Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Holst, Jens J.; Knop, Filip K.; Vilsbøll, Tina; Krarup, Thure; Madsbad, Sten

doi:10.2337/dc11-s227

Cited by 246 publications

(207 citation statements)

References 63 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%

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%

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

et al. 2014

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“…the incretin effect [18]). Impairment of the incretin effect is an early and specific sign of inadequate glucose metabolism [19] and, hypothetically, levels of these hormones could be lower in individuals predisposed to type 2 diabetes due to low BW. Although the level of fasting GLP-1 was higher in the twin with the lower BW, levels of GIP and GLP-1 were similar in those with higher and lower BW during and after a 2 h OGTT, suggesting that BW is not associated with the levels of incretin hormones measured in later life.…”

Section: Discussionmentioning

confidence: 99%

Adult glucose metabolism in extremely birthweight-discordant monozygotic twins

et al. 2012

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Aims/hypothesis Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment. Methods Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5 kg) were assessed using a 2 h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-β) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5 kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease).Results No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-β, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120 min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5 kg. Conclusions/interpretation BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.

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“…The main impairments are recognised as reduced postprandial GLP-1 secretion and defective GIP receptor signalling [1]. The inadequacy in the GLP-1 arm of the incretin effect can be easily overcome through administration of exogenous GLP-1, which significantly amplifies circulating concentrations [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…A defect in the postprandial insulin-secretory incretin response, mediated by the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is a specific pathophysiological characteristic of type 2 diabetes [1]. The main impairments are recognised as reduced postprandial GLP-1 secretion and defective GIP receptor signalling [1].…”

Section: Introductionmentioning

confidence: 99%

“…For GIP, the first 14 N-terminal amino acid residues contain the bioactive domain important for insulin-secretory function [25,26]. Based on this knowledge, we constructed a novel GIP/xenin hybrid peptide, (DAla 2 )GIP/xenin-8-Gln, by linking GIP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) to xenin-8-Gln, retaining the regions of each peptide known to be important for biological activity (see electronic supplementary material [ESM] Table 1). Importantly, since GIP is a substrate for dipeptidyl peptidase-4 (DPP-4) [27], the hybrid peptide includes substitution of the naturally occurring alanine L isomer residue by a D isomer at position 2 [28,29].…”

Section: Introductionmentioning

confidence: 99%

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An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla 2 )GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla 2 )GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla 2 )GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla 2 )GIP/xenin-8-Gln was determined in high-fat-fed mice.

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Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Cited by 246 publications

References 63 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?

Adult glucose metabolism in extremely birthweight-discordant monozygotic twins

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

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