scholarly journals In vivo and in vitro suppression by leptin of glucose-stimulated insulin hypersecretion in high glucose-fed rats

2000 ◽  
pp. 431-437 ◽  
Author(s):  
G Widdup ◽  
JM Bryson ◽  
D Pawlak ◽  
JL Phuyal ◽  
GS Denyer ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Basal Insulin ◽  
Insulin Response ◽  
Fold Increase ◽  
Tolerance Test ◽  
Glycaemic Index ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

OBJECTIVES: Chronic feeding to rats of high glycaemic index (GI) diets results in the hypersecretion of insulin in response to an i.v. glucose load. The first aim of this study was to see if this exaggerated insulin response was accompanied by a hypersensitivity to glucose stimulation in isolated islets in vitro. The second aim was to see if the adipocyte factor, leptin, was able to alter insulin secretion in this model both in vivo and in vitro. DESIGN AND METHODS: Rats were fed for 6 weeks either a high GI diet in which the carbohydrate component was mostly glucose (GLUC diet) or a low GI diet containing mostly amylose (AMOSE diet). Rats then underwent an i.v. glucose tolerance test (ivGTT) (1g/kg) with and without a prior infusion of leptin (133 microg/kg perh). Islets were then isolated from these rats and basal and glucose-stimulated insulin secretion (GSIS) measured in both the absence and presence (100ng/ml) of leptin. RESULTS AND CONCLUSIONS: Peak insulin response during the ivGTT was 3-fold greater in GLUC rats (P<0.001). Leptin had no effect on AMOSE rat insulin response but lowered the GLUC rat response to AMOSE rat levels. In vitro, basal insulin secretion was 4-fold greater in GLUC rats (P<0.05). At 20mmol/l glucose, there was no further increase in insulin secretion in GLUC rats but a 2-fold increase in AMOSE rats. Leptin had no effect on basal insulin secretion or GSIS in AMOSE rats but reduced basal insulin secretion and GSIS in GLUC rats. These results show insulin hypersecretion in high GI-fed rats may be reduced by leptin.

scholarly journals Loss-of-Function Mutation of the Galanin Gene Is Associated with Perturbed Islet Function in Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3190-3196 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini ◽  
David Wynick ◽  
Nils Wierup ◽  
Frank Sundler
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Insulin Response ◽  
Tolerance Test ◽  
Glucose Disposal ◽  
Islet Function ◽  
Loss Of Function ◽  
Euglycemic Hyperinsulinemic Clamp

Abstract The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1–5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P &lt; 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P &lt; 0.001) and in isolated islets (P &lt; 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P &lt; 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.

Abstract 14: The Anti-atherosclerosis ABCA1 Agonist CS6253 Confer Glucose Control by Improved Pancreas Beta-cell Insulin Secretion and Enhanced Peripheral Insulin Utility

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
John K Bielicki ◽  
Anouar Hafiane ◽  
Jacques Genest ◽  
Jan O Johansson ◽  
Stefanie Bittner ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Uptake ◽  
Cell Function ◽  
Insulin Response ◽  
Fold Increase ◽  
Liver Weight ◽  
Metabolic Effects ◽  
Cvd Risk

