| 271. |
- Omar, Bilal, et al.
(författare)
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Enhanced Insulin Sensitivity by Adipose Tissue Browning Alters Islet Morphology and Hormone Secretion in Response to Autonomic Nervous Activation in Female Mice.
- 2016
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 310:1, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance results in compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin sensitive mice, due to adipocyte specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with reduced insulin secretion compared to wild type mice, however when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild type mice. In response to autonomic nervous activation the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice suggesting impaired adrenergic signaling in the islet. Basal glucagon was increased in Foxc2TG mice but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.
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| 272. |
- Omar, Bilal, et al.
(författare)
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Fibroblast Growth Factor 21 (FGF21) and Glucagon Like-Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor Deficient Mice.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:1, s. 101-110
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Tidskriftsartikel (refereegranskat)abstract
- Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential anti-diabetic actions of FGF21 in insulin deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTT). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide (GLP-1) also has insulin independent glucose lowering properties and elevated circulating GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21 while concurrently blocking the GLP-1 receptor with the antagonist Exendin9-39 resulted in significant hyperglycemia in insulin deficient Gcgr(-/-) mice, while Exendin9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.
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| 273. |
- Omar, Bilal, et al.
(författare)
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Impact of glucose dosing regimens on modeling of glucose tolerance and β-cell function by intravenous glucose tolerance test in diet-induced obese mice.
- 2014
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 2:5
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Tidskriftsartikel (refereegranskat)abstract
- Insulin sensitivity declines in overweight and obese individuals and, under normal conditions, insulin secretion adaptively increases which in healthy non-diabetic subjects maintains normal glycemia. This adaptation is best described by the disposition index derived from modeling of insulin and glucose data from an intravenous glucose tolerance testing (IVGTT). One caveat of the IVGTT is that basing the glucose dose on the individual total body weight can result in large differences in the amount of glucose given to lean and obese individuals. The effect this has on determination of insulin sensitivity and β-cell function is unknown. In this study, we therefore evaluated alternative glucose dosing regimens for determination of the impact of glucose dosing on measures of β-cell function in normal and diet-induced obese (DIO) mice. The glucose dosing regimens used for the IVGTT were 0.35 mg per kg total body weight (BW) or per kg lean BW or a fixed glucose dose based on the average BW for all experimental mice. Each regimen detected a similar decrease in insulin sensitivity in DIO mice. The different glucose dosing regimens gave, however, diverging results in regard to glucose elimination and the acute insulin response. Thus, the fixed-dose regimen was the only that revealed impairment of glucose elimination, whereas dosing according to total BW was the only regimen which showed significant increases in acute insulin response in DIO mice. The fixed-dose glucose dosing regimen was the only that revealed a significant decline in the disposition index value in DIO mice, which is characteristic of type 2 diabetes in humans. Our results therefore show that using different glucose dosing regimens during IVGTT in DIO mice one can model different aspects of physiology which are similar to prediabetes and type 2 diabetes in humans, with the fixed-dose regimen producing a phenotype that most closely resembles human type 2 diabetes.
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| 274. |
- Omar, Bilal, et al.
(författare)
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Incretin hormone receptors are required for normal beta cell development and function in female mice
- 2016
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 79, s. 58-65
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Tidskriftsartikel (refereegranskat)abstract
- The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment of beta cell function both in vivo and in vitro in a process that appears to be independent of the intestinally secreted incretin hormones. We therefore conclude that the incretin hormones together significantly impact both beta-cell function and beta-cell development.
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| 275. |
- Omar, Bilal, et al.
(författare)
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Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors.
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:7, s. 2196-2202
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Tidskriftsartikel (refereegranskat)abstract
- Dipeptidyl peptidase (DPP)-4 inhibition is a glucose-lowering treatment for type 2 diabetes. The classical mechanism for DPP-4 inhibitors is that they inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, in turn increasing glucose utilization and diminishing hepatic glucose production, which, through reduction in postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but also to a limited degree in humans have found additional mechanisms for DPP-4 inhibitors that may contribute to their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which prevents inactivation of newly released GLP-1, which in turn augments GLP-1-induced activations of autonomic nerves and results in high portal GLP-1 levels, resulting in inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents inactivation of locally produced intact GLP-1 in the islets, thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation; and 3) prevention of the inactivation of other bioactive peptides apart from GLP-1, such as glucose-dependent insulinotropic polypeptide, stromal-derived factor-1α, and pituitary adenylate cyclase-activating polypeptide, which may improve islet function. These pleiotropic effects may contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.
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| 276. |
- Otten, Julia, et al.
