| 51. |
- Ahrén, Bo
(författare)
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Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes.
- 2008
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Ingår i: Expert Opinion on Emerging Drugs. - : Informa Healthcare. - 1472-8214 .- 1744-7623. ; 13:4, s. 593-607
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) prevents the inactivation of glucagon-like peptide-1 (GLP-1). This increases circulating levels of active GLP-1, stimulates insulin secretion and inhibits glucagon secretion, resulting in lowering of glucose levels and improvement of glycemic control in patients with type 2 diabetes. Several DPP-4 inhibitors are emerging for therapeutic use. Most experience exists for sitagliptin, vildagliptin, saxagliptin and alogliptin. They all improve metabolic control in type 2 diabetes in monotherapy and in combination therapy with metformin, sulfonylurea and thiazolidinediones. Vildagliptin and alogliptin have also been shown to improve glycemic control when added to insulin therapy, and sitagliptin improves glycemic control in triple therapy with metformin plus thiazolidinedione. DPP-4 inhibition also shows a favorable safety profile, high tolerability, only a minimal risk of hypoglycemia, and body-weight neutrality. The main clinical indication for DPP-4 inhibitors will be in the early stage of type 2 diabetes, in combination with metformin or other treatments in subjects with inadequate glycemic control on these treatments alone. The durability and long-term safety of DPP-4 inhibition, as well as clinical positioning in relation to GLP-1 mimetics, remain now to be established.
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| 52. |
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| 53. |
- Ahrén, Bo, et al.
(författare)
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Estimation of the Relative Contribution of Postprandial Glucose Exposure to Average Total Glucose Exposure in Subjects with Type 2 Diabetes
- 2016
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Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2016
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that the relative contribution of fasting plasma glucose (FPG) versus postprandial plasma glucose (PPG) to glycated haemoglobin (HbA1c) could be calculated using an algorithm developed by the A1c-Derived Average Glucose (ADAG) study group to make HbA1c values more clinically relevant to patients. The algorithm estimates average glucose (eAG) exposure, which can be used to calculate apparent PPG (aPPG) by subtracting FPG. The hypothesis was tested in a large dataset (comprising 17 studies) from the vildagliptin clinical trial programme. We found that 24 weeks of treatment with vildagliptin monotherapy (n = 2523) reduced the relative contribution of aPPG to eAG from 8.12% to 2.95% (by 64%, p < 0.001). In contrast, when vildagliptin was added to metformin (n = 2752), the relative contribution of aPPG to eAG insignificantly increased from 1.59% to 2.56%. In conclusion, glucose peaks, which are often prominent in patients with type 2 diabetes, provide a small contribution to the total glucose exposure assessed by HbA1c, and the ADAG algorithm is not robust enough to assess this small relative contribution in patients receiving combination therapy.
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| 54. |
- Ahrén, Bo
(författare)
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Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans.
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 51:6, s. 1018-1024
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. METHODS: Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2 +/- 3.4 kg/m(2), fasting glucose 5.1 +/- 0.4 mmol/l, fasting insulin 46 +/- 6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3-0.6 mg kg(-1) min(-1)). RESULTS: As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75 +/- 8 pmol/l, p < 0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64 +/- 12% at fasting glucose, by 80 +/- 19% at 13-15 mmol glucose and by 43 +/- 12% at >28 mmol glucose; p <0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasone-induced insulin resistance was reduced by trimethaphan by 48 +/- 6% at fasting glucose, 61 +/- 8% at 13-15 mmol/l glucose and 62 +/- 8% at >28 mmol/l glucose (p < 0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. CONCLUSIONS/INTERPRETATIONS: Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.
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| 55. |
- Ahrén, Bo
(författare)
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GLP-1 and extra-islet effects.
- 2004
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 36:11-12, s. 842-845
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Forskningsöversikt (refereegranskat)
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| 56. |
- Ahrén, Bo
(författare)
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GLP-1-based therapy of type 2 diabetes: GLP-1 mimetics and DPP-IV inhibitors.
- 2007
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Ingår i: Current Diabetes Reports. - 1539-0829. ; 7:5, s. 340-347
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1)-based therapy is a novel treatment for type 2 diabetes. It is executed either by GLP-1 mimetics or by dipeptidyl peptidase-IV inhibitors. In type 2 diabetes, the two strategies reduce hemoglobin A(1c) by 0.6% to 1.1% from baseline levels of 7.7% to 8.5%. They are efficient both in monotherapy and in combination with metformin or thiazolidinediones. Both treatments are well tolerated with low risk of hypoglycemia.
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| 57. |
- Ahrén, Bo
(författare)
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GLP-1 for type 2 diabetes
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 317:9, s. 1239-1245
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Forskningsöversikt (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1)-based therapy of type 2 diabetes is executed either by GLP-1 receptor agonists, which stimulate the GLP-1 receptors, or by dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the inactivation of endogenous GLP-1 thereby increasing the concentration of endogenous active GLP-1. GLP-1 activates pancreatic receptors resulting in improved glycemia through glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. There is also a potential beta cell preservation effect, as judged from rodent studies. GLP-1 receptors are additionally expressed in extrapancreatic tissue, having potential for the treatment to reduce body weight and to potentially have beneficial cardio- and endothelioprotective effects. Clinical trials in subjects with type 2 diabetes have shown that in periods of 12 weeks or more, these treatments reduce HbA1c by approximate to 0.8-1.1% from baseline levels of 7.7-8.5%, and they are efficient both as monotherapy and in combination therapy with metformin, sulfonylureas, thiazolidinediones or insulin. Furthermore, GLP-1 receptor agonists reduce body weight, whereas DPP-4 inhibitors are body weight neutral. The treatment is safe with very low risk for adverse events, including hypoglycaemia. GLP-1 based therapy is thus a novel and now well established therapy of type 2 diabetes, with a particular value in combination with metformin in patients who are inadequately controlled by metformin alone. (C) 2011 Elsevier Inc. All rights reserved.
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| 58. |
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| 59. |
- 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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| 60. |
- 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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