| 1. |
- Yabe, Daisuke, et al.
(författare)
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Effects of DPP-4 inhibitor linagliptin and GLP-1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes : A randomized, open-label, 2-arm parallel comparative, exploratory trial
- 2017
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 19:3, s. 442-447
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Tidskriftsartikel (refereegranskat)abstract
- Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose-dependent insulinotropic polypeptide (GIP) action, but not that of glucagon-like peptide-1 (GLP-1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP-4 inhibitor linagliptin on glucagon and other counter-regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP-1 receptor agonist liraglutide in a multi-centre, randomized, open-label, 2-arm parallel comparative, exploratory trial. Three-step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2-week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2-week treatment. Changes in other counter-regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2-week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.
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| 2. |
- Ahrén, Bo, et al.
(författare)
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Islet adaptation in GIP receptor knockout mice
- 2019
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781.
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Forskningsöversikt (refereegranskat)abstract
- Glucose-dependent insulinotropic polypeptide (GIP) receptor knockout (KO) mice are tools for studying GIP physiology. Previous results have demonstrated that these mice have impaired insulin response to oral glucose. In this study, we examined the insulin response to intravenous glucose by measuring glucose, insulin and C-peptide after intravenous glucose (0.35 g/kg) in 5-h fasted female GIP receptor KO mice and their wild-type (WT) littermates. The 1 min insulin and C-peptide responses to intravenous glucose were significantly enhanced in GIP receptor KO mice (n = 26) compared to WT mice (n = 30) as was beta cell function (area under the 50 min C-peptide curve divided by area under the 50 min curve for glucose) (P = 0.001). Beta cell function after intravenous glucose was also enhanced in GIP receptor KO mice in the presence of the glucagon-like peptide-1 receptor antagonist exendin 9 (30 nmol/kg; P = 0.007), the muscarinic antagonist atropine (5 mg/kg; P = 0.007) and the combination of the alpha-adrenoceptor antagonist yohimbine (1.4 mg/kg) and the beta-adrenoceptor antagonist propranolol (2.5 mg/kg; P = 0.042). Analysis of the regression between fasting glucose (6.8 ± 0.1 mmol/l in GIP receptor KO mice and 7.5 ± 0.2 mmol/l in WT mice, P = 0.003) and the 1 min C-peptide response to intravenous glucose showed a negative linear regression between these variables in both WT (n = 60; r = −0.425, P = 0.001) and GIP receptor KO mice (n = 56; r = −0.474, P < 0.001). We conclude that there is a beta cell adaptation in GIP receptor KO mice resulting in enhanced insulin secretion after intravenous glucose to which slight long-term reduction in circulating glucose in these mice may contribute.
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| 3. |
- Ahrén, Bo, et al.
(författare)
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The incretin effect in female mice with double deletion of GLP-1 and GIP receptors
- 2020
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUCC-peptide) correlated linearly with suprabasal AUCglucose both in WT (r = 0.942, P = .017) and DIRKO mice (r = 0.972, P = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose, P = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.
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| 4. |
- Ahrén, Bo, et al.
(författare)
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The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice : Review of the Literature and Stepwise Glucose Dose Response Studies in Female 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 key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.
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| 5. |
- Ahrén, Bo, et al.
(författare)
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The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice
- 2021
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 135
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Tidskriftsartikel (refereegranskat)abstract
- To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.
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| 6. |
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| 7. |
- Lim, Lee Ling, et al.
(författare)
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Aspects of Multicomponent Integrated Care Promote Sustained Improvement in Surrogate Clinical Outcomes: A Systematic Review and Meta-analysis.
- 2018
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Ingår i: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 41:6, s. 1312-1320
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of the Chronic Care Model (CCM) improves health care quality. We examined the sustained effectiveness of multicomponent integrated care in type 2 diabetes.We searched PubMed and Ovid MEDLINE (January 2000-August 2016) and identified randomized controlled trials comprising two or more quality improvement strategies from two or more domains (health system, health care providers, or patients) lasting ≥12 months with one or more clinical outcomes. Two reviewers extracted data and appraised the reporting quality.In a meta-analysis of 181 trials (N = 135,112), random-effects modeling revealed pooled mean differences in HbA1c of -0.28% (95% CI -0.35 to -0.21) (-3.1 mmol/mol [-3.9 to -2.3]), in systolic blood pressure (SBP) of -2.3 mmHg (-3.1 to -1.4), in diastolic blood pressure (DBP) of -1.1 mmHg (-1.5 to -0.6), and in LDL cholesterol (LDL-C) of -0.14 mmol/L (-0.21 to -0.07), with greater effects in patients with LDL-C ≥3.4 mmol/L (-0.31 vs. -0.10 mmol/L for <3.4 mmol/L; Pdifference = 0.013), studies from Asia (HbA1c -0.51% vs. -0.23% for North America [-5.5 vs. -2.5 mmol/mol]; Pdifference = 0.046), and studies lasting >12 months (SBP -3.4 vs. -1.4 mmHg, Pdifference = 0.034; DBP -1.7 vs. -0.7 mmHg, Pdifference = 0.047; LDL-C -0.21 vs. -0.07 mmol/L for 12-month studies, Pdifference = 0.049). Patients with median age <60 years had greater HbA1c reduction (-0.35% vs. -0.18% for ≥60 years [-3.8 vs. -2.0 mmol/mol]; Pdifference = 0.029). Team change, patient education/self-management, and improved patient-provider communication had the largest effect sizes (0.28-0.36% [3.0-3.9 mmol/mol]).Despite the small effect size of multicomponent integrated care (in part attenuated by good background care), team-based care with better information flow may improve patient-provider communication and self-management in patients who are young, with suboptimal control, and in low-resource settings.
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| 8. |
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| 9. |
- 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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| 10. |
- Tura, Andrea, et al.
(författare)
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Glucagon and insulin secretion, insulin clearance, and fasting glucose in GIP receptor and GLP-1 receptor knockout mice
- 2019
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 316:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- It is not known whether GIP receptor and GLP-1 receptor knockout (KO) mice have perturbations in glucagon secretion or insulin clearance, and studies on impact on fasting glycemia have previously been inconsistent in these mice. We therefore studied glucagon secretion after oral whey protein (60 mg) and intravenous arginine (6.25 mg), insulin clearance after intravenous glucose (0.35 g/kg) and fasting glucose, insulin, and glucagon levels after standardized 5-h fasting in female GIP receptor and GLP-1 receptor KO mice and their wild-type (WT) littermates. Compared with WT controls, GIP receptor KO mice had normal glucagon responses to oral protein and intravenous arginine, except for an enhanced 1-min response to arginine, whereas glucagon levels after oral protein and intravenous arginine were enhanced in GLP-1 receptor KO mice. Furthermore, the intravenous glucose test revealed normal insulin clearance in both GIP receptor and GLP-1 receptor KO mice, whereas β-cell glucose sensitivity was enhanced in GIP receptor KO mice and reduced in GLP-1 receptor KO mice. Finally, GIP receptor KO mice had reduced fasting glucose (6.7 ± 0.1, n = 56, vs. 7.4 ± 0.1 mmol/l, n = 59, P = 0.001), whereas GLP-1 receptor KO mice had increased fasting glucose (9.1 ± 0.2, n = 44, vs. 7.7 ± 0.1 mmol/l, n = 41, P < 0.001). We therefore suggest that GIP has a limited role for glucagon secretion in mice, whereas GLP-1 is of importance for glucagon regulation, that GIP and GLP-1 are of importance for the regulation of β-cell function beyond their role as incretin hormones, and that they are both of importance for fasting glucose.
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