.31X heavier than NLRP3-\-HFD, while the AUC for the IGTT was 1.28X larger for the WT-HFD than NLRP3-\-HFD. Body weights were not significantly different between genotypes at the time of echo. The results suggest that knockout of NLRP3 may be protective against HFD induced cardiovascular dysfunction. A protective effect on glucose tolerance is not strongly supported.

Studies on hypoglycaemic effects of polyherbal preparation in streptozotocin-induced diabetic male albino rats

2009 ◽  
Vol 28 (11) ◽  
pp. 679-687
Author(s):  
A. Ismail Khan ◽  
S. Yuvaraj ◽  
E. Suthagar ◽  
C. Parthasarathy ◽  
K. Balasubramanian
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Skeletal Muscles ◽  
Glucose Oxidation ◽  
Serum Insulin ◽  
Insulin Level ◽  
Diabetic Rats ◽  
Vehicle Group ◽  
Albino Rats ◽  
Serum Insulin Level

Many traditional treatments have been recommended in the alternative system of medicine for diabetes mellitus. However, the mode of action of most of the herbals used has not been defined. It has been reported that sex hormones are important regulators of insulin-mediated events in skeletal muscles. In view of this, a novel herbal preparation containing antidiabetic and aphrodisiac plants was used in the present study. Adult male albino rats were divided into following groups after induction of diabetes. Rats were given an intraperitoneal (i.p.) injection of streptozotocin (STZ), at a dose of 65 mg/kg body weight after overnight fasting, to induce diabetic state with blood glucose levels >250 mg/dL. Group 1—Control rats treated with single i.p. injection of vehicle, Group 2—Rats treated with polyherbal preparation (PHP; 500 mg/kg body weight by oral intubation, morning and evening for 30 days), Group 3—STZ-diabetic rats treated orally with equal volumes of vehicle (water) alone and Group 4—STZ-diabetic rats treated with PHP after 10 days of diabetic induction. STZ-diabetes decreased the body weight, serum insulin level and glucose oxidation in liver and skeletal muscles but increased the fasting blood glucose level. After polyherbal treatment, body weight and glucose oxidation were completely restored to control level while serum insulin level was restored partially and the glucose tolerance was significantly improved. There was a significant decrease in total haemoglobin (Hb) level of diabetic rats when compared to control but polyherbal treatment significantly improved the same. However, the other parameters studied (red blood cell [RBC], white blood corpuscle [WBC], packed cell volume [PCV], mean corpuscular volume [MCV] and mean corpuscular haemoglobin [MCH]) were unaltered. In conclusion, the anti-diabetic properties of PHP appear to be mediated through pancreatic β-cell regeneration, resulting in maintenance of optimal blood glucose and its oxidation in liver and skeletal muscles.

scholarly journals Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

2016 ◽  
Vol 311 (2) ◽  
pp. E380-E395 ◽  
Author(s):  
María S. Bianchi ◽  
Stefanía Bianchi ◽  
Andrés Hernado-Insúa ◽  
Leandro M. Martinez ◽  
Néstor Lago ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Glucose ◽  
Autoimmune Diabetes ◽  
Serum Insulin ◽  
Diabetic Mice ◽  
Cell Recovery ◽  
Β Cell ◽  
Diabetes Model ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1

Type 1 diabetes (T1D) originates from autoimmune β-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cell cloning capacity and reverts toxic diabetes in rats. Here, we evaluated long-term (20 doses) and short-term (2–6 doses) effects of IMT504 (20 mg·kg−1·day−1 sc) in an immunodependent diabetes model: multiple low-dose streptozotocin-injected BALB/c mice (40 mg·kg−1·day−1 ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced β-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased β-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproi nsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine ( Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule- 1 ( Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 ( Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate β-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.

Detection of Glycemic Abnormalities in Young Adult Patients with Beta Thalassemia Major Using Continuous Glucose Monitoring System (CGMS) and Oral Glucose Tolerance Test (OGTT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2158-2158
Author(s):  
Mohamed A. Yassin ◽  
Ahmed M Elawa ◽  
Ashraf T Soliman
Keyword(s):  
Glucose Tolerance ◽  
Oral Glucose Tolerance Test ◽  
Glucose Tolerance Test ◽  
Cell Function ◽  
Serum Insulin ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Β Cell ◽  
Β Cell Function

Abstract Abstract 2158 Introduction: Both insulin deficiency and insulin resistance are reported in patients with β thalassemia major (BTM). The use of continuous blood glucose monitoring system (CGMS) among the different methods for early detection of glycaemic abnormalities has not been studied thoroughly in these patients. Aims: The aims of this study were: 1. to detect glycaemic abnormalities, if any, in young adults with BTM using fasting blood glucose (FBG), oral glucose tolerance test (OGTT), 72-h continuous glucose concentration by CGMS system, and serum insulin and C-peptide concentrations 2. To compare the results of these two methods in detecting glycaemic abnormalities in these patients and 3. To calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in these patients. In order to evaluate whether glycaemic abnormalities are due to insulin deficiency and/or resistance. Materials and methods: Randomly selected young adults (n = 14) with BTM were the subjects of this study. All patients were investigated using a standard oral glucose tolerance test (OGTT) (using 75 gram of glucose) and 72-h continuous glucose concentration by CGM system (Medtronic system). Fasting serum insulin and C-peptide concentrations were measured and HOMA-B, HOMA-IR were calculated accordingly. Results: Using OGTT, 5 patients had impaired fasting glucose (IFG) (Fasting BG from 5.6 to 6.9 mmol/L). Two of them had impaired glucose tolerance IGT (BG from 7.8 and < 11.1 mmol/L) and one had BG = 16.2 mmol/L after 2-hrs (diabetic). Using CGMS in addition to the glucose data measured by glucometer (3–5 times/ day), 6 patients had IFG. The maximum (postprandial) BG recorded exceeded 11.1 mmol/L in 4 patients (28.5%) (Diabetics) and was > 7.8 but < 11.1 mmol/L in 8 patients (57%) (IGT). The mean values of HOMA and QUICKI in patients with BTM were < 2.6 (1.6± 0.8) and > 0.33 (0.36±0.03) respectively ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B %) on the one hand and the fasting and the 2-h BG (r= −0.6, and − 0.48, P< 0.01 respectively) on the other hand. Serum insulin concentrations were not correlated with fasting BG or ferritin levels. The average and maximum BG levels recorded by CGMS were significantly correlated with the fasting BG (r= 0.69 and 0.6 respectively with P < 0.01) and with the BG at 2-hour after oral glucose intake (r= 0.87and 0.86 respectively with P < 0.01). Ferritin concentrations were positively correlated with the fasting BG and the 2-h BG levels in the OGTT (r= 0.69, 0.43 respectively, P < 0.001) as well as with the average and the maximum BG recorded by CGM (r =0.75, and 0.64 respectively with P < 0.01). Ferritin concentrations were negatively correlated with the β-cell function (r= −0.41, P< 0.01). Conclusion: CGMS has proved to be superior to OGTT for the diagnosis of glycaemic abnormalities in young adult patients with BTM. In our patients, defective β-cell function rather than insulin resistance appeared to be the cause for these abnormalities. The significant correlations between serum ferritin concentrations and the beta cell functions suggested the importance of adequate chelation to prevent β-cell dysfunction Disclosures: No relevant conflicts of interest to declare.

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