scholarly journals Endogenous islet uncoupling protein-2 expression and loss of glucose homeostasis in ob/ob mice

2006 ◽  
Vol 190 (3) ◽  
pp. 659-667 ◽  
Author(s):  
Monique C Saleh ◽  
Michael B Wheeler ◽  
Catherine B Chan
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Uncoupling Protein ◽  
Isolated Islets ◽  
Oral Glucose ◽  
Uncoupling Protein 2 ◽  
Short Term ◽  
Ucp2 Expression

We hypothesized that the loss of glucose homeostasis in ob/ob mice is associated with upregulation of islet uncoupling protein-2 (UCP2) expression, leading to impaired glucose-stimulated insulin secretion (GSIS). Changes in glucose homeostasis in lean and ob/ob mice from 5 to 16 weeks were assessed by fasting blood glucose, plasma insulin, oral glucose tolerance, and tissue insulin sensitivity. In vitro GSIS and ATP content were assayed in isolated islets, while UCP2 expression was determined by quantitative real-time PCR and immunoblotting. Short-term reduction of UCP2 expression was achieved through transfection of islets with specific small interfering RNA. Insulin resistance was detected in 5-week-old ob/ob mice, but GSIS and blood glucose levels remained normal. By 8 weeks of age, ob/ob mice displayed fasting hyperglycemia, hyperinsulinemia and glucose intolerance, and also had elevated non-esterified fatty acid concentration in plasma. In vitro, GSIS and ATP generation were impaired in ob/ob islets. Islet UCP2 expression was elevated at 5 and 8 weeks of age. Short-term knockdown of islet UCP2 increased GSIS in islets of lean mice, but had no effect in islets from ob/ob mice. Loss of glucose homeostasis and impairment of insulin secretion from isolated islets at 8 weeks in ob/ob mice is preceded by an increase in UCP2 expression in islets. Moreover, the glucolipotoxic conditions observed are predicted to increase UCP2 activity, contributing to lower islet ATP and GSIS.

scholarly journals Mitochondrial uncoupling protein-2 deficiency protects steatotic mouse hepatocytes from hypoxia/reoxygenation

2012 ◽  
Vol 302 (3) ◽  
pp. G336-G342 ◽  
Author(s):  
Zachary P. Evans ◽  
Arun P. Palanisamy ◽  
Alton G. Sutter ◽  
Justin D. Ellett ◽  
Venkat K. Ramshesh ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Uncoupling Protein ◽  
Thiobarbituric Acid ◽  
Atp Depletion ◽  
Uncoupling Protein 2 ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein ◽  
Ucp2 Expression ◽  
Hypoxia Reoxygenation

Steatotic livers are sensitive to ischemic events and associated ATP depletion. Hepatocellular necrosis following these events may result from mitochondrial uncoupling protein-2 (UCP2) expression. To test this hypothesis, we developed a model of in vitro steatosis using primary hepatocytes from wild-type (WT) and UCP2 knockout (KO) mice and subjected them to hypoxia/reoxygenation (H/R). Using cultured hepatocytes treated with emulsified fatty acids for 24 h, generating a steatotic phenotype (i.e., microvesicular and broad-spectrum fatty acid accumulation), we found that the phenotype of the WT and UCP2 KO were the same; however, cellular viability was increased in the steatotic KO hepatocytes following 4 h of hypoxia and 24 h of reoxygenation; Hepatocellular ATP levels decreased during hypoxia and recovered after reoxygenation in the control and UCP2 KO steatotic hepatocytes but not in the WT steatotic hepatocytes; mitochondrial membrane potential in WT and UCP2 KO steatotic groups was less than control groups but higher than UCP2 KO hepatocytes. Following reoxygenation, lipid peroxidation, as measured by thiobarbituric acid reactive substances, increased in all groups but to a greater extent in the steatotic hepatocytes, regardless of UCP2 expression. These results demonstrate that UCP2 sensitizes steatotic hepatocytes to H/R through mitochondrial depolarization and ATP depletion but not lipid peroxidation.

scholarly journals Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

2015 ◽  
Vol 225 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Astrid C Hauge-Evans ◽  
James Bowe ◽  
Zara J Franklin ◽  
Zoheb Hassan ◽  
Peter M Jones
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Beta Cells ◽  
Plasma Insulin ◽  
Inhibitory Effect ◽  
Isolated Islets ◽  
Glucose Levels ◽  
Blood Glucose Levels

