Magnesium requirement for somatostatin inhibition of insulin secretion

1984 ◽  
Vol 105 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Donald L. Curry ◽  
Leslie L. Bennett
Keyword(s):  
Insulin Secretion ◽  
Calcium Concentration ◽  
Inhibitory Effect ◽  
Secretory Process ◽  
Magnesium Ion ◽  
Second Phase ◽  
Intracellular Membrane ◽  
Calcium Magnesium ◽  
First Phase Insulin Secretion ◽  
Insulin Secretory Response

Abstract. Rat pancreas perfusions were performed using a perfusate with a fixed calcium concentration of 5 mEq/l and magnesium varying from 0 to 0.6 mEq/dl. Insulin secretion was stimulated by a constant glucose infusion of 300 mg/dl. This glucose concentration produces the typical biphasic insulin secretory response. We observed that in the absence of magnesium, somatostatin concentrations of 0.5 and 2.0 ng/ml were without effect on first phase insulin secretion. However, these same somatostatin levels produced 50% or more inhibition of insulin secretion in the presence of magnesium at 0.3 or 0.6 mEq/l. Similarly, in the absence of magnesium, somatostatin at 50 ng/ml failed to inhibit second phase insulin secretion, whereas this same somatostatin level produced about 50% inhibition of insulin secretion in the presence of magnesium at 0.3 mEq/l. Thus, altering perfusate magnesium concentrations without changing calcium is an important determinant of the degree of inhibition of secretion produced by somatostatin. In particular, in the absence of magnesium ion, somatostatin concentrations which would 'normally' produce 50% inhibition of secretion (ID50) are without effect. Therefore, magnesium ion is necessary for the full inhibitory effect of somatostatin to occur. These results suggest that inhibitors, as well as potentiators, of the insulin secretory process may act by altering intracellular/membrane calcium-magnesium ratios, but in opposite directions.

Differential effects of microtubule-altering agents on beta-cells during development

1983 ◽  
Vol 245 (4) ◽  
pp. E391-E400
Author(s):  
R. S. Hill ◽  
W. B. Rhoten
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Insulin Release ◽  
High Glucose ◽  
Deuterium Oxide ◽  
Inhibitory Effect ◽  
Secretory Response ◽  
Second Phase ◽  
Insulin Secretory Response

The effect of microtubule-altering agents on the insulin secretory response to glucose during the perinatal period was investigated with an in vitro perifusion system. Rat pancreatic mince from day 17 of gestation (D17G) to day 6 postnatally (D6PN) were perifused for 60 min in basal glucose followed by 45 min with high glucose (3.5 mg/ml) or with high glucose plus 10 mM arginine (D17G). The two phases of insulin secretion in response to high glucose developed in an age-dependent and asynchronous manner. The first phase matured between D17G and D18G, and maturation of the second phase occurred subsequently. Vinblastine (VB) (20 or 100 microM) had a differential effect on the insulin secretory response. VB did not inhibit stimulated insulin release at D17G. This absence of an inhibitory effect of VB at D17G could not be explained by the absence of polymerized tubulin because microtubules were present in the control beta-cells and, in addition, VB treatment resulted in the formation of paracrystalline deposits. Subsequently in development, and with isolated islets of the adult, VB inhibited stimulated insulin release. Heavy water (deuterium oxide, D2O) inhibited stimulated insulin secretion at D17G but blocked completely insulin release from the near-term beta-cell. The inhibition of insulin secretion by D2O was rapidly reversed when water replaced D2O in the perifusion media. The results indicate that the maturation of the second phase of insulin secretion coincides with the ability of the microtubule-altering agents to modify the insulin secretory response. One possible explanation for these findings is that at D17G the microtubules are not coupled physicochemically to other molecules or structures necessary for their role in insulin secretion to be expressed fully.

scholarly journals Age-Related Reduction in Glucose Elimination Is Accompanied by Reduced Glucose Effectiveness and Increased Hepatic Insulin Extraction in Man1

1998 ◽  
Vol 83 (9) ◽  
pp. 3350-3356 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Tolerance Index ◽  
Second Phase ◽  
Oral Glucose Tolerance ◽  
Glucose Effectiveness ◽  
First Phase Insulin Secretion