(författare)
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Surrogate measures of insulin sensitivity vs the hyperinsulinaemic-euglycaemic clamp: a meta-analysis
- 2014
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 57:9, s. 1781-1788
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis We aimed to identify which surrogate index of insulin sensitivity has the strongest correlation with the reference measurement, the hyperinsulinaemic-euglycaemic clamp (HEC), to determine which surrogate measure should be recommended for use in large-scale studies. Methods A literature search (1979-2012) was conducted to retrieve all articles reporting bivariate correlations between the HEC and surrogate measures of insulin sensitivity (in fasting samples or during the OGTT). We performed a random effects meta-analysis for each surrogate measure to integrate the correlation coefficients of the different studies. Results The OGTT-based surrogate measures with the strongest pooled correlations (r) to the HEC were the Stumvoll metabolic clearance rate (Stumvoll MCR; r=0.70 [95% CI 0.61, 0.77], n=5), oral glucose insulin sensitivity (OGIS; r=0.70 [0.57, 0.80], n=6), the Matsuda index (r=0.67 [0.61, 0.73], n=19), the Stumvoll insulin sensitivity index (Stumvoll ISI; r=0.67 [0.60, 0.72], n=8) and the Gutt index (r=0.65 [0.60, 0.69], n=6). The fasting surrogate indices that correlated most strongly with the HEC and had narrow 95% CIs were the revised QUICKI (r=0.68 [0.58, 0.77], n=7), the QUICKI (r=0.61 [0.55, 0.65], n=35), the log HOMA-IR (r=-0.60 [-0.66, -0.53], n=22) and the computer generated HOMA of insulin sensitivity (HOMA-%S; r=0.57 [0.46, 0.67], n=5). Conclusions/interpretation The revised QUICKI fasting surrogate measure appears to be as good as the OGTT-based Stumvoll MCR, OGIS, Matsuda, Stumvoll ISI and Gutt indices for estimating insulin sensitivity. It can therefore be recommended as the most appropriate index for use in large-scale clinical studies.
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| 277. |
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| 278. |
- Ovlund, Tina, et al.
(författare)
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Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- A large contribution to glucose elimination from the circulation is achieved by insulin-independent processes. We have previously shown that the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) increase this process and, therefore, seem to contribute to glucose disposal both through this effect and through the classical incretin effect resulting in enhanced insulin levels. We have now explored in more detail the potential contribution by incretin hormone receptors to insulin-independent processes for glucose elimination. To that end, we have performed intravenous glucose tests (0.35g/kg) in C57BL/6J mice and analyzed glucose elimination rate and glucose effectiveness (i.e., insulin-independent glucose disposal, SG) in wildtype mice and in mice with genetic deletion of GIP receptors or GLP-1 receptors. We performed studies with or without complete blockade of insulin secretion by the drug diazoxide (25 mg/kg). The mice were anesthetized with a novel fentanyl citrate/fluanisone formulation, called Fluafent, together with midazolam. Initially we demonstrated that glucose and insulin data after intravenous and oral glucose were not different using this anesthesia compared to the previously commonly used combination of HypnormR and midazolam. The results show that SG was reduced in GLP-1 receptor knockout mice, whereas there was no difference between GIP receptor knockout mice and wildtype mice, and this was evident both under normal conditions and after complete inhibition of insulin secretion. The study therefore indicates that insulin-independent glucose elimination requires active GLP-1 receptors and thus that the two incretin hormone receptor types show dissociated relevance for this process.
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| 279. |
- Pacini, Giovanni, et al.
(författare)
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Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function : Review on Mathematical Modelling Approaches
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
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Forskningsöversikt (refereegranskat)abstract
- Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.
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| 280. |
- Pacini, Giovanni, et al.
(författare)
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Dissociated effects of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide-1 on beta-cell secretion and insulin clearance in mice
- 2010
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 59:7, s. 988-992
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) potently augment insulin response to glucose. It is less known what their effects are insulin clearance, which also contributes to peripheral hyperinsulinemia observed after administration of incretins together with glucose. The aims of this study were the quantification of C-peptide secretion and the evaluation of insulin clearance after administration of GIP with glucose. This allows the assessment of GIP's effects on hyperinsulinemia. In addition, GIP's effects were compared with those of GLP-1. Anesthetized female NMRI mice were injected intravenously with glucose alone (1 g/kg, n = 35) or glucose together with GIP (50 mu g/kg, n = 12). Samples were taken through the following 50 minutes, and C-peptide and insulin concentrations were used to reconstruct C-peptide secretion rate and insulin clearance. In a previous study, GLP-1 (10 mu g/kg) was used in 12 mice; and we used those GLP-1 results to compare GIP effects with those of GLP-1. C-peptide secretion rate peaked at 1 minute after glucose injection, and the immediate part of the insulin-releasing process was markedly augmented by both incretin hormones (1-minute suprabasal increment secretory rate was 20 +/- 2 pmol/min for GIP and 28 +/- 2 pmol/min for GLP-1, vs only 9 +/- 1 pmol/min for glucose alone; P < .001). Until 10 minutes after administration, C-peptide secretion remained higher with incretins (P < .0001), whereas starting from 20 minutes, the 3 patterns were undistinguishable (P > .2). Insulin clearance, previously shown to be abridged by 46% with GLP-1, was reduced only by a nonsignificant (P = .27) 21% with GIP. This study thus shows that the 2 incretins markedly augment glucose-stimulated insulin secretion in mice by a preferential action on the immediate response to glucose of insulin secretion. However, the action of GIP is less effective than that of GLP-1. Insulin clearance with GIP is not significantly reduced. We conclude that GIP is less potent than GLP-1 in inducing glucose-stimulated hyperinsulinemia in the mouse. (C) 2010 Elsevier Inc. All rights reserved.
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