Incretin dysfunction in type 2 diabetes: Clinical impact and future perspectives

doi:10.1016/j.diabet.2013.03.001

Diabetes & Metabolism

Volume 39, Issue 3, May 2013, Pages 195-201

https://doi.org/10.1016/j.diabet.2013.03.001 Get rights and content

Abstract

The incretin effect refers to the augmentation of insulin secretion after oral administration of glucose compared with intravenous glucose administration at matched glucose levels. The incretin effect is largely due to the release and action on beta-cells of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This system has in recent years had considerable interest due to the success of incretin therapy as a glucose-lowering strategy in type 2 diabetes. In non-diabetic subjects, the incretin effect is responsible for 50–70% of insulin release during oral glucose administration. In type 2 diabetes patients, the incretin effect is impaired and contributes to only 20–35% of the insulin response to oral glucose. The reason for the defective incretin effect in type 2 diabetes has been the subject of many studies. Although the reports in the literature are mixed, most studies of GIP and GLP-1 secretory responses to oral glucose or a mixed meal have shown fairly normal results in type 2 diabetes. In contrast, the insulinotropic effects of both GIP and GLP-1 are impaired in type 2 diabetes with greater suppression of insulin secretion augmentation with GIP than with GLP-1. The suggested causes of these defects are a defective beta-cell receptor expression or post-receptor defects secondary to the diabetes milieu, defective beta-cell function in general resulting in defective incretin effect and genetic factors initiating incretin hormone resistance. Identifying the mechanisms in greater detail would be important for understanding the strengths, weaknesses and efficacy of incretin therapy in individual patients to more specifically target this glucose-lowering therapy.

Résumé

L’effet incrétine correspond à l’augmentation de la sécrétion de l’insuline après une administration orale de glucose, comparée à une administration intraveineuse, pour des niveaux équivalents de glucose. L’effet incrétine est dû en grande partie à la libération et à l’action des cellules β des hormones glucose-dépendantes de l’intestin insulinotropiques polypeptide (GIP) et des peptide-1 glucagon-like (GLP-1). Ce système a bénéficié d’un fort intérêt ces dernières années dans le diabète de type 2. Chez des sujets normaux, l’effet incrétine est responsable de 50 à 70 % de la libération de l’insuline lors d’une administration orale de glucose. Dans un diabète de type 2, l’effet des incrétines est réduit et contribue seulement de 20 à 35 % de la réponse en insuline lors d’une prise orale de glucose. La raison de cet effet réduit des incrétines dans le diabète de type 2 a fait l’objet de nombreuses études. Bien que quelques divergences existent dans la littérature, la plupart des études sur les réponses sécrétoires des GIP et GLP-1 à une administration orale de glucose ou lors d’un repas ont montré des réponses relativement normales dans le diabète de type 2. En revanche, les effets insulinosécrétagogues du GIP et du GLP-1 sont réduits dans le diabète de type 2, avec une réduction plus marquée de l’effet du GIP sur l’augmentation de la sécrétion d’insuline par rapport au GLP-1. Les causes de la diminution de l’effet incrétine impliquent une diminution de l’expression des récepteurs au niveau des cellules β, des altérations de la transduction post-récepteur liées à l’hyperglycémie ou une résistance aux incrétines. La compréhension approfondie de ces mécanismes sera importante pour mieux cibler l’efficacité des thérapeutiques basées sur les incrétines.

Section snippets

The incretin effect

In the 1930s, Dr Jean La Barre from Belgium introduced the term “incretin” to describe a substance in the gut mucosa that produces hypoglycaemia when injected into normal animals, but not in those who had undergone pancreatectomy [1]. Dr Hans Heller from Austria made a similar suggestion a few years later, although he suggested the term “duodenin” for this tentative substance [2]. Both La Barre and Heller suggested that the tentative substance(s) could be used in the treatment of diabetes,

Incretin effect in type 2 diabetes

In 1986 it was demonstrated that the incretin effect is reduced in type 2 diabetes patients; in 14 such patients, it contributed only approximately 20% to the insulin response to oral glucose (50 g) [7]. Later studies confirmed the reduced incretin effect in type 2 diabetes and concluded that the incretin effect contributed to approximately 35% of the insulin response to oral glucose (75 g) in type 2 diabetes, as it was demonstrated in eight patients [10] and 21 patients [11]. Furthermore, by

