scholarly journals The pancreatic β-cell recognition of insulin secretagogues. Effects of calcium and sodium on glucose metabolism and insulin release

1974 ◽  
Vol 138 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Bo Hellman ◽  
Lars-Åke Idahl ◽  
Åke Lernmark ◽  
Janove Sehlin ◽  
Inge-Bert Täljedal
Keyword(s):  
Glucose Metabolism ◽  
Insulin Release ◽  
Glucose Oxidation ◽  
Metabolic Model ◽  
Medium Composition ◽  
Cell Recognition ◽  
Β Cell ◽  
Metabolic Block ◽  
Microdissected Pancreatic Islets ◽  
Stimulus Recognition

The transport and oxidation of glucose, the content of fructose 1,6-diphosphate, and the release of insulin were studied in microdissected pancreatic islets of ob/ob mice incubated in Krebs–Ringer bicarbonate medium. Under control conditions glucose oxidation and insulin release showed a similar dependence on glucose concentration with the steepest slope in the range 5–12mm. The omission of Ca2+, or the substitution of choline ions for Na+, or the addition of diazoxide had little if any effect on glucose transport. However, Ca2+ or Na+ deficiency as well as diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) or ouabain partially inhibited glucose oxidation. These alterations of medium composition also increased the islet content of fructose 1,6-diphosphate, as did the addition of adrenaline. Phentolamine [2-N-(3-hydroxyphenyl)-p-toluidinomethyl-2-imidazoline] counteracted the effects of adrenaline and Ca2+ deficiency on islet fructose 1,6-diphosphate. After equilibration in Na+-deficient medium, the islets exhibited an increase in basal insulin release whereas the secretory response to glucose was inhibited. The inhibitory effects of Na+ deficiency on the secretory responses to different concentrations of glucose correlated with those on 14CO2 production. When islets were incubated with 17mm-glucose, the sudden replacement of Na+ by choline ions resulted in a marked but transient stimulation of insulin release that was not accompanied by a demonstrable increase of glucose oxidation. Galactose and 3-O-methylglucose had no effect on glucose oxidation or on insulin release. The results are consistent with a metabolic model of the β-cell recognition of glucose as insulin secretagogue and with the assumption that Ca2+ or Na+ deficiency, or the addition of adrenaline or diazoxide, inhibit insulin release at some step distal to stimulus recognition. In addition the results suggest that these conditions create a partial metabolic block of glycolysis in the β-cells. Hence the interrelationship between the processes of stimulus recognition and insulin discharge may involve a positive feedback of secretion on glucose metabolism.

scholarly journals Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic β-cell glucose metabolism and insulin secretion

2006 ◽  
Vol 189 (2) ◽  
pp. 301-310 ◽  
Author(s):  
S Patterson ◽  
P R Flatt ◽  
L Brennan ◽  
P Newsholme ◽  
N H McClenaghan
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Insulin Release ◽  
Cell Function ◽  
Tca Cycle ◽  
Gastric Inhibitory Polypeptide ◽  
Β Cell ◽  
The Metabolic Syndrome ◽  
Cell Glucose

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on β-cell function and insulin secretion using clonal BRIN-BD11 β-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7–36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in β-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible β-cell demise merits further investigation.

scholarly journals Attenuated Insulin Release and Storage in Fetal Sheep Pancreatic Islets with Intrauterine Growth Restriction

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1488-1497 ◽  
Author(s):  
Sean W. Limesand ◽  
Paul J. Rozance ◽  
Gary O. Zerbe ◽  
John C. Hutton ◽  
William W. Hay
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Intrauterine Growth Restriction ◽  
Glucose Oxidation ◽  
Placental Insufficiency ◽  
Growth Restriction ◽  
Insulin Content ◽  
Intrauterine Growth

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the β-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

scholarly journals Effects of organic mercurials on mammalian pancreatic β-cells. Insulin release, glucose transport, glucose oxidation, membrane permeability and ultrastructure

1972 ◽  
Vol 129 (2) ◽  
pp. 241-254 ◽  
Author(s):  
Gunnar D. Bloom ◽  
Bo Hellman ◽  
Lars-Åke Idahl ◽  
Åke Lernmark ◽  
Janove Sehlin ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Glucose Transport ◽  
Insulin Release ◽  
Glucose Oxidation ◽  
Sulphonic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Plasma ◽  
Organic Mercurials

