Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes

Manell, Hannes; Staaf, Johan; Manukyan, Levon; Kristinsson, Hjalti; Cen, Jing; Stenlid, Rasmus; Ciba, Iris; Forslund, Anders; Bergsten, Peter

doi:10.1210/jc.2015-3885

Cited by 72 publications

(87 citation statements)

References 40 publications

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“…Individuals with obesity have elevated fasting levels of both glucagon and insulin, which have been linked to the development of T2DM 1, 2 . In the present study we supply evidence that such dual islet hormonal amplification could be the result of elevated concentrations of circulating FFAs, which is characteristic of this patient group 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Subjects with obesity have, in addition to elevated circulating insulin concentrations 1 , high glucagon levels at fasting 1, 2 . Although much attention has been on the raised insulin levels precipitating development of type 2 diabetes mellitus (T2DM) 3 , the high fasting glucagon levels have gained more and more attention as equally important for disease progression towards T2DM 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Given the situation in obese children with concomitant elevation of both insulin and glucagon 1 and elevated FFA levels at normal fasting glucose concentrations 25 , our aim was to examine how chronically elevated FFA levels affected glucagon, insulin and also somatostatin secretion from isolated human islets at fasting glucose concentrations with special focus on the role of FFAR1.…”

Section: Introductionmentioning

confidence: 99%

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Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion

Kristinsson

Sargsyan

Manell

et al. 2017

Sci Rep

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In obesity fasting levels of both glucagon and insulin are elevated. In these subjects fasting levels of the free fatty acid palmitate are raised. We have demonstrated that palmitate enhances glucose-stimulated insulin secretion from isolated human islets via free fatty acid receptor 1 (FFAR1/GPR40). Since FFAR1 is also present on glucagon-secreting alpha-cells, we hypothesized that palmitate simultaneously stimulates secretion of glucagon and insulin at fasting glucose concentrations. In addition, we hypothesized that concomitant hypersecretion of glucagon and insulin was also contributed by reduced somatostatin secretion. We found basal glucagon, insulin and somatostatin secretion and respiration from human islets, to be enhanced during palmitate treatment at normoglycemia. Secretion of all hormones and mitochondrial respiration were lowered when FFAR1 or fatty acid β-oxidation was inhibited. The findings were confirmed in the human beta-cell line EndoC-βH1. We conclude that fatty acids enhance both glucagon and insulin secretion at fasting glucose concentrations and that FFAR1 and enhanced mitochondrial metabolism but not lowered somatostatin secretion are crucial in this effect. The ability of chronically elevated palmitate levels to simultaneously increase basal secretion of glucagon and insulin positions elevated levels of fatty acids as potential triggering factors for the development of obesity and impaired glucose control.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion

Kristinsson

Sargsyan

Manell

et al. 2017

Sci Rep

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“…As recently shown by Manell et al, obese adolescents with impaired glucose tolerance had lower fasting GLP-1 levels than those with normal glucose tolerance, suggesting that this is an early-stage abnormality in obesity-related glucose dysregulation [28]. Moreover, obese adolescents showed elevated insulin and glucagon levels and that the progression to T2D was related to a further increase of these hormones as well as an early-phase hyperglucagonemic response to OGTT [28].…”

Section: Discussionmentioning

confidence: 72%

“…Moreover, obese adolescents showed elevated insulin and glucagon levels and that the progression to T2D was related to a further increase of these hormones as well as an early-phase hyperglucagonemic response to OGTT [28]. However, further longitudinal studies are required to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Increased GLP-1 response to oral glucose in pre-pubertal obese children

Giannini

Pietropaoli

Polidori

et al. 2016

Journal of Pediatric Endocrinology and Metabolism

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Background: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. Conclusions:Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

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A role for methanogens and methane in the regulation of GLP‐1

Laverdure

Mezouari

Carson

et al. 2017

Endocrino Diabet & Metabol

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Summary Introduction The gastrointestinal ( GI ) microbiome has emerged as a potential regulator of metabolism. However, the precise mechanisms of how microorganisms may influence physiology remain largely unknown. Interestingly, GI microorganisms, including methanogens, are localized within the same regions as the glucagon‐like peptide‐1 ( GLP ‐1) secreting L cells. GLP ‐1 plays key roles appetite and glucose regulation. Furthermore, both methane and GLP ‐1 levels are altered in obese humans with metabolic disease. We predict that high‐fat diet‐induced obesity alters the abundance of GI methanogens and that methane may play a role in the GLP ‐1 secretory response from the L cell. Methods To demonstrate this, GLP ‐1 secretion response and faecal methanogens were examined in mice given a high‐fat diet for 14 weeks. In addition, the direct effect of methane on GLP ‐1 secretion was assessed in two L‐cell models ( NCI ‐H716 and GLUT ag). Results High‐fat diet caused a significant increase in both GLP ‐1 secretion and faecal methanogen content. There was a direct correlation between GLP ‐1 secretion response and faecal methanogen levels. In L cells, methane stimulated GLP ‐1 secretion and enhanced intracellular cAMP content. Conclusion These results indicate that alterations in the methanogen communities occurring in obesity may play a vital role in directly enhancing GLP ‐1 secretion, and that methane can directly stimulate the secretion of GLP ‐1.

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Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes

Cited by 72 publications

References 40 publications

Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion

Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion

Increased GLP-1 response to oral glucose in pre-pubertal obese children

A role for methanogens and methane in the regulation of GLP‐1

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