Background: Type 2 Diabetes Mellitus (T2DM) is associated with high cardiovascular disease (CVD) risk. Addressing the underlying atherogenesis and diabetes causing CVD in T2DM is important. CS6253 is an ABCA1 agonist peptide derived from the C-terminal of apoE that has shown macrophage specific reverse cholesterol transport, anti-atherosclerosis and anti-diabetic properties. Further studies were carried out to characterize metabolic effects. Methods: CS6253 was incubated with a) INS-1 823/13 cells to assess effects on insulin secretion and b) with L6-Glut4myc rat myoblasts to assess glucose uptake properties. Diet Induced Obesity (DIO) mice, i.e. C57BL/6 mice that had been fed 60% high-fat diet for 6 weeks, were treated with CS6253 and Glucose Tolerance Tests (GTT) performed after overnights fasting administering glucose 1g/kg ip. Results: CS6253 1mg/mL incubated for 2 hours under standard conditions with 3mM glucose showed a 3-fold increase in insulin secretion compared to control, i.e. 232(32) vs. 79(7) ng/M cells, p<0.001. 3 H-glucose uptake by CS6253 peptide in L6-Glut4myc rat myoblasts increased insulin’s glucose uptake capacity from 3800 to 4619 DPM/well, p<0.001 . CS6253 alone had no effect on 3 H-glucose uptake compared to control. DIO mice were treated with CS6253 30mg/kg sc alternate days or PBS control for 16 weeks. GTTs were performed after 2, 6 and 15 weeks treatment showing 39%, 45% and 57% reductions in the glucose-AUC compared to control, respectively, p<0.01 for all time points. Insulin response to GTT after 5 weeks treatment showed a strong improvement of the insulin-curve by CS6253, p<0.05 vs. placebo. CS6253 treated DIO mice showed a non-significant body weight decrease and a 17% reduction in liver weight, 5.28g vs. 4.36g, p<0.01. Discussion: CS6253 shows potent, sustained and increased anti-diabetic actions over the 16 weeks treatment period in DIO mice. In vivo and in vitro studies show improved pancreas β-cell function with increased glucose-mediated insulin secretion and also insulin sensitizing properties. CS6253’s combined anti-diabetic and anti-atherosclerosis properties suggest utility in the treatment of CVD and T2DM.

scholarly journals Simulated Cholinergic Reinnervation ofβ(INS-1) Cells: Antidiabetic Utility of Heterotypic Pseudoislets ContainingβCell and Cholinergic Cell

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ao Jiao ◽  
Feng Li ◽  
Chengshuo Zhang ◽  
Wu Lv ◽  
Baomin Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
3D Culture ◽  
Cholinergic Neurons ◽  
Fold Increase ◽  
Culture Conditions ◽  
Glucose Stimulated Insulin Secretion ◽  
E Cadherin

Cholinergic neurons can functionally support pancreatic islets in controlling blood sugar levels. However, in islet transplantation, the level of cholinergic reinnervation is significantly lower compared to orthotopic pancreatic islets. This abnormal reinnervation affects the survival and function of islet grafts. In this study, the cholinergic reinnervation of beta cells was simulated by 2D and 3D coculture of INS-1 and NG108-15 cells. In 2D culture conditions, 20 mM glucose induced a 1.24-fold increase (p<0.0001) in insulin secretion from the coculture group, while in the 3D culture condition, a 1.78-fold increase (p<0.0001) in insulin secretion from heterotypic pseudoislet group was observed. Glucose-stimulated insulin secretion (GSIS) from 2D INS-1 cells showed minimal changes when compared to 3D structures. E-cadherin expressed in INS-1 and NG108-15 cells was the key adhesion molecule for the formation of heterotypic pseudoislets. NG108-15 cells hardly affected the proliferation of INS-1 cells in vitro. Heterotypic pseudoislet transplantation recipient mice reverted to normoglycemic levels faster and had a greater blood glucose clearance compared to INS-1 pseudoislet recipient mice. In conclusion, cholinergic cells can promote insulin-secreting cells to function better in vitro and in vivo and E-cadherin plays an important role in the formation of heterotypic pseudoislets.

Evidence for defective glucose sensing by islets of fa/fa obese Zucker rats

1993 ◽  
Vol 71 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Catherine B. Chan ◽  
Ruth M. MacPhail ◽  
Katherine Mitton
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Glucose Sensing ◽  
Zucker Rats ◽  
Rat Islets ◽  
Glucose Levels ◽  
Half Maximal Effective Concentration ◽  
Glucose Stimulated Insulin Secretion

