| 1. |
- 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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| 2. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Matthews, D. R., et al.
(författare)
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Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study
- 2010
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 12:9, s. 780-789
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Tidskriftsartikel (refereegranskat)abstract
- Methods: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. Results: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c < 7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline >= 0.5% or HbA1c < 6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of > 0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. Conclusions: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.
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| 9. |
- Ohlsson, Lena, et al.
(författare)
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GLP-1 released to the mesenteric lymph duct in mice: Effects of glucose and fat.
- 2014
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 189:Feb 28, s. 40-45
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Tidskriftsartikel (refereegranskat)abstract
- Using a newly developed in vivo model measuring glucagon-like peptide-1 (GLP-1) in gut lymphatics in mice, we quantified GLP-1 secretion in vivo after glucose versus fat ingestion with and without concomitant DPP-4 inhibition. The mesenteric lymphatic duct was cannulated in anesthetized C57BL6/J mice and lymph was collected in 30min intervals. Glucose or fat emulsion (Intralipid(R)) (0.03, 0.1 or 0.3kcal) with or without DPP-4-inhibition (NVP DPP728; 10μmol/kg) was administered by gastric gavage. Basal intact GLP-1 levels were 0.37±0.04pmol/l (n=61) in lymph compared to 0.07±0.03 in plasma (n=6; P=0.04) and basal DPP-4 activity was 4.7±0.3pmol/min/μl in lymph (n=23) compared to 22.3±0.9pmol/min/μl in plasma (n=8; P<0.001). Lymph flow increased from 1.2±0.1μl/min to 2.3±02μl/min at 30min after glucose and fat administration, with no difference between type of challenge or dose (n=81). Lymph GLP-1 levels increased calorie-dependently after both glucose and fat but with different time courses in that glucose induced a transient increase which had returned to baseline after 90min whereas the lipid induced a sustained increase which was still elevated above baseline after 210min. Lymph GLP-1 appearance during 210min was two to three-fold higher after glucose (7.4±2.3fmol at 0.3kcal) than after isocaloric fat (2.9±0.8fmol at 0.3kcal; P<0.001). The slope between caloric load and lymph GLP-1 appearance was, however, identical after glucose and fat. We conclude that lymph GLP-1 is higher than plasma GLP-1 whereas lymph DPP-4 activity is lower than plasma DPP-4 activity and that both glucose and fat clearly stimulate GLP-1 secretion calorie-dependently in vivo but with different time courses.
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| 10. |
- Stajich, Jason E., et al.
(författare)
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Insights into evolution of multicellular fungi from the assembled chromosomes of the mushroom Coprinopsis cinerea (Coprinus cinereus)
- 2010
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:26, s. 11889-11894
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Tidskriftsartikel (refereegranskat)abstract
- The mushroom Coprinopsis cinerea is a classic experimental model for multicellular development in fungi because it grows on defined media, completes its life cycle in 2 weeks, produces some 10(8) synchronized meiocytes, and can be manipulated at all stages in development by mutation and transformation. The 37-megabase genome of C. cinerea was sequenced and assembled into 13 chromosomes. Meiotic recombination rates vary greatly along the chromosomes, and retrotransposons are absent in large regions of the genome with low levels of meiotic recombination. Single-copy genes with identifiable orthologs in other basidiomycetes are predominant in low-recombination regions of the chromosome. In contrast, paralogous multicopy genes are found in the highly recombining regions, including a large family of protein kinases (FunK1) unique to multicellular fungi. Analyses of P450 and hydrophobin gene families confirmed that local gene duplications drive the expansions of paralogous copies and the expansions occur in independent lineages of Agaricomycotina fungi. Gene-expression patterns from microarrays were used to dissect the transcriptional program of dikaryon formation (mating). Several members of the FunK1 kinase family are differentially regulated during sexual morphogenesis, and coordinate regulation of adjacent duplications is rare. The genomes of C. cinerea and Laccaria bicolor, a symbiotic basidiomycete, share extensive regions of synteny. The largest syntenic blocks occur in regions with low meiotic recombination rates, no transposable elements, and tight gene spacing, where orthologous single-copy genes are overrepresented. The chromosome assembly of C. cinerea is an essential resource in understanding the evolution of multicellularity in the fungi.
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