Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets

2004 ◽  
Vol 287 (5) ◽  
pp. E828-E833 ◽  
Author(s):  
Subhadra C. Gunawardana ◽  
Yi-Jia Liu ◽  
Michael J. MacDonald ◽  
Susanne G. Straub ◽  
Geoffrey W. G. Sharp
Keyword(s):  
Insulin Release ◽  
Tricarboxylic Acid Cycle ◽  
Acid Methyl Ester ◽  
Time Dependent ◽  
Second Phase ◽  
Acetyl Coa ◽  
Atp Production ◽  
Biphasic Insulin ◽  
Intracellular Ca ◽  
Biphasic Insulin Release

Nutrients that induce biphasic insulin release, such as glucose and leucine, provide acetyl-CoA and anaplerotic input in the β-cell. The first phase of release requires increased ATP production leading to increased intracellular Ca2+ concentration ([Ca2+]i). The second phase requires increased [Ca2+]i and anaplerosis. There is strong evidence to indicate that the second phase is due to augmentation of Ca2+-stimulated release via the KATP channel-independent pathway. To test whether the phenomenon of time-dependent potentiation (TDP) has similar properties to the ATP-sensitive K+ channel-independent pathway, we monitored the ability of different agents that provide acetyl-CoA and anaplerotic input or both of these inputs to induce TDP. The results show that anaplerotic input is sufficient to induce TDP. Interestingly, among the agents tested, the nonsecretagogue glutamine, the nonhydrolyzable analog of leucine aminobicyclo[2.2.1]heptane-2-carboxylic acid, and succinic acid methyl ester all induced TDP, and all significantly increased α-ketoglutarate levels in the islets. In conclusion, anaplerosis that enhances the supply and utilization of α-ketoglutarate in the tricarboxylic acid cycle appears to play an essential role in the generation of TDP.

scholarly journals Biphasic Insulin Release in Rat Islets of Langerhans and the Role of Intracellular Ca++Stores*

Endocrinology ◽  
1979 ◽  
Vol 105 (4) ◽  
pp. 1013-1019 ◽  
Author(s):  
MASATOSHI KIKUCHI ◽  
CLAES B. WOLLHEIM ◽  
EBERHARD G. SIEGEL ◽  
ALBERT E. RENOLD ◽  
GEOFFREY W. G. SHARP
Keyword(s):  
Insulin Release ◽  
Islets Of Langerhans ◽  
Rat Islets ◽  
Biphasic Insulin ◽  
Intracellular Ca ◽  
Biphasic Insulin Release ◽  
Rat Islets Of Langerhans

Chronic exposure to β-hydroxybutyrate inhibits glucose-induced insulin release from pancreatic islets by decreasing NADH contents

2005 ◽  
Vol 288 (2) ◽  
pp. E372-E380 ◽  
Author(s):  
Mihoko Takehiro ◽  
Shimpei Fujimoto ◽  
Makiko Shimodahira ◽  
Dai Shimono ◽  
Eri Mukai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Respiratory Chain ◽  
High Glucose ◽  
Chronic Exposure ◽  
Ketone Bodies ◽  
Second Phase ◽  
Atp Production ◽  
Intracellular Ca

To investigate the effects of chronic exposure to ketone bodies on glucose-induced insulin secretion, we evaluated insulin release, intracellular Ca2+ and metabolism, and Ca2+ efficacy of the exocytotic system in rat pancreatic islets. Fifteen-hour exposure to 5 mM d-β-hydroxybutyrate (HB) reduced high glucose-induced insulin secretion and augmented basal insulin secretion. Augmentation of basal release was derived from promoting the Ca2+-independent and ATP-independent component of insulin release, which was suppressed by the GDP analog. Chronic exposure to HB affected mostly the second phase of glucose-induced biphasic secretion. Dynamic experiments showed that insulin release and NAD(P)H fluorescence were lower, although the intracellular Ca2+ concentration ([Ca2+]i) was not affected 10 min after exposure to high glucose. Additionally, [Ca2+]i efficacy in exocytotic system at clamped concentrations of ATP was not affected. NADH content, ATP content, and ATP-to-ADP ratio in the HB-cultured islets in the presence of high glucose were lower, whereas glucose utilization and oxidation were not affected. Mitochondrial ATP production shows that the respiratory chain downstream of complex II is not affected by chronic exposure to HB, and that the decrease in ATP production is due to decreased NADH content in the mitochondrial matrix. Chronic exposure to HB suppresses glucose-induced insulin secretion by lowering the ATP level, at least partly by inhibiting ATP production by reducing the supply of NADH to the respiratory chain. Glucose-induced insulin release in the presence of aminooxyacetate was not reduced, which implies that chronic exposure to HB affects the malate/aspartate shuttle and thus reduces NADH supply to mitochondria.

