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| 62. |
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| 63. |
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| 64. |
- Ahrén, Bo, et al.
(författare)
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Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies.
- 2004
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 150:2, s. 97-104
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Forskningsöversikt (refereegranskat)abstract
- Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. A correct judgement of insulin secretion therefore requires validation in relation to the insulin sensitivity in the same subject. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant. This product is usually called the disposition index. Several techniques may be used for its estimation such as data derived from the frequently sampled i.v. glucose tolerance test, the oral glucose tolerance test or the glucose-dependent arginine stimulation test or the euglycemic hyperinsulinemic clamp technique in combination with a test on insulin secretion. Using these techniques the compensatory increase in beta cell function in insulin resistance has been verified in obesity, in pregnancy and after glucocorticoid administration as has the defective beta cell function as the underlying cause of impaired glucose tolerance and type 2 diabetes. Similarly, combined analysis of insulin sensitivity and insulin secretion has shown a down-regulation of beta cell function in increased insulin sensitivity accompanying weight reduction in obesity and following exercise. Acknowledging this inverse relationship between insulin secretion and insulin sensitivity therefore requires estimation of both variables for correct assessment in any individual.
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| 65. |
- Ahrén, Bo, et al.
(författare)
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Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism.
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X.
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism.
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| 66. |
- Ahrén, Bo, et al.
(författare)
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Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.
- 2005
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 28:8, s. 1936-1940
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related β-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS—In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5–3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS—In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA1c (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference −1.0 ± 0.2%; P < 0.001; baseline of all subjects combined 7.7 ± 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference −0.9 ± 0.3 mmol/l, P = 0.016; baseline 9.8 ± 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 ± 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 ± 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 ± 4 ml · min−1 · m−2, P = 0.036; baseline 246 ± 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 ± 1.0, P = 0.040; baseline 9.1 ± 0.5). The change in adaptation index correlated to the change in A1C (r = −0.39, P = 0.004). CONCLUSIONS—This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves β-cell function along with improved postmeal insulin sensitivity.
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| 67. |
- Ahrén, Bo, et al.
(författare)
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Improved meal-related insulin processing contributes to the enhancement of B-Cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes
- 2007
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 39:11, s. 826-829
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5 +/- 1.5 years; BMI=29.6 +/- 0.5kg/m(2); FPG = 9.9 +/- 0.2 mmol/l; HbA1c=7.7 +/- 0.1 %) were studied: 29 pateients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4h post-meal) states to evaluate B-cell function. The between-treatment difference (vildaglip-tin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007 +/- 0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010 +/- 0.008 (p = 0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p = 0.023) and postprandially (p = 0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.
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| 68. |
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| 69. |
- Ahrén, Bo
(författare)
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Incretin dysfunction in type 2 diabetes: Clinical impact and future perspectives.
- 2013
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Ingår i: Diabetes & Metabolism. - : Elsevier BV. - 1878-1780 .- 1262-3636. ; 39:3, s. 195-201
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Forskningsöversikt (refereegranskat)abstract
- The incretin effect refers to the augmentation of insulin secretion after oral administration of glucose compared with intravenous glucose administration at matched glucose levels. The incretin effect is largely due to the release and action on beta-cells of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This system has in recent years had considerable interest due to the success of incretin therapy as a glucose-lowering strategy in type 2 diabetes. In non-diabetic subjects, the incretin effect is responsible for 50-70% of insulin release during oral glucose administration. In type 2 diabetes patients, the incretin effect is impaired and contributes to only 20-35% of the insulin response to oral glucose. The reason for the defective incretin effect in type 2 diabetes has been the subject of many studies. Although the reports in the literature are mixed, most studies of GIP and GLP-1 secretory responses to oral glucose or a mixed meal have shown fairly normal results in type 2 diabetes. In contrast, the insulinotropic effects of both GIP and GLP-1 are impaired in type 2 diabetes with greater suppression of insulin secretion augmentation with GIP than with GLP-1. The suggested causes of these defects are a defective beta-cell receptor expression or post-receptor defects secondary to the diabetes milieu, defective beta-cell function in general resulting in defective incretin effect and genetic factors initiating incretin hormone resistance. Identifying the mechanisms in greater detail would be important for understanding the strengths, weaknesses and efficacy of incretin therapy in individual patients to more specifically target this glucose-lowering therapy.
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| 70. |
- Ahrén, Bo, et al.
(författare)
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Incretin hormone secretion over the day.
- 2010
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Ingår i: Vitamines and Hormones. - 0083-6729. ; 84, s. 203-220
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Tidskriftsartikel (refereegranskat)abstract
- The two incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are key factors in the regulation of islet function and glucose metabolism, and incretin-based therapy for type 2 diabetes has gained considerable interest during recent years. Regulation of incretin hormone secretion is less well characterized. The main stimulus for incretin hormone secretion is presence of nutrients in the intestinal lumen, and carbohydrate, fat as well as protein all have the capacity to stimulate GIP and GLP-1 secretion. More recently, it has been established that a diurnal regulation exists with incretin hormone secretion to an identical meal being greater when the meal is served in the morning compared to in the afternoon. Finally, whether incretin hormone secretion is altered in disease states is an area with, so far, controversial results in different studies, although some studies have demonstrated reduced incretin hormone secretion in type 2 diabetes. This review summarizes our knowledge on regulation of incretin hormone secretion and its potential changes in disease states.
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