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness (SG), and hepatic extraction (HE) of insulin are altered by age when glucose tolerance is normal. A frequently sampled iv glucose tolerance test was performed in 20 elderly (E, 10/10 male/female, all 63 yr old) and in 20 young subjects (Y, 10/10 male/female, all 27 yr old), who were similar in body mass index and 2-h blood glucose during oral glucose tolerance test. E exhibited impaired glucose elimination (iv tolerance index, 1.31 ± 0.10 vs. 1.70 ± 0.12% min−1; P = 0.019). First-phase insulin secretion and SI did not differ between the groups, whereas E had lower glucose sensitivity of second-phase insulin secretion (0.40 ± 0.07 vs. 0.70 ± 0.08 (pmol/L)min−2/(mmol/L), P = 0.026), lower SG, 0.017 ± 0.002 vs. 0.025± 0.002 min−1, P = 0.004), and higher HE (81.3 ± 2.4 vs. 73.2 ± 2.1%, P = 0.013). Across both groups, SG correlated positively with glucose tolerance index (r = 0.58, P < 0.001) and negatively with HE (r =− 0.54, P < 0.001). Plasma leptin and glucagon did not change by age, whereas plasma pancreatic polypeptide (PP) was higher in E (122 ± 18 vs.66 ± 6 pg/mL, P = 0.004). PP did not, however, correlate to any other parameter. We conclude that E subjects with normal oral glucose tolerance have reduced SG, impaired second-phase insulin secretion, and increased HE, whereas SI and first-phase insulin secretion seem normal. SG seems most related to age-dependent impairment of glucose elimination, whereas leptin, glucagon, and PP do not seem to contribute.

Regulation of insulin secretion by phospholipase C

1996 ◽  
Vol 271 (3) ◽  
pp. E409-E416 ◽  
Author(s):  
W. S. Zawalich ◽  
K. C. Zawalich
Keyword(s):  
Insulin Secretion ◽  
Phospholipase C ◽  
High Glucose ◽  
Human Islets ◽  
Secretory Response ◽  
Second Phase ◽  
Release Rates ◽  
Mouse Islets ◽  
Insulin Secretory Response ◽  
Hydrolysis Of

Biphasic insulin secretion in response to a sustained glucose stimulus occurs when rat or human islets are exposed to high levels of the hexose. A transient burst of hormone secretion is followed by a rising and sustained secretory response that, in the perfused rat pancreas, is 25- to 75-fold greater than prestimulatory insulin release rates. This insulin secretory response is paralleled by a significant five- to sixfold increase in the phospholipase C (PLC)-mediated hydrolysis of islet phosphoinositide (PI) pools by high glucose. In contrast, mouse islets, when stimulated under comparable conditions with high glucose, display a second-phase response that is flat and only slightly (two- to threefold) greater than prestimulatory release rates. The minimal second-phase insulin secretory response to high glucose is accompanied by the minimal activation of PLC in mouse islets as well. However, stimulation of mouse islets with the protein kinase C (PKC) activator tetradecanoyl phorbol acetate (TPA) or the muscarinic agonist carbachol, which significantly activates an isozyme of PLC distinct from that activated by high glucose, induces a rising and sustained second-phase insulin secretory response. When previously exposed to high glucose, both rat and human islets respond to subsequent restimulation with an amplified insulin secretory response. They display priming, sensitization, or time-dependent potentiation. In contrast, mouse islets primed under similar conditions with high glucose fail to display this amplified insulin secretory response on restimulation. Mouse islets can, however, be primed by brief exposure to either TPA or carbachol. Finally, whereas rat islets are desensitized by chronic exposure to high glucose, mouse islet insulin secretory responses are relatively immune to this adverse effect of the hexose. These and other findings are discussed in relationship to the role being played by agonist-induced increases in the PLC-mediated hydrolysis of islet phosphoinositide pools and the activation of PKC in these species-specific insulin secretory response patterns.

scholarly journals Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
Author(s):  
Andrea Tura ◽  
Roberto Bizzotto ◽  
Yuchiro Yamada ◽  
Yutaka Seino ◽  
Giovanni Pacini ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Clearance ◽  
Second Phase ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Double Deletion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

An effect of hyposmolarity on insulin release in vitro

1975 ◽  
Vol 228 (3) ◽  
pp. 706-713 ◽  
Author(s):  
WG Blackard ◽  
M Kikuchi ◽  
A Rabinovitch ◽  
AE Renold
Keyword(s):  
Insulin Secretion ◽  
Calcium Concentration ◽  
Insulin Response ◽  
Secretory Response ◽  
Calcium Gradient ◽  
Blocking Agents ◽  
Medium Osmolarity ◽  
Pump Activity ◽  
Insulin Secretory Response

An abrupt reduction of medium osmolarity by as little as 20 mosM evoked a discrete short-lived insulin secretory response from perifused chopped pancreas or isolated islets. The insulin response occurred earlier than that induced by either glucose or tolbutamide. None of the usual modifiers of insulin secretion significantly altered this secretory response. Glycolytic inhibitors, adrenergic agonists and blocking agents, cholinergic blocking agents, mitotic spindle inhibitors, and agents influencing sodium pump activity failed to alter hyposmolar-induced insulin secretion. Manipulation of the perifusion medium calcium concentration was the only procedure tested that influenced the secretory response. Perturbations of medium calcium concentration that increased the tissue-to-medium calcium gradient augmented the hyposmolar-induced insulin response and those that decreased tissue-to-medium calcium gradient greatly inhibited the response. The precise cause of the insulin response to a decrease in bathing fluid osmolarity remains undefined; however, the stimulus is not specific for insulin because increases in glucagon and amylase were also elicited by the hyposmolar stimulus.

Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans

1989 ◽  
Vol 257 (2) ◽  
pp. E241-E246 ◽  
Author(s):  
L. Luzi ◽  
R. A. DeFronzo
Keyword(s):  
Insulin Secretion ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Second Phase ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
First Phase Insulin Secretion

To examine the importance of first-phase insulin secretion on total body glucose homeostasis, six normal subjects (age, 24 +/- 1 yr; ideal body wt, 100 +/- 1%) received three hyperglycemic (+75 mg/100 ml) clamp studies in combination with [3-3H]glucose: study I, 150 min hyperglycemic clamp; study II, hyperglycemic clamp plus somatostatin (6 micrograms/min) plus basal glucagon replacement (0.4 ng.kg-1.min-1) plus an insulin infusion designed to mimic only the second phase of insulin secretion; and study III, hyperglycemic clamp plus somatostatin plus basal glucagon plus an insulin infusion designed to mimic both the first and second phase of insulin secretion. Basal plasma C-peptide concentrations averaged 0.21 +/- 0.01 pmol/ml in the three study protocols. In study I the plasma C-peptide response demonstrated an early burst within the first 10 min followed by a gradually increasing phase of C-peptide secretion that lasted until the end of the study. In studies II and III plasma C-peptide declined within the first 10 min after somatostatin was started and averaged 0.06 +/- 0.01 and 0.05 +/- 0.01 pmol/min, respectively. Basal hepatic glucose production (2.3 +/- 0.2 mg.kg-1.min-1) was suppressed by 90% at 20 min and remained suppressed thereafter in studies I and III. In contrast, in study II hepatic glucose production was inhibited by only 50% (1.1 +/- 0.2 mg.kg-1.min-1) at 60 min (P less than 0.01 vs. studies I and III) and remained incompletely suppressed even after 150 min.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between first-phase insulin secretion and glucose metabolism

1992 ◽  
Vol 127 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Elisabeth IM Widén ◽  
Johan G Eriksson ◽  
Agneta V Ekstrand ◽  
Leif C Groop
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Disposal ◽  
Second Phase ◽  
Cross Sectional ◽  
Oxidation Rates ◽  
First Phase Insulin Secretion ◽  
Total Glucose

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a + 7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p <0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38–62) years; BMI 29.3 (21.7–35.8); fasting plasma glucose 5.5 (4.8–7.2) mmol/l; fasting insulin 57 (37–105) pmol/l with impaired first-phase (148 (29–587) vs controls 485 (326–1086) pmol/l× 10 min; p<0.05) and normal second-phase (1604 (777–4480) vs controls (1799 (763–2771) pmol/l × 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulinresistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2–22.2) vs 34.8 (24.3–62.1) μmol·kg−1·min−1; p<0.01). Restoration of first-phase insulin secretion (1467 (746–2440) pmol/l× 10 min) did not affect glucose uptake (20.2 (9.9–23.8) μmol·kg−1·min−1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments. We conclude that although first-phase insulin secretion correlates with total glucose uptake, replacement of impaired first-phase insulin secretion does not improve glucose uptake in subjects with impaired glucose disposal and normal second-phase insulin secretion. The data dispute a causal relationship between first-phase insulin secretion and impaired glucose uptake in these subjects.

Calcium-binding proteins and insulin release

1987 ◽  
Vol 116 (2) ◽  
pp. 241-246 ◽  
Author(s):  
Yodphat Krausz ◽  
Ludmilla Eylon ◽  
Erol Cerasi
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Calcium Binding ◽  
Binding Proteins ◽  
Insulin Response ◽  
Inhibitory Effect ◽  
Calcium Binding Proteins ◽  
Second Phase ◽  
Glucose Effect ◽  
First Phase Insulin Release