The effects of p-chloromercuribenzoic acid and chloromercuribenzene-p-sulphonic acid on pancreatic islets were studied in vitro. Obese–hyperglycaemic mice were used as the source of microdissected islets containing more than 90% β-cells. p-Chloromercuribenzoic acid and chloromercuribenzene-p-sulphonic acid stimulated insulin release at concentrations of 0.01mm or above. This stimulation was significantly inhibited by the omission of Ca2+or the addition of adrenaline, diazoxide or 2,4-dinitrophenol. p-Chloromercuribenzoic acid or chloromercuribenzene-p-sulphonic acid did not interfere with the insulin-releasing ability of glucose. Micro-perifusion experiments revealed that the release of insulin in response to organic mercurial occurred almost instantaneously, was reversible, and was biphasic. The two mercurials inhibited glucose transport as well as glucose oxidation, and increased the mannitol and sucrose spaces of isolated islets. Compared with the effects on insulin release, those on glucose transport and membrane permeability were characterized by a longer latency and/or required higher concentrations of organic mercurial. Apart from a seemingly higher proportion of β-cells exhibiting certain degenerative features, in islets exposed to 0.1mm-chloromercuribenzene-p-sulphonic acid for 60min, no significant differences with respect to β-cell fine structure were noted between non-incubated islets and islets incubated with chloromercuribenzene-p-sulphonic acid or glucose or both. It is suggested that insulin release may be regulated by relatively superficial thiol groups in the β-cell plasma membrane.

scholarly journals Iodoacetamide-induced sensitization of the pancreatic β-cells to glucose stimulation

1973 ◽  
Vol 132 (4) ◽  
pp. 775-789 ◽  
Author(s):  
Bo Hellman ◽  
Lars-Åke Idahl ◽  
Åke Lernmark ◽  
Janove Sehlin ◽  
Inge-Bert Täljedal
Keyword(s):  
Insulin Release ◽  
Inhibitory Action ◽  
Glucose Oxidation ◽  
Short Pulse ◽  
Calcium Deficiency ◽  
Cell Plasma ◽  
Previous Hypothesis ◽  
Inhibition Of Glycolysis ◽  
Microdissected Pancreatic Islets ◽  
Stimulate Insulin Release

At a glucose concentration of 3mm or less, iodoacetamide had no effect on the release of insulin from microdissected pancreatic islets of ob/ob-mice. At higher glucose concentrations, iodoacetamide exerted both an initial stimulatory and a subsequent inhibitory action. When islets were perifused with 1mm-iodoacetamide and 17mm-glucose the inhibitory action predominated after about 15min of transient stimulation. With decreasing concentrations of iodoacetamide the stimulatory phase was gradually prolonged, and with 0.003–0.1mm-iodoacetamide stimulation only was observed for 75min. Prolonged stimulation was also noted after a short pulse of iodoacetamide. Similar responses to 0.1mm-iodoacetamide were observed with islets from normal mice. With islets from ob/ob-mice the effect of 0.1mm-iodoacetamide was reproduced with 0.1mm-iodoacetate, whereas 0.1mm-acetamide had no apparent effect. Iodoacetamide increased the Vmax. of glucose-stimulated insulin release without altering the apparent Km for glucose. Leucine, glibenclamide or theophylline could not replace glucose in this synergistic action with iodoacetamide. Iodoacetamide rather inhibited the insulin-releasing action of theophylline. Iodoacetamide-induced potentiation of the glucose-stimulated insulin release was rapidly and reversibly inhibited by mannoheptulose, adrenaline, or calcium deficiency. The potentiating effect on insulin release was not paralleled by effects on glucose oxidation or on islet fructose 1,6-diphosphate. However, the inhibitory action of iodoacetamide might be explained by inhibition of glycolysis as evidenced by an inhibition of glucose oxidation and a rise of fructose 1,6-diphosphate. The results support our previous hypothesis that thiol reagents can stimulate insulin release by acting on relatively superficial thiol groups in the β-cell plasma membrane. Glycolysis seems to be necessary in order for iodoacetamide to stimulate in this way.

scholarly journals Effects of glucose and other modifiers of insulin release on the oxidative metabolism of amino acids in micro-dissected pancreatic islets

1971 ◽  
Vol 123 (4) ◽  
pp. 513-521 ◽  
Author(s):  
B. Hellman ◽  
J. Sehlin ◽  
I.-B. Täljedal
Keyword(s):  
Amino Acids ◽  
Glucose Metabolism ◽  
Cyclic Amp ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Β Cells ◽  
Insulin Secretagogues ◽  
Concentration Changes ◽  
Microdissected Pancreatic Islets ◽  
Oxidation Of Glucose

