Regulation of glucagon secretion by incretins

Holst, Jens J.; Christensen, Mikkel B.; Lund, Asger; Heer, Jocelyn de; Svendsen, Berit; Kielgast, Urd; Knop, Filip K.

doi:10.1111/j.1463-1326.2011.01452.x

Cited by 139 publications

(89 citation statements)

References 61 publications

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“…Hyperglucagonaemia is a characteristic feature of type 2 diabetes that has attracted considerable interest because suppression of glucagon secretion is a potential therapeutic aim [2,16]. However, hyperglucagonaemia is also observed in renal disease and obesity, and after operations that alter the gastrointestinal delivery of nutrients, such as RYGB and vagotomy plus pyloroplasty [7][8][9].…”

Section: Discussionmentioning

confidence: 99%

“…Glucagon, a cleavage product of proglucagon, has an important role in the pathology of diabetes [1,2]: increased secretion (hyperglucagonaemia) and impaired glucose-mediated suppression of glucagon are both thought to contribute to diabetic hyperglycaemia [3][4][5][6]. Elevated plasma glucagon levels have also been reported after Roux-en-Y gastric bypass (RYGB) or vagotomy (plus pyloroplasty), or in patients with end-stage renal disease (ESRD) [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels?

et al. 2014

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Aim/hypothesis Hyperglucagonaemia is a characteristic of several clinical conditions (e.g. end-stage renal disease (ESRD), type 2 diabetes, obesity before and after Roux-en-Y gastric bypass (RYGB) and vagotomy with pyloroplasty), but the molecular nature of 'immunoreactive' glucagon is poorly characterised. The specific determination of fully processed, intact glucagon requires a 'sandwich' assay employing a combination of antibodies directed against both N-and C-termini. We compared a novel assay for intact glucagon with a highly sensitive C-terminal RIA (hitherto considered specific) to determine the extent to which the hyperglucagonaemia measured in clinical samples was caused by authentic glucagon. Methods We examined the performance of three commercial glucagon 'sandwich' ELISAs. The ELISA with the best overall performance was selected to compare glucagon measurements in clinical samples with an established glucagon RIA. ResultsThe first assay performed poorly: there was high cross-reactivity with glicentin (22%) and a lack of sensitivity for glucagon. The second and third assays showed minor cross-reactivity (1-5%) with oxyntomodulin and glicentin; however, the second assay had insufficient sensitivity for glucagon in plasma (>10-20 pmol/l). Thus, only the third assay was suitable for measuring glucagon concentrations in clinical samples. The ELISA and RIA measured similar glucagon levels in healthy individuals. Measurements of samples from individuals with abnormally high (type 2 diabetes or obese) or very elevated (post vagotomy with pyloroplasty, post-RYGB) glucagon levels were also similar in both assays. However, glucagon levels in participants with ESRD were much lower when measured by ELISA than by RIA, indicating that the apparent hyperglucagonaemia is not caused by fully processed intact glucagon.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels?

et al. 2014

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“…GLP-1 is known to suppress, while GIP and also GLP-2 stimulate glucagon secretion (45). The lower GLP-1 and the higher GIP response after the mixed meal when compared with oral glucose may explain the relatively higher glucagon secretion.…”

Section: Figure 1 Glucose Insulin and Triglyceride Responses (Meangsmentioning

confidence: 98%

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

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Rijkelijkhuizen²,

Holst³

et al. 2013

European Journal of Endocrinology

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Objective: To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. Design: A population-based study. Methods: A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucosedependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. Results: In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7-28.7) vs 18.0 (95% CI 16.9-19.1), P!0.05) but not after the mixed meal. GIP secretion among diabetic patients was increased on both occasions (82.9 pmol/l (55.9-109.8) vs 47.1 (43.8-50.4) for oral glucose and 130.6 (92.5-168.7) vs 83.2 (77.5-88.9) for mixed meal, both P!0.05). After oral glucose, GLP-1 (tAUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. Conclusion: This study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study.

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“…In recent years, it has become evident that glucosedependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) have glucose-dependent effects on glucagon secretion (1). While GLP-1 lowers glucagon levels during fasting and elevated blood glucose (1-3), GIP raises glucagon levels during fasting and hypoglycemic conditions (4)(5)(6).…”

Section: Glucose-dependent Insulinotropic Polypeptide Augments Glucagmentioning

confidence: 99%

Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

et al. 2014

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Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean 6 SEM] 26 6 1 years, BMI 24 6 0.5 kg/m 2 , HbA 1c 7.3 6 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase. In recent years, it has become evident that glucosedependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) have glucose-dependent effects on glucagon secretion (1). While GLP-1 lowers glucagon levels during fasting and elevated blood glucose (1-3), GIP raises glucagon levels during fasting and hypoglycemic conditions (4-6). In most patients with type 1 diabetes mellitus (T1DM), the glucagon counterregulatory response to insulin-induced hypoglycemia is deficient (7,8), and it is unknown to what extent the incretin hormones might affect this response. We therefore studied the individual effects of GIP and GLP-1 on the glucagon response to insulin-induced hypoglycemia in patients with T1DM without endogenous insulin secretion. RESEARCH DESIGN AND METHODS Study DesignThis was a double-blinded, randomized, crossover study comparing the effects of GIP, GLP-1, and placebo (saline)

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Regulation of glucagon secretion by incretins

Cited by 139 publications

References 61 publications

Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels?

Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels?

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

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