Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Secretory Rate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 793 records · Page 44Linked to original sources
PubMed1989

Interactions between cholinergic agonists and enteric factors in the regulation of insulin secretion from isolated perifused rat islets.

The ability of the cholinergic agonist carbachol to sensitize islets to the action of combined glucose, cholecystokinin and gastric inhibitory polypeptide was determined in isolated rat islets. In response to this combination, peak first phase insulin secretion from control islets averages 85 +/- 5 pg.islet-1.min-1 (mean +/- SEM) and the insulin secretory rates measured 35-40 min after the onset of stimulation averages 127 +/- 34 pg.islet-1.min-1. A prior 20 min exposure to 1 mmol/l carbachol potentiates the modest insulin stimulatory response to this combination of stimulants: peak first phase release is 354 +/- 61 pg.islet-1.min-1, and release measured 35-40 min after the onset of stimulation is 179 +/- 34 pg.islet-1.min-1. This sensitizing effect of carbachol lasts for at least 40 min and can be duplicated by the natural in vivo agonist acetylcholine. These results demonstrate that cholinergic stimulation of isolated islets primes them to the subsequent stimulatory effect of a moderate increase in the circulating glucose level and to several postulated incretin factors. If operative in vivo, this communications network between cephalic and enteric factors represents a remarkable control system to ensure the release of insulin in amounts commensurate to meet the anticipated and actual insulin requirements for insulin-mediated fuel disposition.

Acetylcholine↗
PubMed2000

The in vitro secretion of human leptin is gender-dependent but independent of the body mass index of the donors.

OBJECTIVE: Leptin is an adipocyte-secreted hormone acting as a signal to the central nervous system, where it regulates energy homeostasis and neuroendocrine processes. Leptin plasma levels are mainly regulated by the percentage of body fat, but are also controlled by several metabolic and nutritional variables. Data regarding leptin secretion suggest that it is gender regulated, and higher levels are present in women than men; however, the biological basis for this sex-related difference is unknown. To clarify those points, a systematic study with tissue cultures from human omental adipose tissue was performed. DESIGN AND METHODS: Surgically obtained samples from 137 patients (68 women, 69 men) were evaluated. The assay was standardized in periods of 24 h ending at 96 h. Each adipose tissue sample from a single donor was incubated in triplicate and leptin results expressed as the mean of the integrated secretion into the medium (nanograms of leptin/g tissue per time). RESULTS: Tissue adipose cultures showed a steady leptin secretion throughout the 96 h studied, with the peak of secretory activity reached at 48 h; afterwards, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in the 24 h and 48 h period, as well as the area under the curve analyzed in the 0-48 h period, showed a gender-based difference that was significantly (P<0. 05) higher in women than in men. When data of spontaneous leptin secretion were correlated with the body mass index (BMI) of the donors, no correlation was found. This suggests that in vivo leptin levels are dependent on the total amount of fat of the individual, but independent of the leptin secretory rate by the adipose tissue of the donor. CONCLUSIONS: Leptin secretion from omental adipose tissue in vitro is: (i) significantly higher in samples from women than in samples from men; and (ii) not correlated with the BMI, showing that in vitro leptin secretion is not related to the adiposity of the donor.

Adipose Tissue↗
PubMed2001

Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion.

