| 1. |
- Ahrén, Bo, et al.
(författare)
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A Novel Approach to Assess Insulin Sensitivity Reveals No Increased Insulin Sensitivity in Mice with a Dominant-Negative Mutant Hepatocyte Nuclear Factor-1{alpha}
- 2006
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 291:1, s. 131-137
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Tidskriftsartikel (refereegranskat)abstract
- In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test (r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (beta-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1{alpha} [RIP-DN HNF-1{alpha} (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that SI was the same in the two groups (0.78 ± 0.21 x 10–4 min·pmol–1·l–1 in WT vs. 0.60 ± 0.11 in Tg; P = 0.45) as was the glucose elimination rate (P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1{alpha} mice is not compensated with increased insulin sensitivity.
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| 2. |
- Ahrén, Bo
(författare)
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Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice.
- 2004
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 286:2, s. 269-272
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Tidskriftsartikel (refereegranskat)abstract
- It has been hypothesized that the potent insulinotropic action of the gut incretin hormone glucagon-like peptide-1 (GLP-1) is exerted not only through a direct action on the beta cells but may be partially dependent on sensory nerves. We therefore examined the influence of GLP-1 in mice rendered sensory denervated by neonatal administration of capsaicin performed at days 2 and 5 (50 mg/kg). Control mice were given vehicle. Results show that at 10-16 wk of age in control mice, intravenous GLP-1 at 0.1 or 10 nmol/kg augmented the insulin response to intravenous glucose (1 g/kg) in association with improved glucose elimination. In contrast, in capsaicin-pretreated mice, GLP-1 at 0.1 nmol/kg could not augment the insulin response to intravenous glucose and no effect on glucose elimination was observed. Nevertheless, at the high dose of 10 nmol/kg, GLP-1 augmented the insulin response to glucose in capsaicin-pretreated mice as efficiently as in control mice. The insulin response to GLP-1 from isolated islets was not affected by neonatal capsaicin, and, furthermore, the in vivo insulin response to glucose was augmented whereas that to arginine was not affected by capsaicin. It is concluded that GLP-1-induced insulin secretion at a low dose in mice is dependent on intact sensory nerves and therefore indirectly mediated and that this distinguishes GLP-1 from other examined insulin secretagogues.
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| 3. |
- Albinsson, Sebastian, et al.
(författare)
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Arterial remodeling and plasma volume expansion in caveolin-1 deficient mice.
- 2007
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 293, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Caveolin- 1 ( Cav- 1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide ( NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin- 1 may thus be expected to cause arterial dilatation and increased vessel wall mass ( remodeling). This was tested in Cav- 1 knockout ( KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media- to- lumen ratio in KO. Pressure- induced myogenic tone and flow- induced dilatation were decreased in KO arteries, but both were increased toward wild- type ( WT) levels following NO synthase ( NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length- force relationships in KO, and the force response to alpha 1- adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO ( 38 +/- 6%) compared with WT ( 17 +/- 3%). Tracer- dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav- 1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav- 1 KO mice.
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| 4. |
- Bower, Rebekah L., et al.
(författare)
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Mapping the calcitonin receptor in human brain stem
- 2016
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Ingår i: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 310:9, s. 788-793
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Tidskriftsartikel (refereegranskat)abstract
- The calcitonin receptor (CTR) is relevant to three hormonal systems: amylin, calcitonin, and calcitonin gene-related peptide (CGRP). Receptors for amylin and calcitonin are targets for treating obesity, diabetes, and bone disorders. CGRP receptors represent a target for pain and migraine. Amylin receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract, the hypoglossal nucleus, the cuneate nucleus, spinal trigeminal nucleus, the gracile nucleus, and the inferior olivary nucleus. CTR staining was also observed in the area postrema, the lateral reticular nucleus, and the pyramidal tract. The extensive expression of CTR in the medulla suggests that CTR may be involved in a wider range of functions than currently appreciated.
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| 5. |
- Chan, Hui Min, et al.
(författare)
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Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice
- 2011
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 300:5, s. 1126-1133
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Tidskriftsartikel (refereegranskat)abstract
- Chan HM, Jain R, Ahren B, Pacini G, D'Argenio DZ. Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice. Am J Physiol Regul Integr Comp Physiol 300: R1126-R1133, 2011. First published February 9, 2010; doi:10.1152/ajpregu.00687.2010.-The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first-and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED50 parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of similar to 1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.
