Serum cystatin C is associated with kidney function but not with cardiovascular risk factors or subclinical atherosclerosis in patients with Systemic Lupus Erythematosus.

Cystatin C (CysC) is a protein considered as an excellent marker of renal function, and it has been suggested as an independent predictor of cardiovascular (CV) risk. We evaluated the association of serum CysC with renal function, CV risk factors, inflammation, and subclinical atherosclerosis in Systemic Lupus Erythematosus (SLE) patients. Sixty-one SLE female patients were selected according to estimated glomerular filtration rate (GFR) > 60 ml/min/1.73m2. Renal function parameters, SLE specific factors, CV risk factors, and inflammatory markers were assessed. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry. Serum CysC concentration was measured using a particle-enhanced immunonephelometric assay that established 0.59-1.01 mg/l as reference values. Patients with high CysC showed significantly altered creatinine, microalbuminuria, and GFR in addition to a significant higher presence of traditional CV risk factors such as arterial hypertension (p < 0.001), metabolic syndrome (p < 0.001), hypertrigliceridemia (p < 0.001), tobacco habit (p < 0.05), and a strong association with arterial stiffness (p = 0.017). Positive correlation between CysC, homocysteine (r = 0.511; p < 0.001) and fibrinogen levels (r = 0.304; p < 0.02) were also observed. A significantly higher SLICC/ACR score was related to high CysC level (p = 0.011), together with higher endothelin-1 and lower TNF serum concentration (p < 0.005). Considering only patients without any renal impairment (microalbumin/creatinine <30 mg/g), no association between CysC level and CV risk factors, arterial stiffness, or SLE-related factors was found. Serum CysC is a good marker of renal function in SLE patients, but it is not independently associated with cardiovascular risk factor or subclinical atherosclerosis.

Electromyographic adjustments during continuous and intermittent incremental fatiguing cycling.

We studied the sensitivity of electromyographic (EMG) variables to load and muscle fatigue during continuous and intermittent incremental cycling. Fifteen men attended three laboratory sessions. Visit 1: lactate threshold, peak power output, and VO2max . Visits 2 and 3: Continuous (more fatiguing) and intermittent (less fatiguing) incremental cycling protocols [20%, 40%, 60%, 80% and 100% of peak power output (PPO)]. During both protocols, multichannel EMG signals were recorded from vastus lateralis: muscle fiber conduction velocity (MFCV), instantaneous mean frequency (iMNF), and absolute and normalized root mean square (RMS) were analyzed. MFCV differed between protocols (P < 0.001), and only increased consistently with power output during intermittent cycling. RMS parameters were similar between protocols, and increased linearly with power output. However, only normalized RMS was higher during the more fatiguing 100% PPO stage of the continuous protocol [continuous-intermittent mean difference (95% CI): 45.1 (8.5% to 81.7%)]. On the contrary, iMNF was insensitive to load changes and muscle fatigue (P = 0.14). Despite similar power outputs, continuous and intermittent cycling influenced MFCV and normalized RMS differently. Only normalized RMS was sensitive to both increases in power output (in both protocols) and muscle fatigue, and thus is the most suitable EMG parameter to monitor changes in muscle activation during cycling.

Correlación entre el Puntaje Obtenido en la Prueba "Timed up and go" y Momentos Articulares del Miembro Inferior Registrados Durante la Transferencia de Sedente a Bípedo en Adultos Mayores con Antecedentes de Caídas Frecuentes / Correlation between the Scores of "Timed up and go" Test and Registered Joint Moments of Lower Limb During the Sit-to-Stand Transfer in Elderly with Antecedents of Frequent Falls

Los cambios producidos durante el envejecimiento predisponen al adulto mayor a las caídas frecuentes, en el ambiente clínico el riesgo de caída es valorado mediante pruebas clínicas que muchas veces carecen de poder analítico, por lo cual es necesario describir cual de dichas pruebas puede tener mayor relación con parámetros biomecánicos analíticos con la finalidad de conferirle a dichas pruebas funcionales tales características. El objetivo de este trabajo fue describir la existencia de correlación entre los puntajes obtenidos en la prueba funcional "Timed up and go" (TUG) y momentos articulares del miembro inferior obtenidos durante la ejecución de la transferencia de sedente a bípedo (TSB) en sujetos adultos mayores con antecedentes de caídas frecuentes. Se obtuvo una muestra de 30 voluntarios, todos adultos mayores con antecedentes de caídas frecuentes, los que fueron evaluados con la prueba funcional de TUG. También se evaluó mediante un sistema de análisis de movimiento la TSB donde se registraron los parámetros biomecánicos necesarios para determinar los momentos articulares del miembro inferior. Existió una correlación significativa (r=-0,39; p=0,03) entre el puntaje obtenido en el TUG y el momento articular máximo de rodilla. Para la muestra evaluada, el tiempo de ejecución de la prueba "Timed up and go" fue indicador de la capacidad de generar momento articular por parte de los músculos flexo-extensores de rodilla en sujetos con antecedentes de caídas frecuentes.

