Effects Of Islet Amyloid Polypeptide Research Articles

The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation

Aims/hypothesisInflammasome activation and subsequent IL-1β production is a driver of islet pathology in type 2 diabetes. Oligomers, but not mature amyloid fibrils, of human islet amyloid polypeptide (IAPP), which is co-secreted with insulin, trigger NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome activation. C4b-binding protein (C4BP), present in serum, binds to IAPP and affects transition of IAPP monomers and oligomers to amyloid fibrils. We therefore hypothesised that C4BP inhibits IAPP-mediated inflammasome activation and IL-1β production.MethodsMacrophages were exposed to IAPP in the presence or absence of plasma-purified human C4BP, and inflammasome activation was assessed by IL-1β secretion as detected by ELISA and reporter cell lines. IAPP fibrillation was assessed by thioflavin T assay. Uptake of IAPP–C4BP complexes and their effects on phagolysosomal stability were assessed by flow cytometry and confocal microscopy. The effect of C4BP regulation of IAPP-mediated inflammasome activation on beta cell function was assessed using a clonal rat beta cell line. Immunohistochemistry was used to examine the association of IAPP amyloid deposits and macrophage infiltration in isolated human and mouse pancreatic islets, and expression of C4BP from isolated human pancreatic islets was assessed by quantitative PCR, immunohistochemistry and western blot.ResultsC4BP significantly inhibited IAPP-mediated IL-1β secretion from primed macrophages at physiological concentrations in a dose-dependent manner. C4BP bound to and was internalised together with IAPP. C4BP did not affect IAPP uptake into phagolysosomal compartments, although it did inhibit its formation into amyloid fibrils. The loss of macrophage phagolysosomal integrity induced by IAPP incubation was inhibited by co-incubation with C4BP. Supernatant fractions from macrophages activated with IAPP inhibited both insulin secretion and viability of clonal beta cells in an IL-1β-dependent manner but the presence of C4BP during macrophage IAPP incubation rescued beta cell function and viability. In human and mouse islets, the presence of amyloid deposits correlated with higher numbers of infiltrating macrophages. Isolated human islets expressed and secreted C4BP, which increased with addition of IL-1β.Conclusions/interpretationIAPP deposition is associated with inflammatory cell infiltrates in pancreatic islets. C4BP blocks IAPP-induced inflammasome activation by preventing the loss of macrophage phagolysosomal integrity required for NLRP3 activation. The consequence of this is the preservation of beta cell function and viability. C4BP is secreted directly from human pancreatic islets and this increases in response to inflammatory cytokines. We therefore propose that C4BP acts as an extracellular chaperone protein that limits the proinflammatory effects of IAPP.

Sex and Immunogen-Specific Benefits of Immunotherapy Targeting Islet Amyloid Polypeptide in Transgenic and Wild-Type Mice.

Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to β-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males. Furthermore, IAPP7-19-TT-immunized Tg females cleared a glucose bolus more efficiently than controls, while IAPP-immunized Tg females showed an impaired ability to clear a glucose bolus compared to their adjuvant injected Tg controls. Interestingly, IAPP or IAPP7-19-TT treatments had no effect on glucose clearance in Tg males. Overall, these beneficial effects of IAPP targeted immunization depend on Tg status, sex, and immunogen. Hence, future studies in this field should carefully consider these variables that clearly affect the therapeutic outcome. In conclusion, IAPP targeting immunotherapy may have benefits in patients with type 2 diabetes.

The effects and mechanism of islet amyloid polypeptide on insulin secretion in INS-1 cells stimulated by glibenclamide