The episodicity of 24 h leptin release was studied in seven women (mean age 39 years, range 22-56 years) with pituitary-dependent hypercortisolism and in seven age- and body mass index (BMI)-matched female controls. Pulsatile leptin release was quantified by model-free cluster analysis and deconvolution, the orderliness of leptin patterns by the approximate entropy statistic (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis. Blood samples were taken at 10 min intervals for 24 h. Both cluster and deconvolution analysis revealed 2.4-fold increased leptin secretion in patients, caused by combined and equal amplification of basal and pulsatile secretion. Cluster analysis identified 7.1+/-1.5 peaks per 24 h in patients and 6.0+/-0.5 in controls (not significant). The statistical distribution of the individual sample secretory rates was similarly skewed in patients and controls (0.55+/-0.12 vs 0.52+/-0.07). The acrophase (timing of the nyctohemeral leptin peak) in patients occurred at 2314 h (+/-76 min) and at 0058 h (+/-18 min) in controls (not significant). The approximate entropy of leptin release was equivalent in patients and controls (1.67+/-0.03 vs 1.61+/-0.05). The approximate entropy (ApEn) for cortisol in patients was 1.53+/-0.09 and in controls was 0.93+/-0.07 (P<0.0005). Cross-ApEn showed significant pattern synchrony between leptin and cortisol release, which (unexpectedly) was not disrupted by the cortisol excess (patients, 2.02+/-0.04; controls, 1.88+/-0.09; P=0.233). Insulin levels in fasting patients ('fasting insulin') were 27+/-5.7 mU/l vs 14+/-1.6 mU/l in controls (P=0.035). Leptin secretion correlated with fasting insulin levels (R(2)=0.34, P=0.028) and with the cortisol production rate (R(2)=0.33, P=0.033) when patients and controls were combined. In summary, Cushing's disease in women increases leptin production about twofold in an amplitude-specific way. The pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern the 24 h leptin release are not altered. The increased secretion is not explained by BMI and is probably only partly explained by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.

Adult↗
PubMed2001

Glucose-regulated pulsatile insulin release from mouse islets via the K(ATP) channel-independent pathway.

OBJECTIVE: Regulation of insulin release by glucose involves dual pathways, including or not inhibition of ATP-sensitive K(+) channels (K(ATP) channels). Whereas the K(ATP) channel-dependent pathway produces pulsatile release of insulin it is not clear whether the independent pathway also generates such kinetics. DESIGN AND METHODS: To clarify this matter, insulin secretion and cytoplasmic Ca(2+) ([Ca(2+)](i)) were studied in perifused pancreatic islets from ob/ob mice. Insulin release was measured by ELISA technique and [Ca(2+)](i) by dual-wavelength fluorometry. RESULTS: Insulin secretion was pulsatile (0.2--0.3/min) at 3 mmol/l glucose when [Ca(2+)](i) was low and stable. Stimulation with 11 mmol/l of the sugar increased the amplitude of the insulin pulses with maintained frequency and induced oscillations in [Ca(2+)](i). Permanent opening of the K(ATP) channels with diazoxide inhibited glucose-stimulated insulin secretion back to basal levels with maintained pulsatility despite stable and basal [Ca(2+)](i) levels. Increase of the K(+) concentration to 30.9 mmol/l in the continued presence of diazoxide and 11 mmol/l glucose restored the secretory rate with maintained pulsatility and caused stable elevation in [Ca(2+)](i). Simultaneous introduction of diazoxide and elevation of K(+) augmented average insulin release almost 30-fold in 3 mmol/l glucose with maintained pulse frequency. Subsequent elevation of the glucose concentration to 11 and 20 mmol/l increased the release levels. After prolonged exposure to diazoxide, elevated K(+) and 20 mmol/l glucose, the pulse frequency decreased significantly. CONCLUSIONS: Not only glucose signaling via the K(ATP) channel-dependent but also that via the independent pathway generates amplitude-modulated pulsatile release of insulin from isolated islets.

ATP-Binding Cassette Transporters↗
PubMed1986

Effect of hydrogen ion concentration on aldosterone secretion by isolated perfused canine adrenal glands.

The direct effects of changes in extracellular hydrogen ion (H+) concentration on aldosterone secretion under basal, angiotensin II- and potassium-stimulated conditions were studied in isolated, perfused canine adrenal glands. Changes in extracellular H+ concentration were induced by altering either the partial pressure of CO2 (pCO2) or the HCO3- concentration of the perfusate. Acid-base disturbances had a more pronounced effect on aldosterone secretion under stimulated than under basal conditions. Increasing H+ concentration enhanced angiotensin II- and potassium-stimulated aldosterone secretion, whereas decreasing H+ concentration markedly inhibited the secretory response to these stimuli. Because changes in H+ concentration, whether produced by varying extracellular pCO2 or extracellular HCO3- concentration, had similar effects on angiotensin II-stimulated aldosterone secretion, the data suggest that H+ concentration per se is the important determinant of the aldosterone secretory rate. Interestingly, during the immediate recovery period from pCO2-induced alkalosis under both angiotensin II- and potassium-stimulated conditions, aldosterone secretion always returned to a value significantly higher than that obtained just before alkalosis. The results of this study demonstrate that changes in extracellular H+ concentration influence the rate of aldosterone secretion, possibly via changes in intracellular pH, by a direct action on the canine adrenal gland. Therefore, when evaluating the control of aldosterone secretion, the acid-base status of the whole animal or of in-vitro adrenal tissue must be considered.