The changes that take place during aging predispose the elder adult to frequent falls. In clinical practice fall risk is assessed by clinical tests that many times lack analytical power, therefore making it necessary to describe which of the clinical tests are related to the analytical biomechanical parameters in order to assign such characteristics to these functional tests. The objective of this work was to describe the existence of a correlation between the score of the functional test "Timed up and go" (TUG) and the joint moments of lower limb obtained during the execution of the sit to stand (STS) transfer in elderly subjects with a history of frequent falls. A sample of 30 volunteers was obtained; all were elders with a history of frequent falls. They were assessed with the functional test of TUG. Also assessed were the joint moments of the lower limb with motion analysis system. There is significant correlation (r=0.39; p=0.03) between the score obtained in the TUG and the maximum joint moment of the knee. For the sample assessed, the time of execution of the test "Timed up and go" was indicative of the capacity to generate a joint moment by the flexion-extensor muscles of the knee in subjects with a history of frequent falls.

Kisspeptin-13 inhibits insulin secretion without affecting glucagon or somatostatin release: study in the perfused rat pancreas.

Kisspeptins are a family of peptides encoded by the KISS1 gene, which binds to G-protein-coupled receptor (GPR54), an orphan GPR54 related to galanin receptors. Endogenous forms composed of 54, 14, and 13 amino acids have been identified. Kisspeptin and GPR54 mRNAs have been detected in pancreatic B and A cells. Furthermore, kisspeptin-54 has been shown to slightly stimulate the last phase of glucose-induced insulin secretion in mouse and human islets and to inhibit insulin release in MIN6 cells. We have investigated the effect of kisspeptin-13 on insulin, glucagon, and somatostatin secretion. The study was performed in the perfused rat pancreas. Glucose, arginine, carbachol, and exendin-4 were used as secretagogues. Hormones were measured by RIA. Kisspeptin-13 reduced glucose-induced insulin secretion in a dose-dependent manner (IC(50)=1.2 nM) and inhibited the insulin responses to both carbachol and exendin-4. Kisspeptin-13 blocked arginine-induced insulin secretion without affecting the glucagon or somatostatin responses to this amino acid, thus indicating that kisspeptin-13 influences B cells directly, rather than through an A- or D-cell paracrine effect. The reduction of the insulin response to exendin-4 induced by kisspeptin-13 was also observed in pertussis toxin-treated rats, thus suggesting an inhibition independent of G(i) proteins. In view of the potent insulinostatic effect of kisspeptin-13, it is tempting to speculate that kisspeptins may be implicated in the regulation of B-cell secretion.

Exendin-4 dose-dependently stimulates somatostatin and insulin secretion in perfused rat pancreas.

We have investigated the effect of exendin-4, a GLP-1 analogue, on somatostatin and insulin secretion in perfused rat pancreas. At constant glucose concentration within the type 2 diabetic range (9 mM), exendin-4 stimulated somatostatin and insulin secretion in a dose-dependent manner. Dose-response curves were sigmoidal (R (2) = 0.9954 and R (2) = 0.9973, respectively; p < 0.01) and the EC (50) was 4.3 nM for somatostatin secretion and 1.4 nM for insulin secretion. Exendin-4 stimulated somatostatin output at low (3.2 mM), normal (5.5 mM) and high (9 mM) glucose concentrations, while the insulinotropic effect of exendin-4 was not found at low glucose levels. On the other hand, exendin-4 potentiated somatostatin and insulin responses to an increase in perfusate glucose levels, and to arginine and carbachol. Finally, the insulinotropic effect of exendin-4 was maintained in the absence of a somatostatin response as induced by cysteamine pretreatment, indicating a direct effect of exendin-4 on the B-cell. In summary, exendin-4 behaves as a general stimulatory agent of both insulin and somatostatin release in the perfused rat pancreas. Given that exendin-4 has also been shown to increase gastric somatostatin secretion, it is tempting to speculate that exendin-4 might behave as a general stimulator of D-cell function in other tissues, a point worthy of further investigation.

Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion.

OBJECTIVE: Ghrelin is a 28 amino acid residue peptide identified in both human and rat stomach and which acts as an endogenous ligand for the GH secretagogue receptor (GHS-R) and stimulates GH release. GHS-Rs are expressed in a number of tissues, including the pancreas, and ghrelin-like immunoreactivity is present in peripheral plasma, where its levels increase during fasting and decrease after food intake. The relationship between nutritional status and circulating ghrelin concentrations prompted us to investigate the effect of this peptide on pancreatic hormone secretion. METHODS: The study was performed in the isolated rat pancreas perfused in situ. Insulin, glucagon and somatostatin were measured by radioimmunoassay. RESULTS: Addition of 10 nM ghrelin to the perfusate significantly reduced the insulin response to the secretagogues glucose, arginine and carbachol, which act on the B-cell via different mechanisms, as well as the somatostatin response to arginine. Ghrelin was without effect on the glucagon output induced by this amino acid. At a lower concentration (2 nM) ghrelin was also found to inhibit glucose-induced insulin release. CONCLUSION: These findings support the proposal that the inhibitory effect of ghrelin on insulin release constitutes a tonic regulation of the B-cell, contributing to restrain its secretory activity in the state of food deprivation. On the other hand, the inhibition of pancreatic somatostatin release by ghrelin suggests a blocking effect of this hormone on the widely distributed D-cell population.

Effect of leptin on insulin, glugacon and somatostatin secretion in the perfused rat pancreas.

We have investigated the effect of rat leptin as well as the 22-56 fragment of this molecule on pancreatic hormone secretion in the perfused rat pancreas. In pancreases from fed rats, leptin failed to alter the insulin secretion elicited by glucose, arginine or tolbutamide, but inhibited the insulin response to both CCK-8 and carbachol, secretagogues known to act on the B-cell by increasing phospholipid turnover. This insulinostatic effect was also observed with the 22-56 leptin fragment. In pancreases obtained from 24-hour fasted rats, no effect of leptin on carbachol-induced insulin output was found, perhaps as a consequence of depressed B-cell phospholipid metabolism. Leptin did not influence glucagon or somatostatin release. Our results do not support the concept of leptin as a major regulator of B-cell function. Leptin inhibition of carbachol-induced insulin output might reflect a restraining effect of this peptide on the cholinergic stimulation of insulin release.

Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas.

Amylin, a peptide hormone from pancreatic beta-cells, is reported to inhibit insulin secretion in vitro and in vivo and to inhibit nutrient-stimulated glucagon secretion in vivo. However, it has been reported not to affect arginine-stimulated glucagon secretion in vitro. To resolve if the latter resulted from inactive peptide (a problem in the early literature), those experiments were repeated here with well-characterized peptide and found to be valid. In isolated perfused rat pancreas preparations, coperfusion with 1 nM amylin had no effect on arginine-, carbachol-, or vasoactive intestinal peptide-stimulated glucagon secretion. Amylin also had no effect on glucagon output stimulated by decreasing glucose concentration from 11 to 3.2 mM or on glucagon suppression caused by increasing glucose from 3.2 to 7 mM. Amylin at 100 nM had no effect in isolated islets in which glucagon secretion was stimulated by exposure to 10 mM arginine, even though glucagon secretion in the same preparation was inhibited by somatostatin. In anesthetized rats, amylin coinfusion had no effect on glucagon secretion stimulated by insulin-induced hypoglycemia. To reconcile reports of glucagon inhibition with the absence of effect in the experiments just described, anesthetized rats coinfused with rat amylin or with saline were exposed sequentially to intravenous L-arginine (during a euglycemic clamp) and then to hypoglycemia. Amylin inhibited arginine-induced, but not hypoglycemia-induced, glucagon secretion in the same animal. In conclusion, we newly identify a selective glucagonostatic effect of amylin that appears to be extrinsic to the isolated pancreas and may be centrally mediated.

Effects of sodium tungstate on insulin and glucagon secretion in the perfused rat pancreas.