The hypothesis that a defect in glucose sensing by islets of fa/fa Zucker rats contributes to hyperinsulinemia in these animals was tested. Islets from lean and fa/fa rats were isolated by collagenase digestion and step-density gradient purification and then cultured overnight in Dulbecco's modified Eagle's medium containing 12.5 mM glucose. Obese rat islets were more sensitive to hypoglycemic glucose levels with half-maximal effective concentration (EC50) of 5.6 mM compared with an EC50 of 8.2 mM for lean rat islets. In contrast, responsiveness of both phenotypes to α-ketoisocaproate and quinine was similar. Mannoheptulose did not inhibit insulin secretion from fa/fa islets, although inhibitors of later events in the stimulus–secretion coupling pathway were normally inhibited by iodoacetate and diazoxide. Finally, starvation in vivo and culture of islets in low glucose concentrations (5 mM) in vitro both decreased glucose-stimulated insulin secretion from lean but not fa/fa rat islets. We conclude that fa/fa rat islets have an exaggerated insulin response to hypoglycemic stimuli, possibly as a result of a defect in B-cell glucokinase function.Key words: insulin secretion, obesity, glucose metabolism, starvation.

scholarly journals Disruption of the Dopamine D2 Receptor Impairs Insulin Secretion and Causes Glucose Intolerance

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1441-1450 ◽  
Author(s):  
Isabel García-Tornadú ◽  
Ana M. Ornstein ◽  
Astrid Chamson-Reig ◽  
Michael B. Wheeler ◽  
David J. Hill ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Insulin Response ◽  
Wild Type ◽  
Β Cell ◽  
Insulin Response To Glucose

The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2−/−) mice and in isolated islets from wild-type and Drd2−/− mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2−/− male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2−/− mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2−/− mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic β-cell mass in Drd2−/− mice and decreased β-cell replication in 2-month-old Drd2−/− mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops.

Abstract 606: Impaired Glucose Metabolism in the Triggering Receptor Expressed in Myeloid Cells Like Transcript- 1 Null Mice A Link to Obesity

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Elizabeth Castro Rivera ◽  
Abdías Díaz Rosado ◽  
Anthony V Washington
Keyword(s):  
Serum Insulin ◽  
Insulin Response ◽  
Myeloid Cells ◽  
Tolerance Test ◽  
Similar Response ◽  
Fatty Acid Production ◽  
Glucose Levels ◽  
Significant Difference

Fat rich foods have been shown to produce increased body weight and diabetes in various strains of mice. When fed ad libitum with a high fat diet (HFD), apolipoprotein E deficient ( apoe -/- ) mice develop hypercholesterolemia, but are not known to be obese. Our laboratory demonstrated that the triggering receptor expressed in myeloid cells (TREM) like transcript-1 (TLT-1), as a potential target for intervention during atherosclerosis, diabetes, and obesity. Crossing the treml1 -/- mouse onto an apoe -/- background (DKO), we found DKO mice had smaller lesions than apoe -/- mice, yet had significantly higher triglycerides and weight gain over a 20-week period of HFD. Further investigation demonstrated treml1 -/- mice to have higher cholesterol than wild type mice (wt), suggesting the treml1 mutation contributes to the phenotype observed in DKO mice. Glucose evaluation of treml1 -/- , treml1 +/- and wt mice, showed a significant difference in basal glucose, and in plasma glucose clearance, as revealed by intraperitoneal (IP) glucose tolerance test. Analysis of serum insulin by ELISA showed no differences, while IP insulin tolerance test revealed treml1 -/- and treml1 +/- mice present apparent insulin hypersensitivity, as represented by the steady glucose decline 15 min post injection, with no recovery after two hours. Western blot performed in various tissues, demonstrated the presence of a TLT-1 splice variant that lacks the extracellular domain (TLT-1s), in the adipose tissue of treml1 -/- but not wt mice. Analysis of insulin response, in vivo by insulin sensitivity assay and in vitro using TSA 201 cells transfected with TLT-1s to determine the effect on AKT activation, revealed enhanced phosphorylation in the presence of TLT-1, with a similar response observed in vitro. This data support a model where TLT-1s modulation of AKT phosphorylation, increases adipocyte glucose uptake, leading to: low blood glucose levels, increased fatty acid production and storage, and the obese phenotype we observed in our mice.

scholarly journals Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4171-4180 ◽  
Author(s):  
Takashi Nakakura ◽  
Chihiro Mogi ◽  
Masayuki Tobo ◽  
Hideaki Tomura ◽  
Koichi Sato ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Insulin Secretion ◽  
G Protein ◽  
Normal Glucose Tolerance ◽  
Extracellular Ph ◽  
G Protein Coupled Receptor ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of Gq/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/Gq/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl.

scholarly journals Can Manipulation of Durum Wheat Amylose Content Reduce the Glycaemic Index of Spaghetti?