Abstract. Calcium and cAMP are interdependent regulators of glucose-induced insulin release. In the present study we investigated the importance of cAMP and calcium-binding proteins for biphasic insulin secretion by assessing the effects of two phenothiazines known to block such proteins, trifluoroperazine (TFP) and promethazine (PMZ). In isolated rat islets, during 60-min incubations with 16.7 mmol/l glucose both agents inhibited the insulin response with ID50 values of 15 μmol/l for TFP and 5 μmol/l for PMZ. Both agents decreased the maximal insulin response without gross changes in the islet sensitivity to glucose. TFP (15 μmol/l), whereas inducing 50% inhibition of second-phase insulin release, totally suppressed the cAMP response to glucose and the accompanying first-phase insulin secretion (5-min incubations); these effects of TFP could be partially reversed by isobutyl methylxanthine (IBMX). In contrast, 5 μmol/l PMZ, which produced 60% inhibition of second-phase insulin release, had no effect on first-phase insulin and cAMP responses to glucose. Furthermore, IBMX did not modify the inhibitory effect of PMZ on second-phase insulin secretion. The following is concluded: 1. TFP acts preferentially on first-phase insulin release and inhibits cAMP formation; this suggests that calmodulin plays a major role in mediating the initial glucose effect on secretion via stimulation of cAMP. 2. The islet probably contains calcium-sensitive proteins other than calmodulin, since the low concentrations of PMZ shown to inhibit second-phase insulin release lack effects on calmodulin. Synexin could be such a protein. 3. PMZ had no effect on cAMP generation and first-phase insulin release; it is speculated that synexin-like proteins may mediate the glucose effect on second-phase release by increasing the responsiveness of the islet to calcium/cAMP.

Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 β-cells

2004 ◽  
Vol 286 (5) ◽  
pp. E818-E827 ◽  
Author(s):  
Jingsong Li ◽  
Ruihua Luo ◽  
Anjaneyulu Kowluru ◽  
GuoDong Li
Keyword(s):  
Insulin Secretion ◽  
Time Course ◽  
Morphological Changes ◽  
Secretory Granules ◽  
Late Phase ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Secretory Process ◽  
Β Cells ◽  
Rac1 Gtpase

Stimulation of insulin secretion by glucose and other secretagogues from pancreatic islet β-cells is mediated by multiple signaling pathways. Rac1 is a member of Rho family GTPases regulating cytoskeletal organization, and recent evidence also implicates Rac1 in exocytotic processes. Herein, we report that exposure of insulin-secreting (INS) cells to stimulatory glucose concentrations caused translocation of Rac1 from cytosol to the membrane fraction (including the plasmalemma), an indication of Rac1 activation. Furthermore, glucose stimulation increased Rac1 GTPase activity. Time course study indicates that such an effect is demonstrable only after 15 min stimulation with glucose. Expression of a dominant-negative Rac1 mutant (N17Rac1) abolished glucose-induced translocation of Rac1 and significantly inhibited insulin secretion stimulated by glucose and forskolin. This inhibitory effect on glucose-stimulated insulin secretion was more apparent in the late phase of secretion. However, N17Rac1 expression did not significantly affect insulin secretion induced by high K+. INS-1 cells expressing N17Rac1 also displayed significant morphological changes and disappearance of F-actin structures. Expression of wild-type Rac1 or a constitutively active Rac1 mutant (V12Rac1) did not significantly affect either the stimulated insulin secretion or basal release, suggesting that Rac1 activation is essential, but not sufficient, for evoking secretory process. These data suggest, for the first time, that Rac1 may be involved in glucose- and forskolin-stimulated insulin secretion, possibly at the level of recruitment of secretory granules through actin cytoskeletal network reorganization.

scholarly journals Impaired adaptation of first-phase insulin secretion in postmenopausal women with glucose intolerance

1997 ◽  
Vol 273 (4) ◽  
pp. E701-E707 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
B Cell ◽  
Postmenopausal Women ◽  
Second Phase ◽  
Hepatic Extraction ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
First Phase Insulin Secretion

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness, and hepatic extraction of insulin are altered in subjects with impaired glucose tolerance (IGT). The frequently sampled intravenous glucose tolerance test was performed in postmenopausal women (age 63 yr, body mass index range 21.6–28.9 kg/m2) with IGT ( n = 10) or normal glucose tolerance (NGT; n = 10). Insulin sensitivity (SI) was significantly lower in IGT than in NGT ( P = 0.030). In contrast, insulin secretion was not significantly different between the two groups as determined by area under the curve for insulin and C-peptide, acute insulin response to glucose (AIRG), and glucose sensitivity of first-phase (φ1) or of second-phase (φ2) insulin secretion. In NGT ( r = −0.68, P = 0.029) but not in IGT ( r = −0.05, not significant), SIcorrelated negatively with φ1. The B-cell “adaptation index” (SI × φ1) was lower in IGT than in NGT [83 ± 25 vs. 171 ± 29 min−2/(mmol/l), P = 0.042]. Also, the B-cell “disposition index” (SItimes AIRG) was lower in IGT (83 ± 25 10−4min−1) than in NGT (196 ± 30 10−4min−1, P = 0.011). In contrast, glucose effectiveness or hepatic extraction of insulin was not different between IGT and NGT. We conclude that postmenopausal women with IGT fail to adequately adapt to lowered SI by increasing first-phase insulin secretion.

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