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.

Small molecule glucokinase activators as novel anti-diabetic agents

2005 ◽  
Vol 33 (2) ◽  
pp. 371-374 ◽  
Author(s):  
B. Leighton ◽  
A. Atkinson ◽  
M.P. Coghlan
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Type Ii Diabetes Mellitus ◽  
Glucose Sensing ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucokinase Activators

The monomeric enzyme GK (glucokinase) has a low affinity for glucose and, quantitatively, is largely expressed in the liver and pancreatic β-cells, playing a key ‘glucose sensing’ role to regulate hepatic glucose balance and insulin secretion. Mutations of GK in man can be inactivating, to cause a form of diabetes mellitus, or activating, to lower blood glucose levels. Recently, models of GK protein structure have helped to elucidate the role of inactivating and activating mutations, with the latter revealing an allosteric binding site, possibly for an unknown physiological activator. However, this discovery was pre-dated by Drug Discovery projects that have identified small organic molecules that activate pancreatic and liver GK enzyme activity. These compounds stimulate insulin secretion in islets and glucose metabolism in hepatocytes. The profile of these GK activators, both in vitro and in vivo and the potential role that GK activators play in lowering blood glucose levels in Type II diabetes mellitus will be discussed.

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.

Ethanol inhibition of insulin secretion by perifused rat islets

1980 ◽  
Vol 93 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Sant P. Singh ◽  
D. G. Patel ◽  
Ann K. Snyder
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Significant Inhibition ◽  
Rat Islets ◽  
Insulin Response To Glucose ◽  
Pre Treatment ◽  
In Vitro Effects ◽  
Kinetics Of

Abstract. In vivo and in vitro effects of ethanol on the kinetics of insulin secretion in response to glucose and tolbutamide were studied in perifused rat islets. Phases I and II insulin response to 16.7 mm glucose was decreased 46% and 48%, respectively, in islets of rats given ethanol intragastrically 1 g/kg 1 h prior to sacrifice. Mean blood ethanol levels at the time of animal sacrifice were 19.4 mmol/l. The magnitude of insulin suppression was not significantly enhanced with higher ethanol doses, 2 or 3 g/kg, although mean blood ethanol levels increased to 25.9 and 60.3 mmol/l, respectively. Similarly, significant inhibition of both phases of insulin response to glucose occurred when ethanol 1 or 3 g/kg was given intraperitoneally instead of orally. Ethanol had no effect on insulin secretion when given orally 4 h instead of 1 h prior to islet isolation. Ethanol, 65 mmol/l, added directly to rat islets perifusate simultaneously with 16.7 m m glucose decreased both phases I and II insulin response nearly half; whereas addition of 21.7 instead of 65 mmol/l ethanol had no effect. Pre-treatment of islets with 21.7 or 65 mmol/l ethanol during 30 min basal islets perifusion period had no effect on subsequent insulin response to 16.7 mm glucose. Insulin response to 10 mm tolbutamide was decreased nearly 81% by the simultaneous presence of 65 mmol/l ethanol in islets perifusate.

scholarly journals Glucose-dependent and Glucose-sensitizing Insulinotropic Effect of Nateglinide: Comparison to Sulfonylureas and Repaglinide

2001 ◽  
Vol 2 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Shiling Hu ◽  
Shuya Wang ◽  
Beth E. Dunning
Keyword(s):  
Insulin Secretion ◽  
Mechanism Of Action ◽  
Basic Mechanism ◽  
Glucose Levels ◽  
Physiologic Effect ◽  
Glucose Sensitivity ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulinotropic Effect

Nateglinide, a novel D-phenylalanine derivative, stimulates insulin releaseviaclosure ofKATPchannels in pancreaticβ-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS)in vitrofrom isolated rat islets. TheEC50of nateglinide to stimulate insulin secretion was 14 μM in the presence of 3mM glucose and was reduced by 6-fold in 8mM glucose and by 16-fold in 16mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (~2xEC50in the presence of 8mM glucose) nateglinide and repaglinide shifted theEC50s for GSIS to the left by 1.7mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of theEC50. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemiain vivo.