The oxidation of alanine, arginine, leucine, glucose, and pyruvate was studied in microdissected pancreatic islets of obese–hyperglycaemic mice. The following main observations were made. The oxidation of glucose was enhanced severalfold when its concentration was raised from 3 to 20mm. At the latter concentration the rate was about 65mmol/h per kg dry wt. The oxidation of 17mm-pyruvate amounted to 20mmol/h per kg dry wt. indicating a significant entry of this compound into the β-cells. Leucine oxidation was little affected by concentration changes above 5mm, the rate at 20mm corresponding to about 25% of that obtained with 20mm-glucose. In the absence of glucose, the oxidation of alanine or arginine was barely significant. Glucose stimulated the oxidation of alanine but depressed that of leucine. These effects of glucose were blocked by mannoheptulose or iodoacetamide but were not influenced by adrenaline, diazoxide, dibutyryl 3′:5′-cyclic AMP, or glibenclamide. The rate of alanine oxidation was doubled in the presence of 17mm-pyruvate but was unaffected by citrate or succinate. Succinate depressed the oxidation of leucine. Neither alanine nor leucine significantly affected the oxidation of glucose. It is suggested that the effects of glucose on the oxidation of alanine and leucine were mediated by metabolism of the sugar, and that amino acids do not act as insulin secretagogues by serving as fuels for the β-cells. The results are consistent with the existence of mechanisms auxiliary to glucose metabolism for control of insulin release.

Maternofetal inflammation induced for two weeks in late gestation reduced birthweight and impaired neonatal growth and skeletal muscle glucose metabolism in lambs

2021 ◽  
Author(s):  
Robert J Posont ◽  
Caitlin N Cadaret ◽  
Joslyn K Beard ◽  
Rebecca M Swanson ◽  
Rachel L Gibbs ◽  
...  
Keyword(s):  
Body Composition ◽  
Glucose Metabolism ◽  
Fetal Programming ◽  
Glucose Oxidation ◽  
Cell Function ◽  
Density Lipoprotein ◽  
Late Pregnancy ◽  
Late Gestation ◽  
Β Cell ◽  
Poor Growth

Abstract Intrauterine stress impairs growth and metabolism in the fetus and offspring. We recently found that sustained maternofetal inflammation resulted in intrauterine growth restricted fetuses (MI-IUGR) with asymmetric body composition, impaired muscle glucose metabolism, and β-cell dysfunction near term. These fetuses also exhibited heightened inflammatory tone, which we postulated was a fetal programming mechanism for the IUGR phenotype. Thus, the objective of this study was to determine whether poor growth and metabolism persisted in MI-IUGR lambs after birth. Polypay ewes received serial lipopolysaccharide or saline injections in the first 2 wk of the 3 rd trimester of pregnancy to produce MI-IUGR (n = 13) and control (n = 12) lambs, respectively. Lambs were catheterized at 25 d of age. β cell function was assessed at 29 d, hindlimb glucose metabolism at 30 d, and daily blood parameters from d 26 to 31. Glucose metabolism was also assessed in flexor digitorum superficialis (FDS) muscle isolated at necropsy on d 31. Asymmetric body composition persisted in MI-IUGR neonates, as these lambs were lighter (P < 0.05) than controls at birth and 31 d, but body and cannon bone lengths did not differ at either age. FDS muscles from MI-IUGR lambs were smaller (P < 0.05) and exhibited reduced (P < 0.05) glucose oxidation and Akt phosphorylation but similar glucose uptake compared to controls when incubated in basal or insulin-spiked media. Similarly, hindlimb glucose oxidation was reduced (P < 0.05) in MI-IUGR lambs under basal and hyperinsulinemic conditions, but hindlimb glucose utilization did not differ from controls. Circulating urea nitrogen and cholesterol were reduced (P < 0.05) and triglycerides, high density lipoprotein-cholesterol, and glucose-to-insulin ratios were increased (P < 0.05) in MI-IUGR lambs. Glucose and insulin concentrations did not differ between groups during basal or hyperglycemic conditions. Although circulating monocyte and granulocyte concentrations were greater (P < 0.05) in MI-IUGR lambs, plasma TNFα was reduced (P < 0.05). FDS muscle contained greater (P < 0.05) TNFR1 and IκBα protein content. These findings indicate that maternofetal inflammation in late pregnancy results in fetal programming that impairs growth capacity, muscle glucose oxidation, and lipid homeostasis in offspring. Inflammatory indicators measured in this study appear to reflect heightened cytokine sensitivity in muscle and compensatory systemic responses to it.

scholarly journals Islet adaptive changes to fructose-induced insulin resistance: β-cell mass, glucokinase, glucose metabolism, and insulin secretion