To observe the effects, and study the mechanism of islet amyloid polypeptide (IAPP) on insulin secretion in INS-1 cells stimulated by glibenclamide. Whole cell patch clamp technique was employed to study the influences of short exposure to IAPP on electrophysiological characteristics of ATP-sensitive K+ channel (K(ATP) channel) upon sulfonylurea stimulation. Intracellular free calcium changes in this process was observed by laser scanning confocal microscope. Insulin was measured by enzyme-linked immunoassay. (1) Insulin secretion stimulated by 1 micomol/L glibenclamide was significantly decreased from (11.43 +/- 1.22) microg/L to (9.40 +/- 0.87) microg/L and to (7.11 +/- 1.85) microg/L after 1 micromol/L and 10 micromol/L IAPP incubation, respectively. (2) Glibenclamide-stimulated calcium influx was dose dependently inhibited by IAPP from 1 micromol/L to 10 micromol/L, with the AUC of fluorescence intensity-time reduced from 427.78 +/- 2.32 to 380.59 +/- 1.49, and to 246.53 +/- 8.41, respectively. (3) Compared with that in control cells (14.59 +/- 0.69) mV, the half activation voltage of KA, channel in response to glibenclamide was significantly increased to (28.75 +/- 0.77) mV and to (46.95 +/- 1.81) mV in cells pretreated with 1 micromol/L and 10 micromol/L IAPP, implicating an inhibitory effect of IAPP on activation of K(ATP) channel. Short-term exposure to high concentration of IAPP inhibited glibenclamide-induced closure of K(ATP) channels and decreased calcium influx, which may ultimately lead to the reduction of insulin secretion in INS-1 cells

Synthesis of 2,5‐Diaryl‐Substituted Thiophenes as Helical Mimetics: Towards the Modulation of Islet Amyloid Polypeptide (IAPP) Amyloid Fibril Formation and Cytotoxicity

A range of 2,5-diarylated thiophenes were synthesised as small molecule mimetics of the α-helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide (IAPP). 3-Substituted thiophene-2-carboxylic acids were used as key intermediates and functionalised by palladium decarboxylative cross-coupling and direct C-H activation successively with overall yields ranging from 23 to 95 %. The effect of the ligands on IAPP amyloid fibril formation was evaluated with the thioflavin T (ThT) fluorescence-based assay. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using β-pancreatic cells.

Comparison of the effects of chronic central administration and chronic peripheral administration of islet amyloid polypeptide on food intake and meal pattern in the rat

Islet amyloid polypeptide (IAPP) is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and reduce adipose energy reserves. The present study compared the effects of chronic peripheral and chronic central administration of IAPP on food intake and meal pattern in rats. IAPP was administered subcutaneously (SC) for 7 days at doses of 0, 0.25, 2.5 and 25 pmol kg −1 min −1 using an osmotic minipump or administered centrally at doses of 0, 0.025, 0.25 and 2.5 pmol kg −1 min −1 using an osmotic minipump connected to an intracerebroventricular (ICV) catheter inserted into the third ventricle. Both SC and ICV infusion decreased total food intake dose-dependently. The minimal effective dose was 2.5 pmol IAPP kg −1 min −1 for SC administration and 0.25 pmol kg −1 min −1 for ICV infusion. The decrease in food intake produced by infusion of IAPP was mainly due to decreased meal size, although a significant decrease in meal number also occurred at the highest SC and ICV doses. SC administration produced a larger, more persistent decrease in food intake during the light period than in the dark period, while ICV infusion caused a larger, more persistent decrease during the dark period. The 10-fold difference in minimal effective doses indicates that ICV-administered IAPP acted primarily in the brain to inhibit food intake. The difference between the effects of IAPP on meal pattern with the two methods of administration suggests that IAPP does not act on the same target(s) when administered centrally as it does when it is administered peripherally.

Chronic low dose islet amyloid polypeptide infusion reduces food intake, but does not influence glucose metabolism, in unrestrained conscious rats: studies using a novel aortic catheterization technique.

Islet amyloid polypeptide (IAPP) is a 37-amino acid polypeptide coproduced with insulin in the beta-cells of the pancreatic islets. The physiological effects of IAPP have not been established. Although effects on glucose metabolism are seen only at pharmacological doses both in vitro and in vivo, effects on food intake have been shown at near-physiological concentrations. The aim of the present study was to investigate the effects of similar elevations of circulating plasma IAPP levels on glucose metabolism in rats and to evaluate the function of a novel aortic catheterization technique. In a cross-over design, two sets of experiments in which conscious unrestrained rats received chronic IAPP infusions at 0 and 2 or 0 and 7 pmol/kg min were performed. Peripheral glucose disposal was determined by means of the hyperinsulinemic euglycemic clamp technique. Chronic elevations of circulating IAPP at concentrations that reduced food intake [43.5 +/- 6.2 g (control) vs. 35.7 +/- 8.2 g (IAPP; P < 0.01) and 34.0 +/- 2.2 g (control) vs. 28.8 +/- 1.4 g (IAPP; P = 0.07) for the 7 and 2 pmol/kg x min experiments, respectively] had no effect on the glucose metabolic rate [GMR; 18.5 +/- 0.6 mmol/kg x h (control) vs. 18.7 +/- 0.9 mmol/kg x h (IAPP) and 14.4 +/- 0.7 mmol/kg x h (control) vs. 15.6 +/- 0.7 mmol/kg x h (IAPP) for the 7 and 2 pmol/kg x min experiments, respectively]. Thus, effects on glucose metabolism are unlikely to explain the anorectic effect of IAPP.

