The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice

Åhrén, Bo; Winzell, Maria Sörhede; Pacini, Giovanni

doi:10.1677/joe-07-0460

Cited by 36 publications

(28 citation statements)

References 25 publications

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“…In animals in which intravenous catheters are implanted, i.v. administration of glucose can be a useful route of administration, circumventing the gut-derived incretin effect and thus generating a reduced insulin response and a higher peak in blood glucose, similar to intraperitoneal glucose loading (Ahren et al 2008). However, the dynamics of the responses to i.p.…”

Section: Route and Dose Of Glucose Administrationmentioning

confidence: 99%

“…During GTTs, in addition to blood glucose measurements, further 50 ml blood samples were taken by capillary from a superficial incision on the tail vein at both baseline and 30 min after glucose administration for the separation of plasma and measurement of insulin levels. Other studies have previously taken additional plasma samples during mouse GTTs for the measurement of plasma insulin (Ahren et al 2008, Andrikopoulos et al 2008, Barbosa-Sampaio et al 2013, and modern insulin assays allow the measurement of insulin levels in plasma samples as small as 5 ml. However, for the purposes of this study, the critical information required was the baseline fasting plasma insulin level and the peak insulin secretion in response to the glucose challenge (30 min).…”

Section: Scenario 1 -Assessing Glucose Homeostasis In Pregnant Micementioning

confidence: 99%

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METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

Bowe

Franklin

Hauge-Evans

et al. 2014

Journal of Endocrinology

215

142

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The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic b-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the b-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.

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Section: Route and Dose Of Glucose Administrationmentioning

confidence: 99%

Section: Scenario 1 -Assessing Glucose Homeostasis In Pregnant Micementioning

confidence: 99%

METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

Bowe

Franklin

Hauge-Evans

et al. 2014

Journal of Endocrinology

215

142

View full text Add to dashboard Cite

show abstract

“…injection 16 ) and two different mouse models (lean or diet-induced obese (DIO) mice 17, 18 ). These four conditions were chosen to survey the role of IDE activity under a broad range of endogenous insulin levels and insulin sensitivities 16, 17 . Oral glucose administration results in greater insulin secretion compared to injected glucose delivery (Extended Data Fig.…”

mentioning

confidence: 99%

“…Oral glucose administration results in greater insulin secretion compared to injected glucose delivery (Extended Data Fig. 6) that arises from the ‘incretin effect’ 17, 19 . DIO mice display hyperinsulinaemia and insulin resistance, and serve as a model for early type-2 diabetes in humans 18 .…”

mentioning

confidence: 99%

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Maianti

McFedries

Foda

et al. 2014

Nature

223

255

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Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes1, 2, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene3, 4, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide−/− mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction5, 6. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

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“…The incretin effect has been documented in humans (1) and in experimental animals (2). The underlying reason for the incretin effect is attributed to the release of incretin hormones from the gut during oral glucose administration [mainly glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1)]; these incretin hormones potentiate the glucose-stimulated insulin secretion.…”

mentioning

confidence: 99%

Incretin Hormones and the Up-Regulation of Insulin Secretion in Insulin Resistance

Åhrén

2012

The Journal of Clinical Endocrinology &Amp; Metabolism

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T he incretin effect is the augmented insulin secretion that is elicited by oral compared with iv administration of glucose, when glucose levels during the two challenges are matched. The incretin effect has been documented in humans (1) and in experimental animals (2). The underlying reason for the incretin effect is attributed to the release of incretin hormones from the gut during oral glucose administration [mainly glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1)]; these incretin hormones potentiate the glucose-stimulated insulin secretion. It has been estimated that the incretin effect is responsible for at least 60 -70% of insulin secretion after oral glucose in normal humans (3). Recently, it was demonstrated that an incretin effect also exists after oral fat administration, i.e. it is not specific for glucose (4).It is now well documented that the incretin effect is reduced in type 2 diabetes (3). This impairment could be due to impaired incretin hormone secretion (i.e. incretin hormone deficiency) and/or to a defective insulinotropic action of the incretin hormones (i.e. incretin hormone resistance). Although some controversy still exists in the literature, most data support that the impaired incretin effect in type 2 diabetes is due to defective insulin secretory effects of GIP and GLP-1, rather than to defective secretion of the two incretin hormones (3, 5). Still, GLP-1 retains a high efficacy in type 2 diabetes, which is a rationale behind the incretin-based therapy (6).The defective incretin effect in type 2 diabetes has raised two fundamental questions of importance for the understanding of diabetes pathophysiology. One question is whether a defective incretin effect is involved in the pathophysiology of the disease, i.e. whether defective incretin effect participates in the development of the disease itself or is merely a consequence of the disease (7). A second question is whether the defective insulinotropic actions of GIP and GLP-1 in type 2 diabetics, compared with healthy individuals, are due to specific defects in the ␤-cell effects of the hormones or reflect a more generalized ␤-cell dysfunction (8).In regard to the potential pathophysiological contribution of defective incretin effect, only a few studies have explored this important question, and the results have been controversial. For example, on the one hand, it has been shown that the insulin stimulatory effect of GIP is impaired in first-degree relatives of type 2 diabetic patients (9), which would suggest a pathophysiological involvement. On the other hand, it has also been shown that the insulinotropic effect of GIP is normal in women with a history of gestational diabetes (10), which instead suggests that the defect is secondary to developed diabetes. In regard to the question of a specific defect in incretin hormone effect in type 2 diabetes vs. a generalized ␤-cell defect, no studies have directly focused on this issue.In the present issue of the JCEM, a novel study by Hansen et al. (11) has...

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The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice

Cited by 36 publications

References 25 publications

METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

Incretin Hormones and the Up-Regulation of Insulin Secretion in Insulin Resistance

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