scholarly journals Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1653-1666 ◽  
Author(s):  
Mei Huang ◽  
Jamie W. Joseph
Keyword(s):  
Insulin Secretion ◽  
Time Course ◽  
Tricarboxylic Acid Cycle ◽  
Global Analysis ◽  
Tricarboxylic Acid ◽  
Second Phase ◽  
Data Set ◽  
Negatively Associated ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with l-valine, trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, dl-3-aminoisobutyric acid, l-glutamine, sarcosine, l-lysine, and thymine and positively with l-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5′-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, α-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, dl-3-aminobutyric acid, and l-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.

scholarly journals Defective calcium handling and insulin release in islets from diabetic Chinese hamsters

1979 ◽  
Vol 180 (1) ◽  
pp. 233-236 ◽  
Author(s):  
E G Siegel ◽  
C B Wollheim ◽  
G W Sharp ◽  
L Herberg ◽  
A E Renold
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Chinese Hamster ◽  
Calcium Handling ◽  
Biphasic Insulin ◽  
Chinese Hamsters ◽  
Diabetic Chinese Hamsters ◽  
Biphasic Insulin Release

In pancreatic islets from normal Chinese hamsters preloaded with 45Ca2+, glucose-induced biphasic insulin release was associated with increased 45Ca2+ efflux; islets from diabetic hamsters showed decreased insulin release and no increase in 45Ca2+ efflux. The lack of stimulated 45Ca2+ efflux persisted even when glucose-induced insulin release was potentiated by 3-isobutyl-1-methylxanthine. Since glucose-stimulated 45Ca2+ uptake by diabetic islets was not impaired, a defect in intracellular Ca2+ handling may be involved in the defective insulin release of the diabetic Chinese hamster.

Effect of a glucokinase inhibitor on energy production and insulin release in pancreatic islets

1996 ◽  
Vol 271 (3) ◽  
pp. E606-E625 ◽  
Author(s):  
I. R. Sweet ◽  
G. Li ◽  
H. Najafi ◽  
D. Berner ◽  
F. M. Matschinsky
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Tricarboxylic Acid Cycle ◽  
Maximal Velocity ◽  
Phosphate Potential ◽  
Complete Control ◽  
Atp Production ◽  
Control Strength ◽  
Wide Range ◽  
High Control

Glucokinase has exclusively high control strength on glucose usage in the pancreatic beta-cell. However, glucokinase also has extraordinarily high control strength on insulin secretion, which is linked to the phosphate potential, [ATP]/([ADP][Pi]) (F.M. Matschinsky, Y.Liang, P. Kesavan, L. Wang, P. Froguel, G. Velho, D. Cohen, M.A. Permutt, Y. Tanizawa, T.L. Jetton, K. Niswender, and M.A. Magnuson. J. Clin. Invest. 92: 2092-2098, 1993). We propose that the ATP produced via the tricarboxylic acid cycle is approximately constant, irrespective of the glucose level. Furthermore, the component of ATP production that is derived from glycolysis and glycolytically derived NADH, which is shuttled into the mitochondria, is a critical signal controlling the ionic events leading to insulin secretion, as suggested previously (M. J. MacDonald. Diabetes 39: 1461-1466, 1990 and I.D. Dukes, M.S. McIntyre, R.J. Mertz, L.H. Philipson, M.W. Roe, B. Spencer, and J.F. Worley III. J. Biol. Chem. 269: 10979-10982, 1994). To test this hypothesis, glucose usage, oxidation, and insulin secretion were measured in cultured rat islets over a wide range of concentrations of glucose and mannoheptulose, an inhibitor of glucokinase. These data were fit to a mathematical model that predicts that glucokinase will govern the rate of glucose usage and ATP production and will also have a strong, but not complete, control over the rate of glucose oxidation, the phosphate potential, and insulin release. Mannoheptulose caused an inhibition of all three fluxes. The estimates of the mechanistic parameters of the model [maximal velocity (Vmax) and Michaelis constant for glucokinase, Vmax for hexokinase and glucose transport, and the inhibition constant of mannoheptulose to glucokinase] were similar to those obtained in vitro. Thus the data are consistent with a model in which the primary importance of glycolysis in transducing the glucose signal into changes of the phosphate potential imparts to glucokinase a high control strength on glucose-induced insulin secretion.