Effect of islet amyloid polypeptide on somatostatin inhibition of insulin secretion from isolated rat pancreatic islets

In this study, we investigated the presence of islet amyloid polypeptide (IAPP) in somatostatin cells of rat endocrine pancreas and the effect of exogenous IAPP and somatostatin, separate or combined, on in vitro insulin secretion. By immunocytochemistry, IAPP was found in both B and D cells of rat pancreatic islets. Furthermore, the labeling density of IAPP in D cells was nearly four times higher than in B cells. After a 2-day preincubation in RPMI 1640 (11.1 mM glucose), isolated rat pancreatic islets were exposed to IAPP and/or somatostatin for 90 min in modified Krebs-Ringer bicarbonate (KRB) buffers containing 11.1 or 22.2 mM glucose, or 11.1 mM glucose+10 mM l-arginine, respectively. At 11.1 mM glucose, insulin secretion was not affected by IAPP and/or somatostatin at concentrations investigated. Insulin response to 22.2 mM glucose was inhibited by exogenous somatostatin. Arginine-stimulated insulin secretion was also inhibited by somatostatin, and the effect was significantly potentiated with additional 10 −5 M IAPP. The study shows that rat pancreatic D cells have higher IAPP density than B cells in the same islets and that IAPP and somatostatin may cooperate on rat pancreatic B cells to regulate the insulin secretion in response to potent stimulation.

Islet amyloid polypeptide inhibits insulin secretion in conscious rats.

To investigate the effect of islet amyloid polypeptide (IAPP, amylin) exposure on insulin secretion in vivo, the plasma glucose level of conscious rats was clamped at 11.1 mmol/l (hyperglycemic clamp) during the last 2 h of a 24-h infusion study. Group parameters were A, 24-h saline; B and C, 22-h saline followed by 2-h IAPP (B, 8.5 pmol/min; C, 85 pmol/min), and D, 24-h IAPP (85 pmol/min). Induced hyperglycemia increased plasma insulin concentration by 426 +/- 34 pmol/l in control rats (group A). This effect on plasma insulin was reduced by 31% and 53% during short-term IAPP infusion (group B, 8.5 pmol/min, 294 +/- 41 pmol/l; C, 85 pmol/min, 202 +/- 25 pmol/l; short-term effect, P < 0.0001), whereas insulin levels tended to increase after 24 h of continuous IAPP exposure (group D, 682 +/- 120 pmol/l; P < 0.05 vs. group A). Glucose infusion rate required to maintain constant hyperglycemia fell dose dependently during short-term but not during long-term IAPP infusion (mumol.kg-1.min-1: group A, 203 +/- 11; B, 154 +/- 7; C, 119 +/- 7; D, 212 +/- 9; short-term effect, P < 0.0001). In parallel, muscle glycogen content was dose dependently reduced by short-term IAPP exposure. We conclude that IAPP inhibits glucose-stimulated insulin secretion and decreases muscle glycogen storage in conscious rats in vivo.

Transgenic mice overproducing islet amyloid polypeptide have increased insulin storage and secretion in vitro

To determine whether chronic overproduction of islet amyloid polypeptide alters beta-cell function, we studied a line of transgenic mice which overexpress islet amyloid polypeptide in their beta-cells. At 3 months of age, these transgenic mice had greater pancreatic content of both islet amyloid polypeptide and insulin. Further, basal and glucose-stimulated secretion of both islet amyloid polypeptide and insulin were also elevated in the perfused pancreas of the transgenic animals. These findings demonstrate that chronic overproduction and secretion of islet amyloid polypeptide are associated with increased insulin storage and enhanced secretion of insulin in vitro. This increase in insulin storage and secretion may be due to a direct effect of islet amyloid polypeptide on the beta-cell or a beta-cell adaptation to islet amyloid polypeptide-induced insulin resistance.