Foods ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 693 ◽  
Author(s):  
Mike Sissons ◽  
Francesco Sestili ◽  
Ermelinda Botticella ◽  
Stefania Masci ◽  
Domenico Lafiandra
Keyword(s):  
Durum Wheat ◽  
Wheat Cultivar ◽  
Amylose Content ◽  
Fold Increase ◽  
Glycaemic Index ◽  
Glycaemic Response ◽  
Branching Enzymes ◽  
Lifestyle Diseases

Resistant starch (RS) in foods has positive benefits for potentially alleviating lifestyle diseases. RS is correlated positively with starch amylose content. This study aimed to see what level of amylose in durum wheat is needed to lower pasta GI. The silencing of starch synthases IIa (SSIIa) and starch branching enzymes IIa (SBEIIa), key genes involved in starch biosynthesis, in durum wheat cultivar Svevo was performed and spaghetti was prepared and evaluated. The SSIIa and SBEIIa mutants have a 28% and 74% increase in amylose and a 2.8- and 35-fold increase in RS, respectively. Cooked pasta was softer, with higher cooking loss but lower stickiness compared to Svevo spaghetti, and with acceptable appearance and colour. In vitro starch digestion extent (area under the digestion curve) was decreased in both mutants, but much more in SBEIIa, while in vivo GI was only significantly reduced from 50 to 38 in SBEIIa. This is the first study of the glycaemic response of spaghetti prepared from SBEIIa and SSIIa durum wheat mutants. Overall pasta quality was acceptable in both mutants but the SBEIIa mutation provides a clear glycaemic benefit and would be much more appealing than wholemeal spaghetti. We suggest a minimum RS content in spaghetti of ~7% is needed to lower GI which corresponded to an amylose content of ~58%.

Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting

1995 ◽  
Vol 269 (3) ◽  
pp. E478-E488 ◽  
Author(s):  
N. Porksen ◽  
S. Munn ◽  
J. Steers ◽  
S. Vore ◽  
J. Veldhuis ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Portal Vein ◽  
Basal Insulin ◽  
Deconvolution Analysis ◽  
Insulin Secretion In Vivo ◽  
Endogenous Insulin Secretion ◽  
Endogenous Insulin ◽  
Basal Insulin Secretion ◽  
Secretion Rates

The purpose of the present study was to determine the contributions of discrete insulin secretory bursts vs. basal insulin release to total insulin secretion in vivo. Quantification of the partitioning of pulsatile and basal insulin secretion is complicated by physiological delivery of these pulses into the portal vein and the absence of validated methods of measuring the rates of pulsatile and basal insulin secretion in vivo. We therefore 1) developed a canine model with chronically implanted portal vein catheters, 2) validated an established deconvolution technique as well as a novel direct catheterization technique (Clustcath) for measurement of pulsatile and nonpulsatile insulin secretion rates in this model, and 3) applied these methods to study insulin secretion in the overnight-fasted dog in vivo to determine the contribution of pulsatile vs. basal insulin secretion to total rates of endogenous insulin secretion. Rates of total, pulsatile, and nonpulsatile endogenous insulin secretion measured by Cluscath closely parallel those measured by deconvolution analysis (54 +/- 15 vs. 51 +/- 11, 38 +/- 12 vs. 36 +/- 11, and 16 +/- 4 vs. 14 +/- 4 pmol/min, respectively). Clustcath and deconvolution indicated that the majority of insulin was secreted as pulses (70 +/- 6 and 66 +/- 7%, respectively). These data infer that any process that selectively decreases the pulsatile component of insulin secretion (e.g., diabetes mellitus) will likely have a major impact on total insulin secretion.

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