Adrenal Glands↗
PubMed1990

Participation of tri-iodothyronine and metabolic clearance rate in the inhibition of growth hormone secretion in thyroxine-treated domestic fowl.

Surgical thyroidectomy increases basal and TRH-induced GH concentrations in the peripheral plasma of immature domestic fowl. Replacement therapy with thyroxine (T4; 100 micrograms/kg per day for 7 days, i.m.) suppressed the GH responses to thyroidectomy. Bolus administration of T4 (10 micrograms/kg, i.m.) to thyroidectomized birds promptly lowered the circulating GH concentrations, which remained suppressed for at least 4 h. Chronic (daily injections for 7 days) or acute (one injection) pretreatment of thyroidectomized birds with iopanoic acid (IOP; 40 mg/bird, i.m.) before the bolus administration of T4 attenuated, but did not prevent, inhibition of circulating GH levels by T4. Administration of IOP (40 mg/bird i.m.) 24 h and immediately before the administration of tri-iodothyronine (T3; 3 micrograms/kg, i.m.) or T4 (10 micrograms/kg, i.m.) also failed to suppress thyroidal inhibition of circulating GH concentrations in thyroidectomized birds. Administration of IOP alone had no effect on GH concentrations. Circulating T3 concentrations were not enhanced following the administration of T4 to IOP-treated birds, indicating its inhibition of hepatic monodeiodinase activity. The metabolic clearance rate (MCR) of 125I-labelled chicken GH in the plasma of thyroidectomized fowl was less than that in sham-thyroidectomized birds. Following pretreatment with T4 (100 micrograms/kg per day for 7 days) sham-thyroidectomized and thyroidectomized birds did not differ significantly in their MCR. The GH secretion rate in thyroidectomized birds was similar to that in sham-thyroidectomized birds and in both groups was markedly reduced following pretreatment with T4. These results demonstrate thyroidal inhibition of circulating GH concentrations in fowl.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Replenishment of LH stores of gonadotrophs in relation to gene expression, synthesis and secretion of LH after the preovulatory phase of the sheep oestrous cycle.

The pattern of replenishment of LH secretory granule stores in sheep pituitary gonadotrophs, after an induced LH surge, was determined by immunogold localisation at the ultrastructural level by electron microscopy. Twenty-four Welsh Mountain ewes were initially synchronised with progestagen devices for 14 days before luteolysis was induced by a prostaglandin F(2 alpha) analogue, cloprostenol. A further 24 h later, a preovulatory LH surge was induced by intravenous injection of a GnRH agonist, buserelin. Animals were divided into four groups (n=6) and blood sampled at 2 h intervals from 4 h prior, to 18 h after, buserelin administration and then at infrequent intervals (1 to 8 h) thereafter until death. Pulse profiles of LH were also obtained by an additional collection of blood samples within a 6 h window directly preceding death. Groups of animals were killed at 24, 48, 72 or 96 h after buserelin treatment. Pituitaries were dissected and processed for transmission electron microscopy and frozen for later molecular biological analysis. A characteristic preovulatory surge of LH was observed in all animals. The cytoplasm of gonadotrophs, in animals killed 24 h after buserelin treatment, was completely empty of secretory granules. This was associated with diminutive pituitary LH content, low pituitary GnRH binding levels and an almost complete absence (one pulse in one animal) of LH pulsatile secretion. Despite the lack of apparent secretory activity, clusters of exposed LH beta label present within the cytoplasm at this time and constant LHbeta mRNA expression levels irrespective of tissue collection time, suggest that the cell is actively synthesising LHbeta. The formation of sparse numbers of small LH beta immuno-labelled electron-dense secretory granules was apparent at 48 h after buserelin treatment, and replenishment of LH beta immuno-labelled granule stores continued until total granule numbers had increased two-fold (P<0.01) by 96 h post-treatment. Affiliated with granule replenishment was a significant increase in pituitary LH content (P<0.01), pituitary GnRH binding levels (P<0.01) and the restoration of LH pulsatile secretion. Despite the replenishment of granule stores with time, cytoplasmic area did not vary. These results suggest that restoration of pulsatile LH secretion after a preovulatory LH surge is related to replenishment of LH beta secretory granule stores and an increase in GnRH binding levels.