The effects of IAPP and CGRP on guinea pig tracheal smooth muscle in vitro

Neither the novel peptide, islet amyloid polypeptide (IAPP), nor its homologue, calcitonin gene-related peptide (CGRP), contracted guinea pig isolated trachea (GPT), but on preparations contracted with KCl (40 m M), both caused concentration-related relaxation (1 n M–3 μ M). Relaxant curves to both were shallow and slow in development, with clear maxima not being obtained. The protease inhibitors, phosphoramidon (1 μ M), leupeptin (50 μ M), bestatin (100 μ M), soya bean trypsin inhibitor (1 μ M), and aprotinin (5 μ M), together had no effect on relaxations to CGRP, but depressed those to IAPP. Aprotinin appeared to be responsible for this depression. The specific CGRP antagonist, CGRP(8–37), 1–10 μ M, had no effect on relaxations to either peptide. These findings demonstrate that IAPP relaxes GPT in a similar manner to CGRP.

Inhibitory Effect of Islet Amyloid Polypeptide of Glucose-Induced Proinsulin Biosynthesis in Rat Insulinoma Cells

Islet amyloid polypeptide (IAPP) has been recently identified as the principal constituent of amyloid deposits in pancreatic islets of patients with type 2 (non-insulin-dependent) diabetes mellitus and causes insulin resistance in some target cells. In addition, glucose-induced insulin secretion is inhibited by IAPP. We studied the effect of IAPP on proinsulin biosynthesis in rat insulinoma (RINr) cells. Glucose at concentrations of 0, 15, 30, 60, 100, and 300 mg/dl stimulated proinsulin biosynthesis in a dose-responsive and and actino-mycin D-inhibitable manner after 6 h of incubation. At a glucose concentration of 300 mg/dl, IAPP decreased the mean responses of proinsulin biosynthesis to 61.2 and 29% at concentrations of 0.1 and 1 microM, respectively, compared with the IAPP-free control. In conclusion, IAPP inhibits glucose-induced proinsulin biosynthesis in RINr cells. IAPP might play an important role in the pathogenesis of type 2 diabetes mellitus.

Lack of effect of islet amyloid polypeptide on hepatic glucose output in the in situ-perfused rat liver

Islet amyloid polypeptide (IAPP), a novel peptide isolated from islet amyloid deposits in patients with insulinoma and non-insulin-dependent diabetes mellitus (NIDDM), has been reported to be cosecreted with insulin from pancreatic β cells and to inhibit glucose uptake and glycogen synthesis in muscle tissue in vitro. We investigated the effects of the synthesized, rat-amidated form of IAPP on hepatic glucose output, and IAPP extraction, using an in situ flow-through perfusion system in rats to elucidate the actions of IAPP on the liver. The IAPP (10 −8 mol/L) alone had no effects on the hepatic glucose release. Infusion of 6 × 10 −11 mol/L glucagon alone resulted in an expected elevation in glucose production ( 30.0 ± 1.7 μmol 35 min g liver ). Insulin (3 × 10 −10 mol/L) submaximally decreased the glucagon-stimulated glucose production to 73% ( from 30.0 ± 1.7 to 22.0 ± 1.4 μmol 35 min g liver ; n = 7, P < .01). A simultaneous infusion of 10 −8 mol/L IAPP did not influence the glucagon-stimulated glucose production ( 27.6 ± 1.2 μmol 35 min g liver ) or the insulin-dependent inhibition of glucagon-stimulated glucose production ( 22.6 ± 1.3 μmol 35 min g liver ). IAPP extraction by the liver in a single passage was minimal, in contrast to approximately 50% hepatic insulin extraction. These results indicate that IAPP does not play any important role in modulating glycogen metabolism in the liver.

Stimulatory effects of islet amyloid polypeptide (amylin) on exocrine pancreas and gastrin release in conscious rats

A rat islet amyloid polypeptide (amylin), 37-residue peptide amide was synthesized by the Fmoc-based solid phase method and the biological activity of synthetic rat amylin on exocrine pancreas was evaluated for the first time in conscious rat. Amylin (1, 10 nmol/kg/h) stimulated pancreatic exocrine secretion and plasma gastrin concentration. CR-1409, a CCK receptor antagonist, did not change amylin-stimulated pancreatic secretion. However, omeprazole (proton pump inhibitor) and atropine inhibited amylin-stimulated pancreatic secretion. This study suggests that amylin may play a role in biological action in the exocrine pancreas possibly mediated by gastric acid hypersecretion.