Immediate and time-dependent effects of glucose on insulin release: differential calcium requirements

1988 ◽  
Vol 117 (3) ◽  
pp. 409-416 ◽  
Author(s):  
Rafael Nesher ◽  
Michal Praiss ◽  
Erol Cerasi
Keyword(s):  
Beta Cell ◽  
Insulin Release ◽  
Insulin Response ◽  
High Sensitivity ◽  
Phase Response ◽  
Time Dependent ◽  
Release Time ◽  
Second Phase ◽  
Perfused Rat Pancreas ◽  
Glucose Pulse

Abstract. Glucose regulates insulin release in a complex manner; apart from its acute secretory action it induces time-dependent effects which modulate subsequent islet responses. The Ca2+ sensitivities of the diverse secretory events generated by glucose were investigated in the perfused rat pancreas. First- and second-phase insulin responses to 16.7 mmol/l glucose were obliterated in the presence of 5 mmol/l EgTA; threshold Ca2+ concentrations for significant responses were 0.25 mmol/l for second-phase, and 'O' (no Ca2+ added, approx 20 μmol/l) for first-phase release (both around 10% of control). The apparent Km of the Ca2+ dependencies were 0.6 mmol/l for first-phase, and 1.25 mmol/l for second-phase release. Time-dependent potentiation was demonstrated by subjecting the pancreas to two 40-min 16.7 mmol/l glucose stimuli separated by a 30-min rest period; this amplified the first-phase response to the second stimulus 2.5 ± 0.9-fold. Also the generation of potentiation was Ca2+ dependent, with characteristics similar to those of the acute secondphase insulin response (apparent Km ~1.0 mmol/l Ca2+). In contrast, the amplified first-phase response to the second glucose pulse retained its high sensitivity to Ca2+, thus resembling the unprimed first-phase. The inhibitory message of glucose was demonstrated by applying two sequential 5-min pulses of 8.3 mmol/l glucose: the insulin response to the second stimulus was reduced by 43 ± 9%. Addition of EgTA to the first glucose pulse had no effect on the inhibition of the second insulin response. Thus: 1. Despite its high sensitivity to Ca2+, also first-phase release is fully dependent on extracellular Ca2+. 2. The amplifying effect of glucose priming is Ca2+ dependent, with requirements similar to those of the acute second-phase release. 3. Amplified insulin release does not involve changes in beta cell sensitivity to extracellular Ca2+. 4. The inhibitory effect of a short glucose stimulus is not a Ca2+ dependent event. 5. These findings may relate to the Ca2+ sensitivity of distal steps in insulin release rather than reflecting changes in the Ca2+ economy of the beta cell.

Development of the biphasic response to glucose in fetal and neonatal rat pancreas

1988 ◽  
Vol 254 (2) ◽  
pp. E167-E174 ◽  
Author(s):  
R. L. Hole ◽  
M. C. Pian-Smith ◽  
G. W. Sharp
Keyword(s):  
Beta Cell ◽  
Insulin Release ◽  
Neonatal Rat ◽  
Biphasic Response ◽  
Rat Pancreas ◽  
K Channels ◽  
Fetal Pancreas ◽  
Biphasic Insulin ◽  
Biphasic Insulin Release ◽  
Ca2 Channels

A study on the development of biphasic insulin release and sensitivity to inhibitors has been performed using perifused rat pancreas at 19.5 days of gestation (3 days before birth) and at 3 days after birth. In the fetal pancreas, 16.7 mM glucose caused a marked stimulation of insulin release that did not, however, manifest a biphasic response and was not inhibited by verapamil, a Ca2+ channel blocker. This suggested that the immature response was due to either a lack of voltage-dependent Ca2+ channels or their failure to open in response to glucose. Depolarizing concentrations of KCl stimulated insulin release, which was inhibited by verapamil, demonstrating that functional Ca2+ channels were present. In the presence of 16.7 mM glucose, quinine, which blocks glucose-sensitive k+ channels, potentiated the response of the fetal pancreas that now became sensitive to verapamil, demonstrating that functional K+ channels were also present in the fetal pancreatic beta-cell. The immaturity of the response is not due specifically to a defect in glucose metabolism; rather the metabolism of nutrient secretagogues fails to couple with the K+ channel in the fetal islet and thus fails to depolarize the beta-cell membrane. Three days after birth the pattern of response to high glucose is biphasic. Insulin release in fetal pancreas was inhibited by epinephrine and somatostatin.

Adrenergic Modification of Glucose-Induced Biphasic Insulin Release from Perifused Rat Pancreas

1971 ◽  
Vol 1 (4) ◽  
pp. 216-224 ◽  
Author(s):  
Ian M. Burr ◽  
Luc Balant ◽  
Werner Stauffacher ◽  
Albert E. Renold
Keyword(s):  
Insulin Release ◽  
Rat Pancreas ◽  
Biphasic Insulin ◽  
Biphasic Insulin Release
Sign in / Sign up

Export Citation Format

Share Document