| 1. |
- Deacon, CF, et al.
(author)
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Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes?
- 2004
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In: Expert Opinion on Investigational Drugs. - : Informa Healthcare. - 1744-7658 .- 1354-3784. ; 13:9, s. 1091-1102
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Research review (peer-reviewed)abstract
- Inhibitors of the enzyme dipeptidyl peptidase IV (DPP IV) are of increasing interest to both diabetologists and the pharmaceutical industry alike, as they may become established as the next member of the oral antidiabetic class of therapeutic agents, designed to lower blood glucose and, possibly, prevent the progressive impairment of glucose metabolism in patients with impaired glucose tolerance and Type 2 diabetes. DPP IV has become a focus of attention for drug design, as it has a pivotal role in the rapid degradation of at least two of the hormones released during food ingestion, a property that has warranted the design of inhibitor-based drugs. At the molecular level, DPP IV cleaves two amino acids from the N-terminus of the intact, biologically active forms of both so-called incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (formerly known as gastric inhibitory polypeptide), resulting in truncated metabolites, which are largely inactive. Inhibition of the enzyme, therefore, is thought to increase levels of the active forms of both incretin hormones, culminating in an increase in insulin release after a meal, in a fully glucosedependant manner. DPP IV inhibitors combine several features of interest to the drug design process. They can be readily optimised for their target and be designed as low molecular weight, orally active entities compatible with once-daily administration.
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| 2. |
- Johansson, A, et al.
(author)
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Abnormal release of incretins and cortisol after oral glucose in subjects with insulin-resistant myotonic dystrophy
- 2002
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 146:3, s. 397-405
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Journal article (peer-reviewed)abstract
- Objective: Although the incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), as well as glucagon and cortisol, are known to influence islet function, the role of these hormones in conditions of insulin resistance and development of type 2 diabetes is unknown. An interesting model for the study of hormonal perturbations accompanying marked insulin resistance without concomitant diabetes is myotonic dystrophy (DM1). Design: The work was carried out in an out-patient setting. Methods: An oral glucose tolerance test was performed in 18 males with DM1 and 18 controls to examine the release of incretins and counter-regulatory hormones. Genetic analyses were also performed in patients. Results: We found that the increment in GLP-1 after oral glucose was significantly greater in patients, while there was no significant difference in GIP or glucagon responses between patients and controls, although long CTG repeat expansions were associated with a more pronounced GIP response. Interestingly, the GLP-1 response to oral glucose correlated with the insulin response in patients but not in controls whereas, in controls, the insulin response closely correlated with the GIP response. Furthermore, cortisol and ACTH levels increased paradoxically in patients after glucose; this was more pronounced in patients with long CTG repeat expansions. Conclusions: This study showed that the GLP-1 and ACTH/cortisol responses to oral glucose are abnormal in insulin-resistant DM1. patients and that CTG triplet repeats are linked to GIP release. These abnormalities may contribute both to the severe insulin resistance and hyperinsulinemia in DM1 and to the preservation of adequate islet function, enabling glucose tolerance to be normal in spite of this marked insulin resistance in DM1.
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| 3. |
- Nystrom, T, et al.
(author)
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Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease
- 2004
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In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 287:6, s. 1209-1215
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Journal article (peer-reviewed)abstract
- GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and inhibits small bowel motility, all actions contributing to the anti-diabetogenic peptide effect. Endothelial dysfunction is strongly associated with insulin resistance and type 2 diabetes mellitus and may cause the angiopathy typifying this debilitating disease. Therefore, interventions affecting both endothelial dysfunction and insulin resistance may prove useful in improving survival in type 2 diabetes patients. We investigated GLP-1's effect on endothelial function and insulin sensitivity (S-I) in two groups: 1) 12 type 2 diabetes patients with stable coronary artery disease and 2) 10 healthy subjects with normal endothelial function and S-I. Subjects underwent infusion of recombinant GLP-1 or saline in a random crossover study. Endothelial function was measured by postischemic FMD of brachial artery, using ultrasonography. S-I [in (10(-4) dl.kg(-1).min(-1))/(muU/ml)] was measured by hyperinsulinemic isoglycemic clamp technique. In type 2 diabetic subjects, GLP-1 infusion significantly increased relative changes in brachial artery diameter from baseline FMD(%) (3.1 +/- 0.6 vs. 6.6 +/- 1.0%, P < 0.05), with no significant effects on S-I (4.5 &PLUSMN; 0.8 vs. 5.2 &PLUSMN; 0.9, P = NS). In healthy subjects, GLP-1 infusion affected neither FMD(%) (11.9 &PLUSMN; 0.9 vs. 10.3 &PLUSMN; 1.0%, P = NS) nor S-I (14.8 &PLUSMN; 1.8 vs. 11.6 &PLUSMN; 2.0, P = NS). We conclude that GLP-1 improves endothelial dysfunction but not insulin resistance in type 2 diabetic patients with coronary heart disease. This beneficial vascular effect of GLP-1 adds yet another salutary property of the peptide useful in diabetes treatment.
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