Effects of islet amyloid polypeptide on hepatic insulin resistance and glucose production in the isolated perfused rat liver.

The impact of (pancreatic) islet amyloid polypeptide on glucose metabolism and insulin sensitivity was examined in isolated rat livers perfused in a non-recirculating system. Continuous infusion of 10(-7) mol/l islet amyloid polypeptide affected neither basal nor glucagon (10(-9) mol/l)-stimulated glucose output by livers from fed rats, but it did increase the hepatic cyclic AMP release within 44 min (7.91 +/- 12.07 vs control: 0.07 +/- 0.03 pmol x 100 g body weight-1). The effect of the peptide on the ability of insulin to inhibit glucagon-induced hepatic glycogenolysis was measured in three experimental groups (n = 6). As expected glucagon (7 x 10(-11) mol/l) increased integral hepatic glucose release within 84 min (763.4 +/- 161.7 vs -25.7 +/- 73.2 mumol x 100 g body weight-1 in the control group, p less than 0.001), while insulin (100 mU/l) decreased the glucagon-stimulated glucose production (395.2 +/- 180.0 mumol x 100 g body weight-1, p less than 0.01). Simultaneous infusion of 10(-7) mol/l islet amyloid polypeptide however, was not able to reverse insulin-dependent inhibition of glucagon-stimulated hepatic glucose output (370.0 +/- 102.5 mumol x 100 g body weight-1, NS) or to enhance lactate-induced gluconeogenesis of livers from 24 h fasted rats (n = 8). The glucose production stimulated by 10(-9) mol/l glucagon was slightly greater in islet amyloid polypeptide-pre-treated livers than in a control group without addition of islet amyloid polypeptide (5 min: 3.60 +/- 3.36 vs 1.67 +/- 1.28 mumol.min-1 x 100 g body weight-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of islet amyloid polypeptide (IAPP) on insulin biosynthesis or secretion in rat islets and mouse βTC3 cells. Biosynthesis of IAPP in mouse βTC3 cells

Effects of rat islet amyloid polypeptide (IAPP) on insulin biosynthesis and secretion were examined in isolated rat islets and mouse βTC3 cells. Culture of islets or mouse βTC3 cells for 24 h in the presence of 10 −6 M IAPP and 5.5 mM glucose had no effect on insulin mRNA levels. The rates of proinsulin biosynthesis were not altered in islets incubated in 10 −4–10 −9 M IAPP. In βTC3 cells, proinsulin biosynthesis was stimulated by glucose, though no effects of IAPP were shown. Addition of 10 −5 M IAPP to islets incubated in 11 mM glucose decreased the fractional insulin secretion rates; however, the secretion of insulin from βTC3 cells was not affected by 10 −5 M IAPP. On the other hand, mouse βTC3 cells expressed the elevated level of IAPP mRNA. Metabolic labeling of βTC3 cells revealed the synthesis of both proIAPP and mature IAPP. In pulse chase experiments, proIAPP was processed to IAPP in a manner similar to proinsulin. These data indicate that IAPP is a possible polypeptide hormone synthesized in pancreatic β cells though it is unlikely that IAPP is a physiologically relevant modulator of insulin biosynthesis or secretion.

Effects of islet amyloid polypeptide (amylin) and calcitonin gene-related peptide (CGRP) on glucose metabolism in the rat

In this study, we compared the effects of islet amyloid polypeptide (IAPP) and calcitonin gene-related peptide (CGRP) on glucose metabolism both in vivo and in vitro in the rat. Intravenous injection of rat CGRP caused a significant increase in plasma glucose concentration with a simultaneous increase in plasma insulin levels, whereas neither IAPP-NH 2 nor IAPP-COOH had any effect. Moreover, intravenous infusion of CGRP decreased tolerance to intragastric administration of glucose (O-GTT) without altering plasma insulin levels, but again IAPPs had no effect. On the other hand, 125I-[Tyr 0]rat CGRP specifically bound to the liver plasma membrane, and not only CGRP but also IAPP-NH 2 dose-dependently displaced the specific binding of 125I-[Tyr 0] CGRP, wherease IAPP-COOH had no effect. Conversely, CGRP as well as IAPP-NH 2 but not IAPP-COOH evoked dose-dependent activation of adenylate cyclase in the membranes, and these effects were significantly inhibited by a CGRP receptor antagonist, human CGRP-I(8-37). However, neither CGRP nor IAPP-NH 2 had any effect on glucose production in rat isolated hepatocytes. These results suggest that (1) IAPP-NH 2 but not IAPP-COOH induces adenylate cyclase activation via CGRP receptors on rat liver plasma membranes, and (2) CGRP might not involve its action on the liver in the changes of glucose metabolism.