Basis of the incretin effect

The incretin effect depends largely on the two main incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, both of which are released after oral glucose ingestion and potentiate glucose-stimulated insulin secretion [15]. There are two major components in the incretin effect: release of incretin hormones from the gut; and the effects of incretin hormones on beta-cells, leading to insulin secretion. This suggests that the impaired incretin effect in type 2 diabetes could

Incretin hormone secretion in type 2 diabetes

The incretin hormones GIP and GLP-1 are released when nutrients from meal ingestion (or simple macronutrient ingestion) reach the cells in the gut that produce these incretin hormones [15]. Incretin hormone secretion is mediated through direct stimulation of the enteroendocrine cells by nutrients and is therefore not only dependent on the type of macronutrient or macronutrient load, but also on the rate of gastric-emptying and intestinal transit time. Incretin hormone secretion is also

Incretin hormone-induced insulin secretion

When GIP and GLP-1 are infused intravenously, they both potently potentiate and augment glucose-stimulated insulin secretion. However, this insulinotropic action of GIP has convincingly and repeatedly been demonstrated to be reduced in type 2 diabetes [15], [18], [19], [36], [37]. The effect appears to be associated with the diabetic condition, as it was not found in the relatives of patients with type 2 diabetes [19], [38] or in women with previous gestational diabetes mellitus [39], whereas

Clinical consequences

The impaired incretin effect in type 2 diabetes is a therapeutic target as there are now tools that can both stimulate GLP-1 receptors (using GLP-1 receptor agonists) and increase circulating levels of active incretin hormones (using DPP-4 inhibitors) [4], [51], [52]. Incretin-based therapy may be regarded as a therapy to restore an early defect in type 2 diabetes that, in turn, targets the main islet dysfunction of the disease. Islet dysfunction in type 2 diabetes involves both alpha- and

Future research

Although a considerable body of knowledge has been amassed since the initial discovery of incretins some 80 years ago and the success of incretin therapy in patients with type 2 diabetes has become evident over the past several years, there is much that remains to be studied. It is important that future studies include more detailed evaluations of the variability of incretin hormone secretion and effects in well-defined subpopulations of type 2 diabetes patients, and look at whether the results

Disclosure of interest

The author has received honoraria for lectures and been a member of advisory boards for AstraZeneca, Bristol-Myers Squibb, GSK, Eli Lilly, Novartis, Novo Nordisk, Merck and Sanofi-Aventis, which are all companies producing GLP-1 receptor agonists or DPP-4 inhibitors.

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Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.
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ReviewIncretin dysfunction in type 2 diabetes: Clinical impact and future perspectivesL’effet incrétine dans le diabète de type 2

Abstract

Résumé

Section snippets

The incretin effect

Incretin effect in type 2 diabetes

Basis of the incretin effect

Incretin hormone secretion in type 2 diabetes

Incretin hormone-induced insulin secretion

Clinical consequences

Future research

Disclosure of interest

Exp Cell Res

Lancet

Regul Pept

Vitam Horm

Regul Pept

Metabolism

Metabolism

Metabolism

Regul Pept

Eur J Pharmacol

Lancet

Sur les possibilités d’un traitement du diabète par l’incrétine

Bull Acad R Med Belg

Über das insulinotrope Hormon der Darmschleimhaut (Duodenin)

Arch Exp Pharmakol

Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus

N Engl J Med

Plasma insulin responses to oral and intravenous glucose administration

J Clin Endocrinol Metab

Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses

J Clin Endocrinol Metab

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

J Endocrinol

Impaired regulation of the incretin effect in patients with type 2 diabetes

J Clin Endocrinol Metab

Reduced incretin effect in type 2 diabetes. Cause or consequence of the diabetic state?

Diabetes

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as isoglycemic intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes

J Clin Endocrinol Metab

The dynamic incretin adaptation and type 2 diabetes

J Clin Endocrinol Metab

Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance

Am J Physiol Endocrinol Metab

Physiology of incretins in health and disease

Rev Diabet Stud

Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men

J Clin Endocrinol Metab

Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes

Diabetes Care

Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired β-cell function

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Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients

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Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients

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Review
Incretin dysfunction in type 2 diabetes: Clinical impact and future perspectivesL’effet incrétine dans le diabète de type 2