| 11. |
- Ahrén, Bo, et al.
(författare)
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Mechanisms of Action of the DPP-4 Inhibitor Vildagliptin in Man.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:9, s. 775-783
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Forskningsöversikt (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.
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| 12. |
- Ahrén, Bo, et al.
(författare)
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Pronounced Reduction Of Postprandial Glucagon By Lixisenatide: A Meta-Analysis Of Randomized Clinical Trials.
- 2014
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 16:9, s. 861-868
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels.
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| 13. |
- Ahrén, Bo, et al.
(författare)
-
Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials
- 2018
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:9, s. 2210-2219
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. Materials and Methods: Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. Results: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). Conclusions: In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.
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| 14. |
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| 15. |
- Ahrén, Bo
(författare)
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The future of incretin-based therapy: novel avenues-novel targets.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13 Suppl 1, s. 158-166
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Tidskriftsartikel (refereegranskat)abstract
- Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years.
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| 16. |
- Ahrén, Bo, et al.
(författare)
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Using albumin to improve the therapeutic properties of diabetes treatments.
- 2012
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 14, s. 121-129
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Tidskriftsartikel (refereegranskat)abstract
- Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. In order to meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalise on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies.
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| 17. |
- Alam, M, et al.
(författare)
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Gastric bypass surgery, but not caloric restriction, decreases dipeptidyl peptidase 4 activity in obese patients with type 2 diabetes.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:4, s. 378-381
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism by which incretins and their effect on insulin secretion increase markedly following gastric bypass surgery (GBP) is not fully elucidated. We hypothesized that a decrease in the activity of dipeptidyl peptidase-4 (DPP-4), the enzyme which inactivates incretins, may explain the rise in incretin levels post-GBP. Fasting plasma DPP-4 activity was measured after 10 kg equivalent weight loss by GBP (n=16) or by caloric restriction (CR, n=14) in obese patients with type 2 diabetes. DPP-4 activity decreased after GBP by 11.6% (p=0.01), but not after CR. The increased peak GLP-1 and GIP response to oral glucose after GBP did not correlate with DPP-4 activity. The decrease in fasting plasma DPP-4 activity after GBP occurred by a mechanism independent of weight loss and did not relate to change in incretins concentrations. Whether the change in DPP-4 activity contributes to improved diabetes control after GBP remains therefore to be determined.
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| 18. |
- Alamshah, A., et al.
(författare)
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L-arginine promotes gut hormone release and reduces food intake in rodents
- 2016
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902. ; 18:5, s. 508-518
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the anorectic effect of L-arginine (L-Arg) in rodents. Methods: We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. Results: Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L-Arg stimulated GLP-1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP-1 and PYY receptors did not influence the anorectic effect of L-Arg. L-Arg-mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L-Arg suppressed food intake in rats. Conclusions: L-Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L-Arg is unlikely to be mediated by GLP-1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L-Arg suppressed food intake in rats, suggesting that L-Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L-Arg suppresses food intake and its utility in the treatment of obesity.
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| 19. |
- Alba, M., et al.
(författare)
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Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function
- 2013
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 15:12, s. 1101-1110
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Tidskriftsartikel (refereegranskat)abstract
- AimsThe effects of sitagliptin and pioglitazone, alone and in combination, on - and -cell function were assessed in patients with type 2 diabetes. MethodsFollowing a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4mmol/l were randomized (1:1:1:1) to sitagliptin, pioglitazone, sitagliptin+pioglitazone or placebo. At baseline and after 12weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. ResultsAfter 12weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin+pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin+pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin+pioglitazone versus pioglitazone or placebo. (s), a measure of dynamic -cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin+pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin+pioglitazone versus placebo. The disposition index, a measure of the relationship between -cell function and insulin sensitivity, improved with all active treatments versus placebo. ConclusionsSitagliptin and pioglitazone enhanced -cell function (increasing postmeal phi(s)), and sitagliptin improved -cell function (decreasing postmeal glucagon) after 12weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.
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| 20. |
- Alfredsson, Joakim, et al.
(författare)
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Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: A report from TECOS
- 2018
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326. ; 20:10, s. 2379-2388
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo-controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.89, adjusted HR 0.64, 95% CI 0.55-0.74; P amp;lt; .0001). Women also had a significantly lower risk of secondary CV outcomes and all-cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes.
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