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| 6. |
- Christ, George J., et al.
(författare)
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Increased connexin43-mediated intercellular communication in a rat model of bladder overactivity in vivo.
- 2003
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 284:5, s. 1241-1248
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Tidskriftsartikel (refereegranskat)abstract
- Bladder overactivity associated with outflow obstruction is a common human condition recapitulated in the female rat by narrowing the diameter of the urethra. The goal of these studies was to evaluate the role of intercellular communication through connexin43 (Cx43)-derived gap junction channels to bladder overactivity following partial urethral outflow obstruction of 3-day to 6-wk duration. Cx43 mRNA and protein expression were barely detectable by Northern or Western blots, respectively, in the detrusor layer of normal bladders, but bands were found with both techniques after 6 wk of obstruction. Linear regression analysis of the RT-PCR data revealed a statistically significant positive correlation between the duration of obstruction (again, ranging from 3-day to 6-wk duration) and Cx43 mRNA transcript levels, such that after 6 wk of obstruction, Cx43 transcript levels were ≈15-fold greater than initial control values. When taking into account the approximately fivefold increase in bladder weight over this same time frame, the absolute amount of Cx43 mRNA in the bladder apparently increased by ≈75-fold. In that regard, as anticipated, and consistent with previous observations, 6 wk of obstruction was also associated with a significant increase in spontaneous bladder contractions between micturitions. The amplitude of these contractions was significantly reduced by heptanol given intravesically. Furthermore, carbachol-precontracted bladder strips from obstructed animals were more sensitive to heptanol-induced relaxation (100 μM) than their unobstructed counterparts ( n = 6; P < 0.01). When bladder strips were equivalently precontracted via electrical field stimulation (EFS; 20 Hz), similar heptanol-induced relaxation responses were observed. However, the tetrodotoxin-resistant portion of the EFS-induced contraction was greater in the obstructed than in the unobstructed animals, and this portion of the contractile response was more sensitive to heptanol-induced relaxation in obstructed than unobstructed bladders ( n = 7; P < 0.01). Taken together, these observations indicate that partial outlet obstruction produces an overactive bladder that may be more dependent on intercellular communication through gap junctions for modulation of contractile responses than its normal counterpart.
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| 7. |
- Johansson, Rebecka, et al.
(författare)
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Phenotypic modulation of cultured bladder smooth muscle cells and the expression of inducible nitric oxide synthase.
- 2004
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 286:4, s. 642-648
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypic modulation of smooth muscle is associated with various pathological conditions, including bladder dysfunction. Cytoskeletal dynamics modulate the cell phenotype and were recently shown to be involved in regulation of inducible nitric oxide synthase ( iNOS). We tested the hypothesis that the cell differentiation status affects iNOS expression, and that iNOS is preferentially expressed in immature dedifferentiated bladder smooth muscle cells (BSMC). Isolated rat BSMC were put into different stages of differentiation by serum deprivation on laminin-coated plates in the presence of IGF-I and by interaction with Rho signaling and actin polymerization. iNOS and smooth muscle-myosin heavy chain (SM-MHC) protein expression were investigated with Western blot analysis. Our results showed iNOS protein in BSMC exposed to interleukin-1beta ( 2 ng/ml) + TNF-alpha ( 50 ng/ml). Growth of BSMC in serum-free medium on laminin in the presence of IGF-I increased SM-MHC expression, whereas cytokine-induced iNOS was inhibited. Disruption of F-actin with latrunculin B ( 0.5 muM) potentiated iNOS expression and decreased SM-MHC expression. Rho inhibition with C3 (2.5 mug/ml) increased iNOS expression, whereas SM-MHC expression was slightly decreased. Rho-kinase inhibition with Y-27632 ( 10 muM) mediated a decrease in iNOS and a slight increase in SM-MHC expression. In conclusion, the capacity of BSMC to express iNOS was negatively correlated to differentiation status measured as SM-MHC expression. Actin cytoskeletal dynamics and Rho signaling are involved in regulation of cytokine-induced iNOS expression in BSMC. Phenotypic changes and impairment in actin cytoskeleton formation may potentiate cytokine activation and in turn increase nitric oxide production in the bladder during disease.
