Oxyntomodulin: Actions and role in diabetes

Holst, Jens J.; Albrechtsen, Nicolai J. Wewer; Gabe, M

doi:10.1016/j.peptides.2017.09.018

“…The accuracy of glucagon levels measured by an ELISA kit was confirmed with novel liquid chromatography-high resolution mass spectroscopy. Indeed, proglucagon fragments, such as the glicentin and oxyntomodulin, are secreted from the intestine in response to feeding 39,40 . The discrepancy between the correlation of glycemic variability with AUC glcRIA and AUC glcELISA in the present study appeared to show that proglucagon fragments other than glucagon (1-29) could contribute to glycemic variability.…”

Section: Discussionmentioning

confidence: 99%

Contribution of pancreatic α‐cell function to insulin sensitivity and glycemic variability in patients with type 1 diabetes

Takahashi

¹

,

Chujo

²

,

Kajio

³

et al. 2018

J of Diabetes Invest

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Aims/Introduction To evaluate the contribution of pancreatic α‐cell function to the dawn phenomenon, insulin sensitivity, hepatic glucose uptake and glycemic variability in patients with type 1 diabetes. Materials and Methods In 40 patients with type 1 diabetes, arginine stimulation tests were carried out, and the area under the curve (AUC) of glucagon was measured using radioimmunoassays ( AUC glc RIA ) and enzyme‐linked immunosorbent assays ( AUC glc ELISA ). The ratio of the insulin dose delivered by an artificial pancreas to maintain euglycemia between 04.00 and 08.00 hours or between 00.00 and 04.00 hours was measured as the dawn index. The glucose infusion rate and hepatic glucose uptake were measured using hyperinsulinemic euglycemic clamp and clamp oral glucose loading tests. Glycemic variability in 96 h was measured by continuous glucose monitoring. Results The median dawn index (1.7, interquartile range 1.0–2.8) was not correlated with AUC glc RIA ( R 2 = 0.03, P = 0.39) or AUC glc ELISA ( R 2 = 0.04, P = 0.32). The median glucose infusion rate (7.3 mg/kg/min, interquartile range 6.4–9.2 mg/kg/min) was significantly correlated with AUC glc RIA ( R 2 = 0.20, P = 0.02) and AUC glc ELISA ( R 2 = 0.21, P = 0.02). The median hepatic glucose uptake (65.3%, interquartile range 40.0–87.3%) was not correlated with AUC glc RIA ( R 2 = 0.07, P = 0.26) or AUC glc ELISA ( R 2 = 0.26, P = 0.79). The standard deviation of glucose levels measured by continuous glucose monitoring was significantly correlated with AUC glc RIA ( R 2 = 0.11, P = 0.049), but not with AUC glc ELISA ( R 2 = 0.01, P ...

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“…Oxyntomodulin is another gut peptide that affects both sides of glucose homeostasis, by demonstrating glucagon and GLP-1 agonist biological actions. 65 It is derived from the intestinal processing of proglucagon and is produced and released from the endocrine L-cells of the gut after stimulation of luminal nutrients. 66 Oxyntomodulin binds to the glucagon receptor, affecting insulin secretion via the GPCRs expressed by beta cells, as well as acting on the hepatocytes, where it increases glucose production.…”

Section: Studies In Animalsmentioning

confidence: 99%

“…68 Oxyntomodulin has been reported to increase glucagon secretion in vitro and in vivo, 67 but on the other hand, with its ability of activating GLP-1 receptor, it results in a decrease of glucagon secretion. 65 Although its concentrations may increase under conditions of accelerated gastric emptying such as bariatric surgery and its involvement in the observed metabolic shift has not been so far elucidated, its metabolic significance might be limited, since GLP-1 exerts almost 50-fold higher affinity on the GLP-1 receptor resulting in remarkably increased GLP-1 concentrations. 69 The role of GIP in the modulation of postprandial glucose metabolism in T2D could also contribute to the metabolic benefits of bariatric surgery.…”

Section: Studies In Animalsmentioning

confidence: 99%

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Anti‐incretin effect: The other face of Janus in human glucose homeostasis

Karras

¹

,

Koufakis

²

,

Mustafa

³

et al. 2019

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The provocative idea that type 2 diabetes (T2D) may be a surgically treated disorder is based on accumulating evidence suggesting impressive remission rates of obesity and diabetes following bariatric surgery interventions. According to the "anti-incretin" theory, ingestion of food in the gastrointestinal (GI) tract, apart from activating the welldescribed incretin effect, also results in the parallel stimulation of a series of negative feedback mechanisms (anti-incretin effect). The primary goal of these regulations is to counteract the effects of incretins and other postprandial glucose-lowering adaptive mechanisms. Disruption of the equilibrium between incretins and anti-incretins could be an additional pathway leading to the development of insulin resistance and hyperglycemia. This theory provides an alternative theoretical framework to explain the mechanisms behind the optimal effects of metabolic surgery on T2D and underlines the importance of the GI tract in the homeostatic regulation of energy balance in humans. The anti-incretin concept is currently based on a limited amount of evidence and certainly requires further validation by additional studies. The aim of the present review is to discuss and critically evaluate recent evidence on the anti-incretin theory, providing an insight into current state and future perspectives.

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“…Although GLP-1 and GIP can be exploited therapeutically to modulate glycaemic control, additional hormones from the alimentary tract have shown therapeutic potential in early clinical studies. Oxyntomodululin has attracted interest because it interacts with GLP-1 and glucagon receptors to reduce feeding, increase energy expenditure and reduce body weight while lowering blood glucose in type 2 diabetes [54,55]. The satiety and weight-reducing effects of peptide YY, ghrelin antagonists and cholecystokinin analogues are being examined for the treatment of obesity [56][57][58], and emerging evidence from bariatric procedures may reveal additional intestinal peptides with therapeutic potential in type 2 diabetes [59].…”

Section: Other Peptidesmentioning

confidence: 99%

Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides

Bailey

¹

2018

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This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised 'closed loop' artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery ('smart insulins') to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia.

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Oxyntomodulin: Actions and role in diabetes

Cited by 63 publications

References 78 publications

Contribution of pancreatic α‐cell function to insulin sensitivity and glycemic variability in patients with type 1 diabetes

Contribution of pancreatic α‐cell function to insulin sensitivity and glycemic variability in patients with type 1 diabetes

Anti‐incretin effect: The other face of Janus in human glucose homeostasis

Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides

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