Analysis of Variance↗
PubMed1996

Zollinger-Ellison syndrome. Recognition and management of acid hypersecretion.

Zollinger-Ellison syndrome (ZES) should be suspected if a patient has severe peptic ulceration, ulcers and kidney stones, a family history of ulcers or endocrine diseases, watery diarrhoea or malabsorption with or without ulcers, or if hypergastrinaemia is found. Any patient in whom ZES is suspected, and certainly if diagnosed, should be given large doses of antisecretory medication immediately. This should never be stopped except under controlled conditions or unless acid outputs have been reduced surgically. Patients cannot be managed safely without measuring acid outputs. These should be lowered to < 10 mmol/h, or < 5 mmol/h in patients with a previous gastric resection or severe oesophageal disease. Acid secretion can be controlled acutely in 70% of patients with an infusion of ranitidine 1 mg/kg/h, while 4 mg/kg/h will control acid in all. The initial oral dosage of omeprazole or lansoprazole should be 60 mg/day. Doses should then be adjusted daily on the basis of acid outputs. Proton pump inhibitors in a dosage of 60 mg/day will control acid output in most patients and 60 mg every 12 hours will control acid output in all. Doses can then often be slowly and progressively reduced. A parietal cell vagotomy reduces acid secretion and reduces, but does not abolish, the need for antisecretory medication. In patients with multiple endocrine neoplasia type 1 and hyperparathyroidism, a parathyroidectomy that results in normocalcaemia will reduce acid secretion and drug requirements. A total gastrectomy is rarely if ever needed nowadays. Given the high degree of safety of gastric antisecretory medications versus the risks of acid hypersecretion in patients with ZES, the mistakes in management of acid hypersecretion that must be avoided are those of giving insufficient medication and not measuring acid secretory rates.

Animals↗
PubMed1980

Ca2+ removal effects on bullfrog gastric mucosa in the presence of drugs.

Bullfrog gastric mucosa can secrete acid in vitro for more than 24 hr. In Ca2+-deficient media, the acid secretion measured by pH stat method gradually decreased to cease about 200 min after the start of immersion in the media. When A23187 or quinidine, which are known to mobilize Ca2+ from the intracellular pools, was present on the submucosal side, a prolongation of the duration of acid secretion in the absence of Ca2+ was found. Dibutyl c-AMP also induced a similar prolongation. Histamine or theophylline not only prolonged the duration of acid secretion but also transiently increased the acid secretory rate over the control level. Based upon the known fact that there are different intracellular Ca2+ compartments, i.e, one related to the process of acid secretion and the other to the maintenance of junctional complexes, the present results of drug effects were discussed especially in regard to their Ca2+ mobilizing effects. Cessation of acid secretion in a K+- and Ca2+-deficient solution occurred much more quickly than that in a Ca2+-deficient or a K+-deficient medium.

Animals↗
PubMed1988

Continuous measurements of tissue impedance during secretion in dog submandibular gland.

The electrical impedance of the dog submandibular gland, as an indicator of changes in extracellular fluid (ECF) volume, was measured at 5 kHz, 500 kHz, and 5 MHz at intervals of 10 s during secretory stimulation, because the conductivity calculated from impedance at low frequencies reflected the ECF volume. The decrease in conductivity occurred in the first minute of stimulation. Its decrease was more marked during stimulation after circulatory arrest. Salivary secretion under intact circulation consists of two phases: an initial secretion occurring in the first minute of stimulation with a high secretory rate and a steady secretion continuing during stimulation at a constant rate. A decrease in conductivity occurred in the initial secretion. Within a few minutes following the cessation of stimulation, the conductivity increased to a level higher than the resting one with an intact circulation, while the blood flow remained several times higher than in the resting state. The conductivity of the gland slowly recovered to the prestimulation level over a 30-min period. The histological examination revealed that the main compartment of the ECF change was the interlobular space. Impedance and histological studies showed that the ECF volume of salivary glands changes dynamically during secretion. On the other hand, the cellular volume also increased in the initial secretion of an isolated gland. Its increase suggested that the fluid was transported to the lumen via a cellular pathway as well as a paracellular pathway in the initial secretion.