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| 8. |
- Karlsson, Sven, et al.
(författare)
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Gender difference in the glucagon response to glucopenic stress in mice.
- 2002
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - 0363-6119. ; 282:1, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- A gender difference in the glucagon response to insulin-induced hypoglycemia was previously demonstrated in humans. Whether this reflects a gender difference in autonomic activation or in pancreatic alpha-cell regulation is not known. We investigated the glucagon, epinephrine, and norepinephrine responses to neuroglycopenic stress induced by 2-deoxy-D-glucose (2-DG) or insulin in female and male mice. 2-DG increased plasma glucagon levels by 559 +/- 68% in females versus 281 +/- 46% in males (P < 0.01). Plasma levels of epinephrine or norepinephrine after 2-DG administration did not differ between genders. During insulin-induced hypoglycemia, the glucagon response was similarly higher in females (P < 0.001), whereas the plasma catecholamine response was higher in males (P < 0.05). In vivo, the glucagon response to carbachol or clonidine was higher in females (P < 0.05). In isolated islets, the glucagon response to carbachol (100 microM; P = 0.003) but not to clonidine (1 microM) was larger in females. We conclude that in addition to a larger alpha-cell mass (previously described in female mice), an increased sensitivity of the glucagon-producing alpha-cell to cholinergic activation contributes to the larger glucagon response to glucopenic stress in female mice.
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| 9. |
- Pacini, Giovanni, et al.
(författare)
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Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice
- 2009
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 296:5, s. 1316-1324
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Tidskriftsartikel (refereegranskat)abstract
- Pacini G, Ahren M, Ahren B. Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice. Am J Physiol Regul Integr Comp Physiol 296: R1316-R1324, 2009. First published February 11, 2009; doi: 10.1152/ajpregu.90575.2008.- Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CSI). IVGTTs (n = 520) were performed in NMRI and C57BL/6J mice (20-25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (S-perpendicular to). By using the regression CS perpendicular to = alpha(1) + alpha(2) x K-G/AUC(D), where K-G is intravenous glucose tolerance index and AUC(D) is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CSI vs. S-I: r = 0.66, P < 0.0001) and yielded alpha(1) = 1.93 and alpha(2) = 0.24. KG is the slope of log (glucose(5-20)) and AUCD is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed alpha(1) and alpha(2), CSI was validated in 143 control mice (4.7 +/- 0.2 min . mu U- . ml(-1), virtually identical to S-I: 4.7 +/- 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CSI: 6.0 +/- 0.4 vs. SI: 6.1 +/- 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CSI revealed its ability to segregate different categories, as does S-I. This easily usable formula for calculating CSI overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.
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| 10. |
- Smedh, Ulrika, et al.
(författare)
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Peptides that regulate food intake - Separable mechanisms for dorsal hindbrain CART peptide to inhibit gastric emptying and food intake
- 2003
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 284:6, s. 1418-1426
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether dorsal hindbrain and/or peripheral cocaine- and amphetamine-regulated transcript peptide (CARTp) acts to suppress gastric emptying of a caloric stimulus. Furthermore, effects of dorsal hindbrain CARTp on sucrose consumption and licking microstructure was studied, as well as the possible contribution of corticotropin-releasing factor (CRF) receptors to mediate effects of CARTp downstream on emptying and sucrose intake. Rats bearing gastric fistulas received intragastric infusions (1.0 ml/min) of 12 ml 12.5% glucose. Gastric samples were withdrawn immediately after the intragastric infusion to reflect emptying during gastric fill. CARTp injected in the fourth ventricle intracerebroventricularly (0.5 and 1.0 mug) suppressed gastric emptying. CARTp reduced sucrose intake at similar doses and altered a variety of lick microstructure variables ( no. of licks, bursts, clusters, licks/burst, licks/clusters, interlick interval, first meal size, and first meal duration). Pretreatment with the CRF antagonist alpha-helical CRF-(9- 41) blocked the effect of 1.0 mug CARTp on gastric emptying but not on sucrose consumed or on any of the licking microstructure parameters. These data demonstrate differential mediation of the feeding and gastric inhibitory effects of CARTp and suggest that CARTp-induced inhibition of gastric emptying does not contribute to this peptide's ability to inhibit food intake.
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