The inhibitory effect of somatostatin (SST) on insulin secretionin vivois attributed to a direct effect on pancreatic beta cells, but this is inconsistent with somein vitroresults in which exogenous SST is ineffective in inhibiting secretion from isolated islets. We therefore investigated whether insulin secretion from the pancreatic islets may partly be regulated by an indirect effect of SST mediated via the CNS. Islet hormone secretion was assessedin vitroby perifusion and static incubations of isolated islets andin vivoby i.v. or i.c.v. administration of the SST analogue BIM23014C with an i.v. glucose challenge to conscious, chronically catheterised rats. Hormone content of samples was assessed by ELISA or RIA and blood glucose levels using a glucose meter. Exogenous SST14/SST28 or BIM23014C did not inhibit the release of insulin from isolated rodent isletsin vitro, whereas peripheral i.v. administration of BIM23014C (7.5 μg) with glucose (1 g/kg) led to decreased plasma insulin content (2.3±0.5 ng insulin/ml versus 4.5±0.5 ng/ml att=5 min,P<0.001) and elevated blood glucose levels compared with those of the controls (29.19±1.3 mmol/l versus 23.5±1.7 mmol/l,P<0.05). In contrast, central i.c.v. injection of BIM23014C (0.75 μg) had no significant effect on either plasma insulin (3.3±0.4 ng/ml,P>0.05) or blood glucose levels (23.5±1.7 mmol/l,P>0.05) although i.v. administration of this dose increased blood glucose concentrations (32.3±0.7 mmol/l,P<0.01). BIM23014C did not measurably alter plasma glucagon, SST, GLP1 or catecholamine levels whether injected i.v. or i.c.v. These results indicate that SST does not suppress insulin secretion by a centrally mediated effect but acts peripherally on islet cells.

scholarly journals Antidiabetic Effect of Oral Borapetol B Compound, Isolated from the PlantTinospora crispa, by Stimulating Insulin Release

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Faradianna E. Lokman ◽  
Harvest F. Gu ◽  
Wan Nazaimoon Wan Mohamud ◽  
Mashitah M. Yusoff ◽  
Keh Leong Chia ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Release ◽  
Plasma Insulin ◽  
Tolerance Test ◽  
Isolated Islets ◽  
Oral Glucose ◽  
Isolated Pancreatic Islets ◽  
Gk Rats ◽  
Glucose Levels

Aims. To evaluate the antidiabetic properties of borapetol B known as compound 1 (C1) isolated fromTinospora crispain normoglycemic control Wistar (W) and spontaneously type 2 diabetic Goto-Kakizaki (GK) rats.Methods. The effect of C1 on blood glucose and plasma insulin was assessed by an oral glucose tolerance test. The effect of C1 on insulin secretion was assessed by batch incubation and perifusion experiments using isolated pancreatic islets.Results. An acute oral administration of C1 improved blood glucose levels in treated versus placebo groups with areas under glucose curves 0–120 min being72±17versus344±10 mmol/L (P<0.001) and492±63versus862±55 mmol/L (P<0.01) in W and GK rats, respectively. Plasma insulin levels were increased by 2-fold in treated W and GK rats versus placebo group at 30 min (P<0.05). C1 dose-dependently increased insulin secretion from W and GK isolated islets at 3.3 mM and 16.7 mM glucose. The perifusions of isolated islets indicated that C1 did not cause leakage of insulin by damaging islet beta cells (P<0.001).Conclusion. This study provides evidence that borapetol B (C1) has antidiabetic properties mainly due to its stimulation of insulin release.

scholarly journals Uncoupling protein 2 regulates daily rhythms of insulin secretion capacity in MIN6 cells and isolated islets from male mice

2017 ◽  
Vol 6 (7) ◽  
pp. 760-769 ◽  
Author(s):  
Nivedita Seshadri ◽  
Michael E. Jonasson ◽  
Kristin L. Hunt ◽  
Bo Xiang ◽  
Steven Cooper ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Uncoupling Protein ◽  
Isolated Islets ◽  
Uncoupling Protein 2 ◽  
Male Mice ◽  
Daily Rhythms ◽  
Min6 Cells

scholarly journals Glutathionylation State of Uncoupling Protein-2 and the Control of Glucose-stimulated Insulin Secretion

2012 ◽  
Vol 287 (47) ◽  
pp. 39673-39685 ◽  
Author(s):  
Ryan J. Mailloux ◽  
Accalia Fu ◽  
Christine Robson-Doucette ◽  
Emma M. Allister ◽  
Michael B. Wheeler ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Swertiamarin Contributes to Glucose Homeostasis via Inhibition of Carbohydrate Metabolizing Enzymes

2017 ◽  
Vol 16 (4) ◽  
pp. 125 ◽  
Author(s):  
Javed Ahamad ◽  
Naila Hassan ◽  
Saima Amin ◽  
Showkat R. Mir
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
In Vivo Studies ◽  
Metabolizing Enzymes ◽  
Treatment Groups ◽  
Whole Plant ◽  
Peak Blood ◽  
Peak Blood Glucose