Animals↗
PubMed1976

Inhibition of insulin rlease by scorpion toxin in rat pancreatic islets.

Toxin purified from venom of the scorpion Leiurus quinquestriatus was used to release the norepinephrine from adrenergic nerve terminals in isolated pancreatic islets perifused in vitro. Addition of toxin (10 mug./ml) to the perifusion medium caused a sixfold increase in release of norepinephrine in the presence or absence of 3 X 10(-5) M phenoxybenzamine. During 20 minutes of stimulation with toxin, the pancreatic islets released an average of 15 pg. of norepinephrine per islet, which represented 20 per cent of the normal content of norepinephrine in islets. Insulin secretory rates in response to either 1.0 or 3.0 mg./ml. glucose were inhibited similarly by scorpion toxin. Addition of phenoxybenzamine abolished the inhibition of insulin release caused by scorpion toxin. Phenoxybenzamine alone did not affect release of insulin. Neither the enhanced release of norepinephrine nor the decreased release of insulin was reversed by a 20-minute wash-out period after infusion of toxin. These results indicate that the sympathetic nerve terminals in the rat pancreatic islet contain considerable amounts of norepinephrine that can be released by scorpion toxin. The norepinephrine released from sympathetic nerve endings in the pancreatic islet can inhibit release of insulin through an alpha-adrenergic action that is blocked by phenoxybenzamine.

Animals↗
PubMed1991

Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes?

Islet amyloid polypeptide (IAPP) or amylin, a recently discovered minor secretory peptide of the beta-cell related to calcitonin gene-related peptide (CGRP), is a constituent of amyloid deposits in the islets of many non-insulin-dependent (type II) diabetic individuals and some elderly nondiabetic subjects. IAPP is synthesized as a small precursor at a level of approximately 1% that of insulin and is processed, amidated, stored in beta-granules, and released along with insulin and C-peptide. Analysis of its gene (located on chromosome 12) supports an evolutionary relationship to calcitonin and CGRP, peptides with which it shares some biological actions. Like CGRP, IAPP antagonizes the action of insulin mainly at the level of muscle glycogen synthesis, but the levels required for this effect seem to be considerably higher than reported circulating levels. No evidence for overproduction of IAPP in diabetic subjects has been found thus far, but much more work is necessary to define its normal secretory rates and clearance. Other proposed actions of IAPP include serum calcium-lowering effects and smooth muscle relaxation; the latter effect might promote the uptake of insulin into the circulation within the islets. Deposition of amyloid is species selective due to structural differences within the central part of the molecule and may be initiated intracellularly in type II diabetes by several mechanisms. No differences in the structure of IAPP or its precursor have been found in individuals with maturity-onset diabetes of the young or type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Contribution of amino acids and insulin to protein anabolism during meal absorption.

The contribution of dietary amino acids and endogenous hyperinsulinemia to prandial protein anabolism still has not been established. To this end, leucine estimates ([1-14C]leucine infusion, plasma alpha-ketoisocaproic acid [KIC] specific activity [SA] as precursor pool SA) of whole-body protein kinetics and fractional secretory rates (FSRs) of albumin, fibrinogen, antithrombin III, and immunoglobulin G (IgG) were measured in three groups of healthy volunteers during intragastric infusion of water (controls, n = 5), liquid glucose-lipid-amino acid (AA) meal (meal+AA, n = 7), or isocaloric glucose-lipid meal (meal-AA, n = 7) that induced the same insulin response as the meal+AA. The results of this study demonstrate that 1) by increasing (P < 0.01) whole-body protein synthesis and decreasing (P < 0.01) proteolysis, dietary amino acids account for the largest part (approximately 90%) of postprandial protein anabolism; 2) the ingestion of an isocaloric meal deprived of amino acids exerts a modest protein anabolic effect (10% of postprandial protein anabolism) by decreasing amino acid oxidation and increasing (P < 0.01) albumin synthesis; 3) albumin FSR is increased (approximately 20%) by postprandial hyperinsulinemia (meal-AA) and additionally increased (approximately 50%) by amino acid intake (meal+AA); 4) IgG FSR is stimulated (approximately 40%) by amino acids, not by insulin; and 5) fibrinogen and antithrombin III FSR are not regulated by amino acids or insulin.

