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.

STUDIES ON THE MECHANISMS OF SOMATOSTATIN ACTION ON INSULIN RELEASE

1977 ◽  
Vol 85 (2) ◽  
pp. 379-388 ◽  
Author(s):  
A Claro ◽  
V. Grill ◽  
S. Efendić ◽  
R. Luft
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Competitive Inhibition ◽  
Phosphodiesterase Inhibitor ◽  
Adenyl Cyclase ◽  
Phosphodiesterase Activity ◽  
High Concentration ◽  
Isolated Islets Of Langerhans ◽  
Cyclic Amp Accumulation ◽  
Effect Of Glucose

ABSTRACT The effects of somatostatin on insulin release and cyclic AMP metabolism were studied in collagenase-isolated islets of Langerhans from the rat. Concentrations from 500 to 2000 ng/ml significantly inhibited glucose stimulated insulin release, while 100 and 200 ng/ml were ineffective. Somatostatin (2000 ng/ml) inhibited insulin release and [3H]-cyclic AMP accumulation induced by 16.7 mm glucose after 10 and 30 min of incubation. In dose-response studies, the inhibition by somatostatin of the effect of glucose on [3H] cyclic AMP and insulin release could be overcome by a high concentration of the hexose (44.9 mM), suggesting competitive inhibition. In the absence of glucose, somatostatin inhibited [3H] cyclic AMP accumulation induced by the phosphodiesterase inhibitor, IBMX, while no inhibition was seen, again in the absence of hexose, when the [3H] cyclic AMP levels had been raised by the adenyl cyclase stimulator, cholera toxin. Somatostatin did not affect phosphodiesterase activity when added to islet homogenates, but preincubation of the islets with the peptide before homogenization decreased the activity by about 30 %. It is suggested that somatostatin-induced inhibition of insulin release is, at least partially, mediated by cyclic AMP, probably through an action on islet adenyl cyclase.

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.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells

Nature ◽  
1993 ◽  
Vol 363 (6427) ◽  
pp. 356-358 ◽  
Author(s):  
Carina Ämmälä ◽  
Frances M. Ashcroft ◽  
Patrik Rorsman
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Β Cells

POTENTIATION OF INSULIN RELEASE BY GLUCOSE IN MAN

1975 ◽  
Vol 79 (3) ◽  
pp. 502-510 ◽  
Author(s):  
Erol Cerasi
Keyword(s):  
Glucose Metabolism ◽  
Adenylate Cyclase ◽  
Beta Cell ◽  
Insulin Release ◽  
Insulin Response ◽  
Glucose Infusion ◽  
Insulin Responses

ABSTRACT If two consecutive glucose infusions are administered with 40 min of rest between, the insulin response to the second challenge is markedly potentiated. When the insulin response to the first glucose infusion was suppressed by 65 % with the aid of adrenaline, potentiation of the insulin response to the second infusion was not modified. This suggests that the generation of a state of enhancement in the islet does not necessitate that glucose exerts its insulin releasing action. It is postulated that islet glucose metabolism may be involved in producing the potentiation. Pretreatment of the subjects with a glucose infusion enhanced also the insulin responses to glucagon and to tolbutamide, given intravenously 50 min later. Thus, the potentiation generated by glucose is not restricted to the insulinogenic signal induced by glucose. The eventual role that the beta-cell adenylate cyclase may play in this respect is discussed.