<strong>Objective:</strong> Swertiamarin is a common secoiridoid found among the members of Gentianaceae. The present study aimed to establish the effectiveness of swertiamarin in achieving glucose homeostasis via inhibition of carbohydrate metabolizing enzymes by in-vitro and in-vivo studies. <strong>Materials and methods:</strong> Swertiamarin was obtained from dried whole plant samples of <em>Enicostemma littorale</em> Blume chromatographic fractionation over the silica gel column. Its effect on carbohydrate metabolizing enzymes viz., α-amylase and α-glucosidase were evaluated at 0.15 to 10 mg/mL in-vitro. The results were supplemented by anti-hyperglycemic studies in carbohydrate challenged mice pretreated with swertiamarin at a dose of 20 mg/kg body weight orally. <strong>Results:</strong> Swertiamarin was effective in inhibiting α-amylase and α-glucosidase with IC<em>50</em> values of 1.29±0.25 mg/mL and 0.84±0.11 mg/mL, respectively. The studies in starch and sucrose challenged mice showed that swertiamarin effectively restricted the increase in the peak blood glucose level (BGL). The increase in peak BGL was 49 mg/dL and 57 mg/dL only in the treatment groups compared to 70 mg/dL and 80 mg/dL in untreated groups after 30 min in starch and sucrose-fed mice, respectively. Acarbose (10 mg/kg b.w.) also produced significant (p&lt;0.01) blood glucose lowering response in both the models. <strong>Conclusion:</strong> Swertiamarin was effective in the achieving stricter glycemic control in carbohydrate challenged mice through the inhibition of carbohydrate metabolizing enzymes.

The effect of melatonin on incretin hormones – results from experimental and randomized clinical studies

2021 ◽  
Author(s):  
Esben Stistrup Lauritzen ◽  
Julie Støy ◽  
Cecilie Bæch-Laursen ◽  
Niels Grarup ◽  
Niels Jessen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Tolerance Test ◽  
University Hospital ◽  
Oral Glucose ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
In Situ Study

Abstract Context Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms with several lines of evidence suggesting that melatonin affects glucose homeostasis. Objective To evaluate the acute in-vivo and in-situ effects of melatonin on secretion of the incretin hormones, GLP-1 and GIP, and their impact on β-cell insulin secretion. Design A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in-situ study of perfused rat intestines. Setting Aarhus University Hospital. Methods: Fifteen healthy male participants were examined 2 x 2 times: An oral glucose tolerance test (OGTT) was performed on day one and an isoglycemic intravenous glucose infusion replicating the blood glucose profile of the OGTT day was performed on day two. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in-situ study, six rat intestines and four rat pancreases were perfused arterially with perfusion buffer ± melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. Results In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA p=0.003), an effect also observed in the perfused rat intestines (ANOVA p=0.003) in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA p&lt;0.001). Despite a decrease in GIP levels, the in-vivo glucose-stimulated insulin secretion was unaffected by melatonin (p=0.78). Conclusion Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in-situ model of the rat intestine.

scholarly journals GPR119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 374-383 ◽  
Author(s):  
Grace Flock ◽  
Dianne Holland ◽  
Yutaka Seino ◽  
Daniel J. Drucker
Keyword(s):  
Insulin Secretion ◽  
Gastric Emptying ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Peptide Yy ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Glucagon Like Peptide 1

Abstract G protein-coupled receptor 119 (GPR119) was originally identified as a β-cell receptor. However, GPR119 activation also promotes incretin secretion and enhances peptide YY action. We examined whether GPR119-dependent control of glucose homeostasis requires preservation of peptidergic pathways in vivo. Insulin secretion was assessed directly in islets, and glucoregulation was examined in wild-type (WT), single incretin receptor (IR) and dual IR knockout (DIRKO) mice. Experimental endpoints included plasma glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY. Gastric emptying was assessed in WT, Glp1r−/−, DIRKO, Glp2r−/−, and GPR119−/− mice treated with the GPR119 agonist AR231453. AR231453 stimulated insulin secretion from WT and DIRKO islets in a glucose-dependent manner, improved glucose homeostasis, and augmented plasma levels of GLP-1, GIP, and insulin in WT and Gipr−/−mice. In contrast, although AR231453 increased levels of GLP-1, GIP, and insulin, it failed to lower glucose in Glp1r−/− and DIRKO mice. Furthermore, AR231453 did not improve ip glucose tolerance and had no effect on insulin action in WT and DIRKO mice. Acute GPR119 activation with AR231453 inhibited gastric emptying in Glp1r−/−, DIRKO, Glp2r−/−, and in WT mice independent of the Y2 receptor (Y2R); however, AR231453 did not control gastric emptying in GPR119−/− mice. Our findings demonstrate that GPR119 activation directly stimulates insulin secretion from islets in vitro, yet requires intact IR signaling and enteral glucose exposure for optimal control of glucose tolerance in vivo. In contrast, AR231453 inhibits gastric emptying independent of incretin, Y2R, or Glp2 receptors through GPR119-dependent pathways. Hence, GPR119 engages multiple complementary pathways for control of glucose homeostasis.

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