Administration, Oral↗
PubMed2001

Amplitude modulation of pulsatile insulin secretion by intrapancreatic ganglion neurons.

Neuron activity and insulin release were measured simultaneously from 33 preparations of intrapancreatic canine ganglia and pancreatic parenchyma adjacent to the ganglia. The electrical activity of single neurons of the ganglia was recorded with intracellular microelectrodes, and insulin release from the attached islets was determined with an enzyme-linked immunosorbent assay. Insulin release was 62 +/- 18 fmol preparation/min in the presence of 10 mmol/l glucose and pulsatile (3.7 +/- 0.4 min/pulse). Corresponding measurements of neuronal electrical activity showed a stable membrane potential of -53.5 +/- 0.6 mV. Short, high-frequency (20 Hz) preganglionic nerve stimulation evoked action potentials and, in 46% of the preparations, a threefold rise in the insulin secretory rate associated with increased amplitude of the insulin pulses. The effects were blocked by 10 micromol/l tetrodotoxin (TTX). In other preparations, continuous low-frequency (0.05-0.5 Hz) preganglionic nerve stimulation evoked action potentials and, in 50% of the preparations, a gradual increase of insulin release associated with augmentation of insulin pulse amplitude without alteration of the duration. The effects were blocked by 50 micromol/l hexamethonium (HEX). In the remaining preparations, no change in insulin release was observed during nerve stimulation. In the absence of stimulation, neither TTX nor HEX affected the membrane potential or insulin secretion. These first simultaneous measurements of intrapancreatic ganglion activity and insulin secretion are consistent with amplitude modulation of pulsatile insulin secretion induced by changes in electrical activity in a population of intrapancreatic ganglion neurons.

Action Potentials↗
PubMed2001

A model for glucose control of insulin secretion during 24 h of free living.

The aim of this work was to develop a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations during 24 h of free living. We obtained hourly central venous blood samples from a group of healthy volunteers who spent 24 h in a calorimetric chamber, where they consumed standardized meals. Insulin secretory rates were reconstructed from plasma C-peptide concentrations by deconvolution. The relationship between insulin release and plasma glucose concentrations was modeled as the sum of three components: a static component (describing the dependence on plasma glucose concentration itself, with an embedded circadian oscillation), a dynamic component (modeling the dependence on glucose rate of change), and a residual component (including the fraction of insulin secretion not explained by glucose levels). The model fit of the individual 24-h secretion profiles was satisfactory (within the assigned experimental error of glucose and C-peptide concentrations). The static component yielded a dose-response function in which insulin release increased quasi-linearly (from 40 to 400 pmol/min on average) over the range of 4-9 mmol/l glucose. The dynamic component was significantly different from zero in coincidence with meal-related glucose excursions. The circadian oscillation and the residual component accounted for the day/night difference in the ability of glucose to stimulate insulin release. Over 24 h, total insulin release averaged 257+/-58 nmol (or 43+/-10 U). The static and dynamic component together accounted for approximately 80% of total insulin release. The model proposed here provides a detailed robust description of glucose-related insulin release during free-living conditions. In nondiabetic subjects, non-glucose-dependent insulin release is a small fraction of total insulin secretion.