Both the direct effect of sodium tungstate on insulin and glucagon secretion in the perfused rat pancreas, and the insulin response to glucose and arginine in pancreases isolated from tungstate-pretreated rats were studied. Infusion of tungstate stimulated insulin output in a dose-dependent manner. The insulinotropic effect of tungstate was observed at normal (5.5 mM), and moderately high (9 mM) glucose concentrations, but not at a low glucose concentration (3.2 mM). Tungstate-induced insulin output was blocked by diazoxide, somatostatin, and amylin, suggesting several targets for tungstate at the B-cell secretory machinery. Glucagon release was not modified by tungstate. Pancreases from chronically tungstate-treated rats showed an enhanced response to glucose but not to arginine. Our results indicate that the reported reduction of glycemia caused by tungstate administration is, at least in part, due to its direct insulinotropic activity. Furthermore, chronic tungstate treatment may prime the B-cell, leading to over-response to a glucose stimulus.

Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas.

1. Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances. 2. We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas. 3. AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response ( approximately 4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell. 4. AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin. 5. The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion.

Inhibitory effect of enterostatin on the beta cell response to digestive insulinotropic peptides.

OBJECTIVE AND DESIGN: We have investigated the effect of enterostatin on insulin release by the perfused rat pancreas: (1) under conditions of prolonged fasting and (2) under beta cell stimulation by digestive insulinotropic piptides. RESULTS: In pancreases from 24-h starved rats, the insulin response to glucose was reduced (approximately 75%) as compared to that observed in fed rats. This minimal response was abolished by 100 nM enterostatin. In fed rats, 100 nM enterostatin blocked the insulin output evoked by gastric inhibitory peptide (GIP) (approximately 75%) and by glucagon-like peptide-1 (GLP-1) (approximately 80%). Since both peptides exert their insulinotropic activity by activating the adenylate cyclase/cyclic AMP system, the interference of this pathway by enterostatin may be considered. Enterostatin (100 nM) did not modify the insulin responses to 26-33 fragment of cholecystokinin (CCK-8) and carbachol, substances which activate phosphoinositol turnover within the beta cell. The inhibitory effect of 100 nM enterostatin on glucose-induced insulin release was also observed at 50 nM and 10 nM enterostatin. Finally, des-Arg-enterostatin (100 nM) did not modify glucose-induced insulin output. CONCLUSION: Enterostatin inhibits the insulin response to glucose--both under fed and fasted conditions, and to the main digestive insulinotropic peptides--GIP and GLP-I. The entire enterostatic molecule seems to be necessary for it to exert its beta cell blocking effect. White the physiological role of enterostatin has not as yet been established, our observations allow speculation as to whether this peptide is implicated in the entero-insular axis as an antiincretin agent.

Growth hormone secretory response to intravenous galanin infusion in acromegalic patients.

Galanin is a 29-amino acid neuropeptide which stimulates the secretion of growth hormone (GH) in normal men. Although the diagnosis of acromegaly involves demonstrating hypersecretion of GH and/or abnormalities in GH secretory dynamics, sometimes it is difficult to establish the activity of the disease. The aim of our study was to assess the response to galanin infusion in acromegalic patients (active and cured). We studied 19 subjects: 5 healthy volunteers (group I), 9 patients with active acromegaly (group II), and 5 with acromegaly cured after transsphenoidal surgery (group III). We performed a test of infusion with porcine galanin (8 microg/Kg/h) to study the secretory response of the GH. Galanin produced a marked increase in GH in the controls, group I (F9,36 = 5.34; p < 0.01) and in the cured patients, group III (F9,36 = 7.35; p < 0.01). On the other hand, galanin did not significantly modify the secretion of GH in the patients with active disease, group II. The areas under the curve (AUC) were higher in groups I and III compared to group II (p < 0.01). Nevertheless, there were no statistically significant differences in the AUC of groups I and III. Our results indicate that the differences in the GH response to galanin in patients with active and cured acromegaly could be of value in the study of the disease.

Influence of glucose concentration on the inhibitory effect of amylin on insulin secretion. Study in the perfused rat pancreas.

