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- Kappe, C, et al.
(author)
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Evidence for paracrine/autocrine regulation of GLP-1-producing cells
- 2013
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In: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 305:10, s. C1041-C1049
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Journal article (peer-reviewed)abstract
- Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9–39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.
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- 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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