Adult↗
PubMed2002

Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a potent glucose-lowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 +/- 7 years (mean +/- SD), BMI 28.9 +/- 3.0 kg/m(2), HbA(1c) 6.5 +/- 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 microg/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7-8 h) and mealtime (1130-1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg x kg(-1) x min(-1) every 10 min) was evaluated by 1-min sampled measurements of insulin concentrations from 0930 to 1030 h and subsequent time series analysis of the insulin concentration profiles. All results are given as NN2211 versus placebo; statistical analyses were performed by analysis of variance. In the fasting state, plasma glucose was significantly reduced (6.9 +/- 1.0 vs. 8.1 +/- 1.0 mmol/l; P = 0.004), ISR was increased (179 +/- 70 vs. 163 +/- 66 pmol/min; P = 0.03), and plasma glucagon was unaltered (19 +/- 4 vs. 20 +/- 4 pg/ml; P = 0.17) by NN2211. Meal-related area under the curve (AUC)(1130-1530 h) for glucose was markedly reduced (30.6 +/- 2.4 vs. 39.9 +/- 7.3 mmol x l(-1) x h(-1); P < 0.001), ISR AUC(1130-1530 h) was unchanged (118 +/- 32 vs. 106 +/- 27 nmol; P = 0.13), but the increment (relative to premeal values) was increased (65 +/- 22 vs. 45 +/- 11 nmol; P = 0.04). Glucagon AUC(1130-1530 h) was suppressed (77 +/- 18 vs. 82 +/- 17 pmol x l(-1) x h(-1); P = 0.04). Gastric emptying was significantly delayed as assessed by AUC(1130-1530 h) of 3-ortho-methylglucose (400 +/- 84 vs. 440 +/- 70 mg x l(-1) x h(-1); P = 0.02). During pulse entrainment, there was a tendency to increased high frequency regularity of insulin release as measured by a greater spectral power and autocorrelation coefficient (0.05 < P < 0.10). The pharmacokinetic profile of NN2211, as assessed by blood samplings for up to 63 h postdosing, was as follows: T(1/2) = 10.0 +/- 3.5 h and T(max) = 12.4 +/- 1.7 h. Two patients experienced gastrointestinal side effects on the day of active treatment. In conclusion, the long-acting GLP-1 derivative NN2211 effectively reduces fasting as well as meal-related (approximately 12 h postadministration) glycemia by modifying insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

Aged↗
PubMed2002

Phasic insulin release and metabolic regulation in type 2 diabetes.

Type 2 diabetes is a heterogeneous disorder due to prevalent insulin resistance associated with deficient insulin secretion or to a prevalent defect of insulin secretion associated with impaired insulin action. The definition is supported by the high frequency at which insulin resistance can be demonstrated in type 2 diabetic patients. Nonetheless, insulin resistance is not a sufficient mechanism to cause diabetes. Impaired beta-cell function is a necessary defect in all conditions of impaired glucose regulation; however, it manifests itself in a different manner in fasting and glucose-stimulated conditions. In the fasting state, the basal insulin secretory rate increases as a function of the progressive decline in insulin action. As such, the fasting plasma insulin concentration is often taken as a marker for insulin sensitivity. After glucose challenge, a specific alteration of acute insulin release is an early and progressive defect. The latter might represent an intrinsic defect, but its continuous decline is affected by glucotoxicity and lipotoxicity. To understand the impact of beta-cell dysfunction in type 2 diabetes on metabolic homeostasis, it is useful to consider the different phases of insulin secretion separately. Insulin secretion can be divided into basal (postabsorptive) and stimulated (postprandial) states. The former prevails during the interprandial phases and plays a major role during the overnight fast; the latter regulates glucose metabolism when carbohydrate is abundant and must be disposed of. Data in animals and humans support a crucial physiological role of first-phase insulin secretion in postprandial glucose homeostasis. This effect is primarily achieved in the liver, allowing prompt inhibition of endogenous glucose production and limiting the postprandial rise in plasma glucose level. In type 2 diabetes, loss of the early surge of insulin release is an early and quite common defect that may have a pathogenetic role in the development of postprandial hyperglycemia, possibly requiring specific therapeutic intervention.

Blood Glucose↗
PubMedDate not supplied

The effect of external stimuli on cultured rat middle ear epithelium. I. Extracellular calcium concentration.

The effect of the extracellular calcium concentration on serially cultured rat middle ear epithelium was investigated with phase contrast microscopy, scanning electron microscopy, and transmission electron microscopy, as well as by a method to induce cornified envelope formation with a calcium ionophore. The results show that calcium concentration affects cell morphology and terminal differentiation. Furthermore, a role in the proliferation rate, secretory activity and migration seems likely. Since the extracellular calcium concentration may fluctuate locally during osteoresorption or osteodeposition, both of which occur during otitis media, this concentration might be an important factor in the pathogenesis of both acute and chronic otitis media.

Animals↗