| 31. |
- Ahrén, Bo
(författare)
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Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years?
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:8, s. 1740-1744
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Tidskriftsartikel (refereegranskat)abstract
- Research conducted over the last 50 years has produced discoveries on the importance of glucose control for reducing the risk of diabetic complications, the pathophysiology of type 2 diabetes, the development and validation of mechanistic glucose-lowering targets, and the preclinical and clinical development of individual drugs. This science established the different drug classes that are clinically used today in association with lifestyle changes for lowering glucose in type 2 diabetes. For the next 50 years, we can anticipate that science will explore (1) the use of current drugs and, as they become available, newly developed drugs in early (initial) oral combinations followed by intensification with injectable combinations when glycaemia deteriorates, (2) the validation of novel mechanistic biochemical and physiological targets, including indirect effects of future antiobesity drugs, and (3) the development of true disease-modifying strategies based on knowledge of islet cell biology and replacement. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
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| 32. |
- Ahrén, Bo, et al.
(författare)
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Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice.
- 2002
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 51:1, s. 12-19
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.
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| 33. |
- Ahrén, Bo, et al.
(författare)
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Disturbed alpha-cell function in mice with beta-cell specific overexpression of human islet amyloid polypeptide.
- 2008
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Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008
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Tidskriftsartikel (refereegranskat)abstract
- Exogenous administration of islet amyloid polypeptide (IAPP) has been shown to inhibit both insulin and glucagon secretion. This study examined alpha-cell function in mice with beta-cell specific overexpression of human IAPP (hIAPP) after an oral protein gavage (75 mg whey protein/mouse). Baseline glucagon levels were higher in transgenic mice (41 +/- 4.0 pg/mL, n = 6) than in wildtype animals (19 +/- 5.1 pg/mL, n = 5, P = .015). In contrast, the glucagon response to protein was impaired in transgenic animals (21 +/- 2.7 pg/mL in transgenic mice versus 38 +/- 5.7 pg/mL in wildtype mice at 15 minutes; P = .027). Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (P = .018). Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2 mg/mouse) to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with beta-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.
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| 34. |
- Ahrén, Bo
(författare)
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DPP-4 inhibition and islet function
- 2012
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Ingår i: Journal of Diabetes Investigation. - : Wiley. - 2040-1116. ; 3:1, s. 3-10
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Forskningsöversikt (refereegranskat)abstract
- During recent years, dipeptidyl peptidase-4 (DPP-4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add-on to several other therapies. DPP-4 inhibition prevents the inactivation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential beta-cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24-h glucose levels and reduces HbA1c by approximate to 0.81.1% from baseline levels of 7.78.5%. DPP-4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP-4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00184.x, 2012)
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| 35. |
- Ahrén, Bo
(författare)
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DPP-4 inhibition and the path to clinical proof
- 2019
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 10:JUN
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Tidskriftsartikel (refereegranskat)abstract
- In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.
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| 36. |
- Ahrén, Bo, et al.
(författare)
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DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.
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| 37. |
- Ahrén, Bo
(författare)
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DPP-4 inhibitors.
- 2007
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Ingår i: Baillière's Best Practice & Research in Clinical Endocrinology & Metabolism. - : Elsevier BV. - 1521-690X. ; 21:4, s. 517-533
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.
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| 38. |
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| 39. |
- Ahrén, Bo, et al.
(författare)
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Effects of conjugated linoleic acid plus n-3 polyunsaturated fatty acids on insulin secretion and estimated insulin sensitivity in men.
- 2009
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; Sep 3, s. 778-786
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Tidskriftsartikel (refereegranskat)abstract
- Background/Objectives:Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested.Subjects/Methods:CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data.Results:The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024).Conclusions:The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.European Journal of Clinical Nutrition advance online publication, 3 September 2008; doi:10.1038/ejcn.2008.45.
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| 40. |
- Ahren, Bo, et al.
(författare)
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Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes : The adjunct two randomized trial
- 2016
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 39:10, s. 1693-1701
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS A 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS Mean baseline glycated hemoglobin (HbA1c ) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6mmol/mol]; 1.2mg: -0.22% [2.4mmol/mol]; 0.6 mg: -0.23% [2.5mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2mg vs. placebo and of hyperglycemia with ketosis >1.5mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.
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