scholarly journals Cephalic phase insulin secretion is KATP channel independent

2013 ◽  
Vol 218 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Yusuke Seino ◽  
Takashi Miki ◽  
Wakako Fujimoto ◽  
Eun Young Lee ◽  
Yoshihisa Takahashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Critical Role ◽  
Pancreas Perfusion ◽  
Glucose Levels ◽  
Cephalic Phase ◽  
Plasma Insulin Levels ◽  
Atropine Methyl Nitrate ◽  
Nutrient Injection

Glucose-induced insulin secretion from pancreatic β-cells critically depends on the activity of ATP-sensitive K+channels (KATPchannel). We previously generated mice lackingKir6.2, the pore subunit of the β-cell KATPchannel (Kir6.2−/−), that show almost no insulin secretion in response to glucosein vitro. In this study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) andKir6.2−/−mice. Underad libitumfeeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar inKir6.2+/+andKir6.2−/−mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly inKir6.2−/−mice but was markedly attenuated compared with that inKir6.2+/+mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent inKir6.2−/−mice. Pretreatment with a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood–brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate inKir6.2−/−mice. Substantial glucose-induced insulin secretion was induced in the pancreas perfusion study ofKir6.2−/−mice only in the presence of carbamylcholine. These results suggest that a KATPchannel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrientsin vivo.

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.

Ca2+ deficiency, selective alpha-glucosidehydrolase inhibition, and insulin secretion

1993 ◽  
Vol 265 (1) ◽  
pp. E1-E9 ◽  
Author(s):  
A. Salehi ◽  
I. Lundquist
Keyword(s):  
Insulin Secretion ◽  
Acid Phosphatase ◽  
Insulin Release ◽  
Insulin Response ◽  
Selective Inhibition ◽  
Half Maximal Effective Concentration ◽  
Insulin Secretory Response ◽  
Dose Dependent ◽  
Alpha Glucosidase

We investigated the relation between activities of islet glycogenolytic alpha-glucosidehydrolases and insulin secretion induced by glucose and 3-isobutyl-1-methylxanthine (IBMX) by means of suppressing 1) insulin release (Ca2+ deficiency) and 2) islet alpha-glucosidehydrolase activity (selective inhibition by the deoxynojirimycin derivative miglitol). Additionally, the in vivo insulin response to both secretagogues was examined. We observed that, similar to glucose-induced insulin release, islet glycogenolytic hydrolases (acid amyloglucosidase, acid alpha-glucosidase) were highly Ca2+ dependent. Acid phosphatase, N-acetyl-beta-D-glucosaminidase, or neutral alpha-glucosidase (endoplasmic reticulum) was not influenced by Ca2+ deficiency. In Ca2+ deficiency IBMX-induced insulin release was unaffected and was accompanied by reduced activities of islet alpha-glucosidehydrolases. Miglitol strongly inhibited glucose-induced insulin release concomitant with a marked suppression of islet alpha-glucosidehydrolase activities. Direct addition of miglitol to islet homogenates suppressed acid amyloglucosidase [half-maximal effective concentration (EC50) approximately 10(-6) M] and acid alpha-glucosidase. Acid phosphatase and N-acetyl-beta-D-glucosaminidase were unaffected. The miglitol-induced inhibition of glucose-stimulated insulin release was dose dependent (EC50 approximately 10(-6) M) and displayed a remarkable parallelism with the inhibition curve for acid amyloglucosidase. The in vivo insulin secretory response to glucose was markedly reduced in dystrophic mice (low amyloglucosidase), whereas the response to IBMX was unaffected. In summary, islet glycogenolytic hydrolases are Ca2+ dependent, and acid amyloglucosidase is directly involved in the multifactorial process of glucose-induced insulin release. In contrast the mechanisms of IBMX-stimulated insulin secretion operate independently of these enzymes. The effects of miglitol, a drug currently used in diabetes therapy, deserves further investigation.

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.

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