Insulin release by glucagon and secretin: studies with secretin-glucagon hybrids

1988 ◽  
Vol 254 (4) ◽  
pp. E454-E458 ◽  
Author(s):  
H. Kofod ◽  
D. Andreu ◽  
P. Thams ◽  
R. B. Merrifield ◽  
C. J. Hedeskov ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Phosphodiesterase Inhibitor ◽  
Fold Increase ◽  
Camp Accumulation ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Hybrid Molecules ◽  
Mouse Pancreatic Islets ◽  
Ranking Order

Secretin and glucagon potentiate glucose-induced insulin release. We have compared the effects of secretin and glucagon with that of four hybrid molecules of the two hormones on insulin release and formation of cyclic AMP (cAMP) in isolated mouse pancreatic islets. All six peptides potentiated the release of insulin at 10 mM D-glucose, and their effects were indistinguishable with respect to the dynamics of release, dose-response relationship, and glucose dependency. However, measurements of cAMP accumulation in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-4) M) showed that the fold increase compared with glucose alone had the following ranking order: secretin = [Tyr10, Tyr13]-secretin 1.6 less than [Tyr10, Tyr13, Trp25]secretin 1.8 less than glucagon 1.9 less than [Asp3, Glu9, Arg12]glucagon 2.3 = [Asp3, Glu9]glucagon. These results suggest that despite similar potentiating effects of secretin and glucagon on glucose-induced insulin release, their modes of action may be different.

Life and death decisions of the pancreatic β-cell: the role of fatty acids

2006 ◽  
Vol 112 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Philip Newsholme ◽  
Deirdre Keane ◽  
Hannah J. Welters ◽  
Noel G. Morgan
Keyword(s):  
Fatty Acids ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Endogenous Fatty Acid ◽  
Gene And Protein Expression ◽  
Β Cell Function

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion, followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. Therefore changes in the levels of NEFAs are likely to be important for the regulation of β-cell function and viability under physiological conditions. In addition, the switching between endogenous fatty acid synthesis or oxidation in the β-cell, together with alterations in neutral lipid accumulation, may have critical implications for β-cell function and integrity. Long-chain acyl-CoA (formed from either endogenously synthesized or exogenous fatty acids) controls several aspects of β-cell function, including activation of specific isoenzymes of PKC (protein kinase C), modulation of ion channels, protein acylation, ceramide formation and/or NO-mediated apoptosis, and transcription factor activity. In this review, we describe the effects of exogenous and endogenous fatty acids on β-cell metabolism and gene and protein expression, and have explored the outcomes with respect to insulin secretion and β-cell integrity.

scholarly journals Transgenic Expression of Insulin-Response Element Binding Protein-1 in β-Cells Reproduces Type 2 Diabetes

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2611-2617 ◽  
Author(s):  
Betty C. Villafuerte ◽  
Michelle T. Barati ◽  
Ying Song ◽  
Joseph P. Moore ◽  
Paul N. Epstein ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Binding Protein ◽  
Insulin Response ◽  
Receptor Expression ◽  
Β Cells ◽  
Β Cell ◽  
Response Element ◽  
Transgenic Expression ◽  
Element Binding Protein

Recent evidence supports the idea that insulin signaling through the insulin receptor substrate/phosphatidyl-inositol 3-kinase/Akt pathway is involved in the maintenance of β-cell mass and function. We previously identified the insulin-response element binding protein-1 (IRE-BP1) as an effector of insulin-induced Akt signaling in the liver, and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor. In this investigation we found that IRE-BP1 is expressed in the α, β, and δ-cells of the islets of Langerhans, and is localized to the cytoplasm in β-cells in normal rats, but is reduced and redistributed to the islet cell nuclei in obese Zucker rats. To test whether IRE-BP1 modulates β-cell function and insulin secretion, we used the rat insulin II promoter to drive expression of the carboxyl fragment in β-cells. Transgenic expression of IRE-BP1 in FVB mice increases nuclear IRE-BP1 expression, and produces a phenotype similar to that of type 2 diabetes, with hyperinsulinemia, hyperglycemia, and increased body weight. IRE-BP1 increased islet type I IGF receptor expression, potentially contributing to the development of islet hypertrophy. Our findings suggest that increased gene transcription mediated through IRE-BP1 may contribute to β-cell dysfunction in insulin resistance, and allow for the hypothesis that IRE-BP1 plays a role in the pathophysiology of type 2 diabetes.

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