Effect of islet amyloid polypeptide (IAPP/amylin) on 2-deoxyglucose uptake in mouse pancreatic acini

In order to examine the effect of islet amyloid polypeptide (IAPP/amylin), a product of the pancreatic β cell and a major component of islet amyloid deposits, on exocrine pancreatic function, we studied the effect of rat IAPP amide (IAPP-NH 2) on 2-deoxy- d-glucose (2-DG) uptake in isolated mouse pancreatic acini. Mouse pancreatic acini were preincubated for 80 min with various concentrations of IAPP-NH 2 (1 nM - 1 μM) and [ 3H]2-DG uptake for 20 min was measured. The full effect of IAPP-NH 2 on this function was not immediate but increased linearly with time for up to 80 min of incubation. IAPP-NH 2 caused a dose-dependent stimulation of 2-DG uptake by mouse acini; a detectable effect at 10 nM and a maximal effect at 1 μM. In the presence of 1 μM IAPP-NH 2, 2-DG uptake increased by 69 ± 8% above basal (mean ± SD, n = 6). The results indicate that IAPP-NH 2 stimulates glucose uptake in mouse pancreatic acini, and raise the possibility that IAPP-NH 2 plays some physiological role in the insuloacinar axis in mouse pancreas.

Additive effect of islet amyloid polypeptide (IAPP/amylin) and insulin on 2-deoxyglucose uptake in mouse pancreatic acini

The effect of islet amyloid polypeptide (IAPP/amylin) on 2-deoxyglucose (2-DG) uptake was studied in isolated mouse pancreatic acini in the absence or presence of insulin. Synthetic rat IAPP-NH2 caused a dose-dependent stimulation of 2-DG uptake by mouse acini with a half-maximal concentration at 70 nM. The increase in 2-DG uptake by 1 microM IAPP-NH2 or 100 nM insulin was 68% or 60% above basal, respectively. In the presence of both 1 microM IAPP-NH2 and 100 nM insulin, the increase in 2-DG uptake was 145% above basal, indicating that the effects of IAPP-NH2 and insulin on 2-DG uptake were additive. The results suggest that IAPP stimulates glucose uptake in mouse acini probably by a different mechanism from that of insulin.

Lack of Effect of Islet Amyloid Polypeptide in Causing Insulin Resistance in Conscious Dogs During Euglycemic Clamp Studies

In this study, we administered constant intravenous infusions of human islet amyloid polypeptide (hIAPP) to conscious dogs during euglycemic glucose-clamp studies. The doses of hIAPP used (5 and 50 pmol.kg-1.min-1) raised the circulating IAPP levels approximately 12- and 50-fold above basal levels, respectively. Studies were conducted at two different insulin infusion rates, resulting in steady-state plasma insulin levels of approximately 600 and 2800 pM. According to our results, the hIAPP infusions did not lead to any measurable change in the insulin-stimulated glucose disposal rate at either insulin infusion rate. Additionally, we observed no effect of IAPP on hepatic glucose production. Although we did not observe any effect of hIAPP on any of the aspects of glucose or insulin metabolism measured, we did find a consistent hypocalcemic effect of this peptide at the 50-pmol.kg-1.min-1 infusion rate. Shortly after the onset of hIAPP infusion, serum calcium levels fell by 10-15% and remained at these levels throughout the course of the hIAPP infusion. In summary, 1) infusion of hIAPP at doses of 5 or 50 pmol.kg-1.min-1 in conscious dogs raised the circulating IAPP level 12- to 50-fold above basal; 2) during these infusion studies, no effect of hIAPP was observed on any of the aspects of glucose or insulin homeostasis measured; 3) 50 pmol.kg-1.min-1 hIAPP lead to a prompt reduction in plasma calcium concentrations with intravenous administration.

Lack of effect of islet amyloid polypeptide in causing insulin resistance in conscious dogs during euglycemic clamp studies

Lack of effect of islet amyloid polypeptide in causing insulin resistance in conscious dogs during euglycemic clamp studies