The effect of amylin on insulin secretion is a matter of controversy. Short-term experiments have shown that amylin, at 75 pmol/l, inhibits the insulin release elicited by a modest increase in the perfusate glucose concentration (from 5.5 mmol/l to 9 mmol/l). The present work was undertaken to further investigate the effect of amylin on glucose-induced insulin release at different glucose concentrations. The study was performed in the isolated perfused rat pancreas. Amylin, at 75 pmol/l, markedly blocked the insulin response when the perfusate glucose concentration was increased from 3.2 mmol/l to 7 mmol/l (by 90%; P < 0.01) or from 5.5 mmol/l to 9 mmol/l (by 80%; P < 0.01). At the same amylin concentration, no significant inhibition of insulin output was observed when the perfusate glucose level was augmented from 5.5 mmol/l to 16.6 mmol/l, from 7 mmol/l to 11 mmol/l or from 9 mmol/l to 13 mmol/l. At a higher concentration (750 pmol/l), amylin also failed to inhibit the insulin response induced by increasing glucose levels from 5.5 mmol/l to 16.6 mmol/l or from 9 to 13 mmol/l. These findings indicate that, in the rat pancreas, amylin only inhibits insulin release when evoked by elevations of glucose levels comparable to those occurring in normal subjects under physiological conditions.

Effect of enterostatin on insulin, glucagon, and somatostatin secretion in the perfused rat pancreas.

Enterostatin is a pentapeptide generated by trypic digestion of procolipase in the small intestine. Both peripheral and central administration of this peptide to rats has been shown to reduce food intake, this reduction being due to specific suppression of fat intake. In perifused pancreatic rat islets, enterostatin has been shown to inhibit the insulin response to a high glucose concentration. In the present study, we have investigated the effect of exogenous enterostatin on insulin, glucagon, and somatostatin secretion by the isolated perfused rat pancreas. Enterostatin, at 100 mmol/l, inhibited the insulin response to 9 mmol/l glucose (by 70%), 0.1 mmol/l tolbutamide (by 40%), and 5 mmol/l arginine (by 70%). Enterostatin had no effect on glucagon and somatostatin release at a maintained glucose level (5.5 mmol/l) or in response to 5 mmol/l arginine. Finally, preinfusion of the rat pancreas with a high enterostatin concentration (500 nmol/l) did not alter the insulin response to glucose, an observation that would rule out a toxic effect of this peptide on the beta-cell. In summary, in the perfused rat pancreas, enterostatin, at putatively physiological concentrations, inhibits insulin secretion without affecting glucagon or somatostatin output, thus pointing to a direct effect of enterostatin on the beta-cell and not through an alpha-cell or delta-cell paracrine effect. Because enterostatin is generated in the small intestine after feeding, it might play a role in the enteroinsular axis as an anti-incretin agent.

Effect of (8-32) salmon calcitonin, an amylin antagonist, on insulin, glucagon and somatostatin release: study in the perfused pancreas of the rat.

1. The 8-32 fragment of salmon calcitonin ((8-32) sCT) has been proposed as a highly selective amylin receptor antagonist. 2. In the present study, we have studied the influence of (8-32) sCT on the inhibitory effect of both amylin and its structural congener, calcitonin gene-related peptide (CGRP), on insulin secretion in the rat perfused pancreas. 3. Both amylin and CGRP, at 75 pM, clearly inhibited glucose-induced insulin release (by 80% and by 70%, respectively). Simultaneous infusion of 10 microM (8-32) sCT reversed the inhibitory effect of amylin (by 80%; P < 0.05 vs. amylin experiments) but did not significantly affect the inhibition of glucose-induced insulin output elicited by CGRP. Furthermore, at the same concentration (10 microM), (8-32) sCT alone potentiated the insulin response to 7 mM glucose (2.5 fold; P < 0.05) whilst it did not affect glucagon or somatostatin secretion. 4. The observation that infusion of an amylin antagonist into the rat pancreas potentiates the insulin response to glucose, favours the concept of endogenous amylin as an inhibitor of insulin release. 5. Finally, as an amylin antagonist at the level of the beta-cell, (8-32) sCT might be considered of potential interest in experimental and clinical pharmacology.

Inhibitory effect of amylin (islet amyloid polypeptide) on insulin response to non-glucose stimuli. Study in perfused rat pancreas.

