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| 43. |
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| 44. |
- Abels, Mia, et al.
(författare)
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Overexpressed beta cell CART increases insulin secretion in mouse models of insulin resistance and diabetes
- 2022
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- Impaired beta cell function and beta cell death are key features of type 2 diabetes (T2D). Cocaine- and amphetamine-regulated transcript (CART) is necessary for normal islet function in mice. CART increases glucose-stimulated insulin secretion in vivo in mice and in vitro in human islets and CART protects beta cells against glucotoxicity-induced cell death in vitro in rats. Furthermore, beta cell CART is upregulated in T2D patients and in diabetic rodent models as a consequence of hyperglycaemia. The aim of this study was to assess the impact of upregulated beta cell CART on islet hormone secretion and glucose homeostasis in a transgenic mouse model. To this end, mice with beta cell-specific overexpression of CART (CARTtg mice) were generated. CARTtg mice challenged by aging, high fat diet feeding or streptozotocin treatment were phenotyped with respect to in vivo and in vitro insulin and glucagon secretion, glucose homeostasis, and beta cell mass. In addition, the impact of adenoviral overexpression of CART on insulin secretion was studied in INS-1 832/13 cells. CARTtg mice had a normal metabolic phenotype under basal conditions. On the other hand, with age CARTtg mice displayed increased insulin secretion and improved glucose elimination, compared with age-matched WT mice. Furthermore, compared with WT controls, CARTtg mice had increased insulin secretion after feeding a high fat diet, as well as lower glucose levels and higher insulin secretion after streptozotocin treatment. Viral overexpression of CART in INS-1 832/13 cells resulted in increased glucose-stimulated insulin secretion. Together, these results imply that beta cell CART acts to increase insulin secretion when beta cell function is challenged. We propose that the increase in beta cell CART is part of a compensatory mechanisms trying to counteract the hyperglycaemia in T2D.
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| 45. |
- Ahrén, Bo
(författare)
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Glucagon-early breakthroughs and recent discoveries.
- 2015
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 67, s. 74-81
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Forskningsöversikt (refereegranskat)abstract
- Glucagon was discovered in 1922 as a hyperglycemic factor in the pancreas. During its early history up to 1970, glucagon was shown to increase circulating glucose through stimulating glycogenolysis in the liver. It was also shown to be a constituent of islet non-ß cells and to signal through G protein coupled receptors and cyclic AMP. Furthermore, its chemical characteristics, including amino acid sequence, and its processing from the preproglucagon gene had been established. During the modern research during the last 40 years, glucagon has been established as a key hormone in the regulation of glucose homeostasis, including a key role for the glucose counterregulation to hypoglycemia and for development of type 2 diabetes, and today glucagon is a potential target for treatment of the disease. Glucagon has also been shown to be a key factor beyond glucose control and involved in many processes. For the coming, future research, studies will be focused on α-cell biology beyond glucagon, hyperglucagonemia in other conditions than diabetes, its involvement in the regulation of body weight and energy expenditure and the potential of glucagon as a target for other diseases than type 2 diabetes, such as type 1 diabetes and obesity. This review summarizes the more than 90 years history of this important hormone as well as discusses potential future research regarding glucagon.
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| 46. |
- Ahrén, Bo
(författare)
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Glucagon-like peptide-1 and beta cell glucose sensitivity - a glucose ramp study in mice
- 2021
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- The incretin glucagon-like peptide-1 (GLP-1) is a gut hormone but also locally produced in pancreatic islets. We evaluated effects of GLP-1 on the insulin response to a gradual increase in glucose in mice within physiological levels. We initially developed a glucose ramp technique in mice. Glucose levels were slowly increased by 0.2 mmol/l/min for 40 min under control conditions, during intravenous infusion of GLP-1 and in GLP-1 receptor knockout mice. In control mice, glucose levels increased from 8.5 ± 0.3 to 16.1 ± 0.3 mmol/l over the 40 min, i.e., by 0.22 ± 0.01 mmol/l/min. This resulted in a slow increase in insulin levels by 96 ± 38 pmol/l from the baseline of 319 ± 53 pmol/l. GLP-1 at 0.5 nmol/kg as bolus plus 0.3 nmol/kg/min over 40 min progressively increased this insulin response by 100-fold, to 9.5 ± 0.2 nmol/l (P < 0.001). Higher doses of GLP-1 enhanced the insulin response similarly (1.0 or 3.0 nmol/kg bolus followed by 0.4 or 1.2 nmol/kg/min), whereas a lower dose (0.3 nmol/kg bolus plus 0.15 nmol/kg/min) had no significant effect compared to controls. Moreover, there was no significant difference in insulin responses between controls and GLP-1 receptor knockout mice. Since the increase in glucose levels were standardized, there was no significant difference in glucose levels between the experimental groups. We conclude that the glucose ramp technique is a tool for studies on insulin responses to slow changes in circulating glucose levels in mice. We also conclude that GLP-1 is extraordinarily potent in enhancing the insulin response to a slow increase in glucose levels.
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| 47. |
- 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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| 48. |
- 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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| 49. |
- Al-Najim, W., et al.
(författare)
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Integrated insights into the role of alpha-melanocyte stimulatory hormone in the control of food intake and glycaemia
- 2018
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 100, s. 243-248
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Tidskriftsartikel (refereegranskat)abstract
- Identifying peptide hormones with multipotent actions on both weight and glycaemia can have a significant impact on therapeutic options in the treatment of obesity and diabetes. This has been exemplified by recent advances involving pharmacological exploitation of glucagon-like peptide 1 biology. Herein, we summarise evidence supporting the potential candidacy in this light of alpha-melanocyte stimulatory hormone, an endogenous peptide hormone and a breakdown product of the neuropeptide pro-opiomelanocortin. We reference its well described central actions in the control of food intake and moreover highlight new data pointing to an important role for this peptide hormone in the periphery, in relation to glycaemic control.
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| 50. |
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