2008 ◽  
Vol 200 (2) ◽  
pp. 139-149 ◽  
Author(s):  
B Maiztegui ◽  
M I Borelli ◽  
M A Raschia ◽  
H Del Zotto ◽  
J J Gagliardino
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Impaired Glucose Tolerance ◽  
Insulin Release ◽  
Cell Mass ◽  
Normal Male ◽  
Β Cell

β-Cell mass, hexokinase/glucokinase (HK/GK) activity, glucose metabolism and insulin secretion were studied in the islets of rats with fructose-induced insulin resistance (IR). Normal male Wistar rats were fed a standard commercial diet and water without (control, C) or with 10% fructose-rich diet (FRD) for 3 weeks. Blood glucose (strips), triglyceride (commercial kit), and insulin (RIA) levels were measured at the time of death. Glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from d-[U-14C]- and d-[5-3H]-glucose) and HK/GK activity (G-6-P production), transcription (RT-PCR), protein expression (Western blot), and cellular compartmentalization were measured in isolated islets (collagenase digestion). FRD rats presented normoglycemia but impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, and increased HOMA-IR index. In these rats, β-cell mass decreased significantly by 33%, with a 44% increase in the percentage of apoptotic cells. Glucose-induced insulin release and islet glucose metabolism were higher in FRD rats. While GK activity (total and cytosolic fraction) and protein expression were significantly higher in FRD islets, HK showed no change in any of these parameters. Our results demonstrate that the changes induced by dietary-induced IR upon β-cell function and mass are strongly conditional on the nutrient model used. In our model (intact animals with impaired glucose tolerance), GK activity increases through mechanisms previously shown only in vitro or under highly hyperglycemic conditions. Such an increase plays a pivotal role in the adaptive increased release of insulin in response to IR, even in the presence of marked β-cell mass reduction.

ON THE ACTION OF TOLBUTAMIDE IN NORMAL MAN

1973 ◽  
Vol 72 (3) ◽  
pp. 532-544 ◽  
Author(s):  
A. Widström ◽  
E. Cerasi
Keyword(s):  
Glucose Metabolism ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Insulin Response ◽  
Phosphodiesterase Inhibitor ◽  
Adenyl Cyclase ◽  
Β Cells ◽  
Β Cell ◽  
Normal Man ◽  
Relationship Of

ABSTRACT Previous studies in normal man suggest that tolbutamide exerts its insulinogenic effect by modulating glucose-induced insulin release. This is probably achieved by increasing the sensitivity of the β-cells to the action of glucose in eliciting an insulinogenic signal, rather than by influencing the glucose metabolism of the islets. The present paper reports on studies on the relation of tolbutamide to the cyclic AMP system of the islets. Aminophylline, which decreases the breakdown of cyclic AMP, was without effect on tolbutamide-induced insulin release. This indicates that tolbutamide probably does not act by stimulating adenyl cyclase. In contrast, the insulin response to glucagon, an agent known to stimulate adenyl cyclase, was markedly potentiated by tolbutamide. Tolbutamide. in this respect, also showed synergism with arginine, which probably acts by enhancing the formation of cyclic AMP. It is therefore concluded that tolbutamide may influence insulin release by acting as a phosphodiesterase inhibitor or as a potentiator of the action of cyclic AMP on the release mechanisms. The possible relationship of the tolbutamide action with the postulated insulinogenic signal of glucose in the β-cell is discussed.

THE EFFECT OF FASTING AND SELECTIVE RE-FEEDING ON INSULIN RELEASE IN THE RAT

1973 ◽  
Vol 72 (1) ◽  
pp. 46-53 ◽  
Author(s):  
D. S. Turner ◽  
D. A. B. Young
Keyword(s):  
Insulin Release ◽  
Acute Effect ◽  
Secretory Response ◽  
Release Mechanism ◽  
Β Cell ◽  
Intestinal Hormones ◽  
Intravenous Glucose ◽  
Glucose Ingestion ◽  
Glucose Test ◽  
Insulin Secretory Response

ABSTRACT The insulin secretory response in the rat to intravenous glucose was found to be greatly impaired by fasting for three days, whereas that to orally administered glucose was not significantly affected. Rats fasted for two days were given either protein or starch pellets for six hours, and then fasted for a further eighteen hours before the intravenous glucose test. The protein pre-feeding failed to affect significantly the subsequent insulin secretory response to intravenous glucose, whereas starch prefeeding greatly enhanced it. It is suggested that intestinal hormones released by glucose ingestion may exert not only an acute effect on insulin release, but also a 'priming' effect on the insulin release mechanism of the β cell, which enables it to respond to the subsequent stimulus of glucose alone.

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