Amylin, also called islet amyloid polypeptide (IAPP), can inhibit the glucose-induced insulin secretion in perfused rat pancreas at 75 pmol/l, a concentration comparable to that found in the effluent of this experimental model. To further explore the influence of amylin on insulin release, we investigated the effect of synthetic rat amylin (75 pmol/l) on insulin response to non-glucose secretagogues. These agents stimulate B-cell secretion via different mechanisms, such as a dihydropyridine derivative (BAY K 8644, 10 mmol/l) which activates Ca(2+)-channels, a sulfonylurea (tolbutamide, 0.2 mmol/l) which blocks ATP-dependent K(+)-channels, KCL (11 mmol/l) which depolarizes B cells and the 26-33 fragment of cholecystokinin (8-CCK, 1 nmol/l) which increases phospholipid turnover. The study was performed in perfused rat pancreas. Amylin significantly inhibited insulin response to BAY K 8644 (65%), KCI (60%) and 8-CCK (80%) as well as the early phase of tolbutamide-induced insulin output (70%). Thus, amylin can inhibit insulin release induced by secretagogues that interact at different levels of B-cell stimulus-secretion coupling. This inhibition may be due to a multifarious influence of amylin on the B-cell secretory mechanism and/or a disturbing effect on a distal, crucial step in the insulin-releasing mechanism, e.g. by affecting exocytosis of the secretory granule or by inhibiting an essential metabolic pathway within the B cell.

Amylin (islet amyloid polypeptide) inhibition of insulin release in the perfused rat pancreas: implication of the adenylate cyclase/cAMP system.

Amylin inhibits glucose-induced insulin secretion in the rat pancreas. To study the mechanism by which amylin acts on the B-cell, we have investigated, in the perfused rat pancreas, the effect of synthetic rat amylin (75 pM) on insulin release elicited by secretagogues acting on the B-cell via the adenylate cyclase/cAMP system, i.e., glucagon (10 nM), gastric inhibitory polypeptide (GIP, 1 nM), forskolin (1 microM) and isobutylmethylxanthine (IBMX, 75 microM). In addition, we examined the effect of amylin on GIP-induced insulin release in pancreata from rats pretreated with pertussis toxin, an agent which inactivates certain Gi proteins coupled to adenylate cyclase. Amylin inhibited the insulin response to glucagon (approx. 70%), GIP (approx. 90%), IBMX (approx. 75%) as well as the early phase of forskolin-induced insulin output (approx. 74%). However, amylin failed to modify GIP-induced insulin release in pancreata obtained from pertussis toxin pretreated rats. These results would indicate that the inhibitory effect of amylin on insulin secretion could be, at least in part, attributed to its interfering with the adenylate cyclase/cAMP system. Furthermore, prevention of the inhibitory effect of amylin on GIP-induced insulin output by pertussis toxin pretreatment, supports the concept that amylin can inhibit insulin release via a pertussis toxin-sensitive Gi protein coupled to the adenylate cyclase system.

Reversal of the inhibitory effects of calcitonin gene-related peptide (CGRP) and amylin on insulin secretion by the 8-37 fragment of human CGRP.

The 8-37 fragment of human calcitonin gene-related peptide [(8-37)hCGRP] antagonizes the effects of calcitonin gene-related peptide (CGRP) and amylin in a number of tissues. We have studied the influence of (8-37)hCGRP on the effects of both CGRP and amylin on insulin secretion. In the perfused rat pancreas, homologous CGRP and amylin, at 75 pM, exerted comparable inhibitory effects on the insulin response to 9 mM glucose (ca. 70%; P < 0.025). These effects were antagonized by (8-37)hCGRP (1 microM). Our results suggest that CGRP and amylin act on the B-cell, at least in part, through a common receptor.

Amylin inhibits glucose-induced insulin secretion in a dose-dependent manner. Study in the perfused rat pancreas.

Islet amyloid polypeptide (IAPP), also called amylin, has been localized in the B-cell secretory granule and is co-secreted with insulin. We have investigated the effect of synthetic amidated rat amylin on the insulin release evoked by 9 mM glucose in the isolated, perfused rat pancreas. Amylin, in a range of 75 nM-75 pM, significantly inhibited this insulin response in a dose-dependent manner. The correlation between the logarithm of amylin concentrations and the percentages of inhibition was highly significant (r = 0.98, P < 0.01). The lowest effective amylin concentration tested (75 pM) is within the range of amylin levels reported for the effluent of the perfused rat pancreas. Finally, pre-infusion of the rat pancreas with a high amylin concentration (75 nM) did not alter the insulin response to glucose, thus excluding a toxic effect of amylin on the B-cell. These observations support the concept that amylin plays a role in the control of insulin secretion.