Endogenous GLP-1 Regulates Postprandial Glycemia in Humans: Relative Contributions of Insulin, Glucagon, and Gastric Emptying

Nicolaus, M.; Brödl, Julia; Linke, Rainer; Woerle, Hans-Juergen; Göke, Burkhard; Schirra, Jörg

doi:10.1210/jc.2010-0841

Cited by 66 publications

(65 citation statements)

References 31 publications

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“…In contrast, Ex-9 impaired oral glucose tolerance, as has been observed in several previous studies in healthy subjects (21)(22)(23)(24)(25) and patients with T2D (13,26). The reduced glucose excursion under sitagliptin was accompanied by a significant increase of insulin and c-peptide concentrations and resulted in a higher IGR.…”

Section: Discussionsupporting

confidence: 62%

“…However, there was an additional increase of active GLP-1 concentrations by Ex-9. This well-known effect has been described under GLP-1r blockade in healthy subjects and patients with type 1 or type 2 diabetes (13,(24)(25)(26)40). It occurs during the postprandial but not in the fasting state and is believed to be due to negative feedback regulation of GLP-1 release in intestinal L-cells and the lack of this feedback during GLP-1r blockade.…”

Section: Discussionmentioning

confidence: 90%

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Defining the Role of GLP-1 in the Enteroinsulinar Axis in Type 2 Diabetes Using DPP-4 Inhibition and GLP-1 Receptor Blockade

et al. 2014

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Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebocontrolled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 90%

Defining the Role of GLP-1 in the Enteroinsulinar Axis in Type 2 Diabetes Using DPP-4 Inhibition and GLP-1 Receptor Blockade

et al. 2014

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“…20). Conversely, there is good evidence that GLP-1 changes within the normal range play no role in the regulation of gastric emptying (25). It is of interest that the greater GLP-1 response, though small (∼20%), should have suppressed glucagon release.…”

Section: Discussionmentioning

confidence: 99%

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Ferrannini¹,

Muscelli²,

Frascerra³

et al. 2014

J. Clin. Invest.

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977

759

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Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. Methods.We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m 2 , HbA 1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.

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“…Nevertheless, it remains unclear how much this mechanism contributes to the glucose-lowering effect of endogenous GLP-1, since GLP-1 receptor antagonism using exendin 9-39 affected gastric empting in some [73], but not all [70,74], studies.…”

Section: Incretin Hormone Actionmentioning

confidence: 99%

Physiology of Incretins in Health and Disease

Deacon

Åhrén²

2011

Rev Diabet Stud

112

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■ AbstractThe incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

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Endogenous GLP-1 Regulates Postprandial Glycemia in Humans: Relative Contributions of Insulin, Glucagon, and Gastric Emptying

Abstract: Released after an oral meal, GLP-1 lowers pp glycemia. In this study, the inhibition of glucagon release was a major determinant of the acute GLP-1 action in healthy subjects. In contrast, gastric emptying was not changed by GLP-1 receptor antagonism.

Cited by 66 publications

References 31 publications

Defining the Role of GLP-1 in the Enteroinsulinar Axis in Type 2 Diabetes Using DPP-4 Inhibition and GLP-1 Receptor Blockade

Defining the Role of GLP-1 in the Enteroinsulinar Axis in Type 2 Diabetes Using DPP-4 Inhibition and GLP-1 Receptor Blockade

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Physiology of Incretins in Health and Disease

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